Review ArticleNeuroprotection in Stroke Past Present and Future

Arshad Majid12

1 Department of Neuroscience Sheffield Institute for Translational Neuroscience (SITraN) University of Sheffield385A Glossop Road Sheffield S10 2HQ UK

2Department of Neurology and Manchester Academic Health Sciences Centre Salford Royal Hospital Stott LaneSalford M6 8HD UK

Correspondence should be addressed to Arshad Majid majidarshadmsncom

Received 7 July 2013 Accepted 16 September 2013 Published 21 January 2014

Academic Editors M Leone and C Sommer

Copyright copy 2014 Arshad MajidThis is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Stroke is a devastating medical condition killing millions of people each year and causing serious injury to many more Despiteadvances in treatment there is still little that can be done to prevent stroke-related brain damage The concept of neuroprotectionis a source of considerable interest in the search for novel therapies that have the potential to preserve brain tissue and improveoverall outcome Key points of intervention have been identified inmany of the processes that are the source of damage to the brainafter stroke and numerous treatment strategies designed to exploit them have been developed In this review potential targetsof neuroprotection in stroke are discussed as well as the various treatments that have been targeted against them In addition asummary of recent progress in clinical trials of neuroprotective agents in stroke is provided

1 Introduction

Stroke is one of the leading causes of death and disabilityworldwide Despite decades of research however treatmentoptions remain limited In ischemic stroke the primaryfocus of treatment is reperfusion Currently the only drugapproved for the treatment of ischemic stroke is recombinanttissue plasminogen activator (rtPA alteplase) which has alimited time window for administration and increases therisk for subsequent hemorrhage Consequently only a smallpercentage of patients receive rtPA treatment [1] While thistreatment is effective in opening up occluded cerebral vesselsin some patients and can lead to improved outcomes afterischemic stroke there are currently no approved treatmentsfor the myriad of damaging pathological processes thatpersist in the brain long after the acute stage These includethe processes of inflammation excitotoxicity oxidative stressapoptosis and edema resulting from disruption of the blood-brain barrier [2] In hemorrhagic stroke additional processesinclude physical damage from themass of accumulated blooditself cytotoxicity of blood components and vasospasm insubarachnoid hemorrhage [3 4]

A considerable amount of research has been invested intothe development of novel treatments capable of protectingthe brain from damage following stroke with limited successNumerous neuroprotective treatments have been identifiedthat show great promise in animal models of stroke Unfortu-nately nearly all have failed to provide protection in humantrials The purpose of this review is to provide an overviewof targets for neuroprotection in stroke and examples ofcurrent research on potential neuroprotective treatmentsSeveral reviews of neuroprotection in both ischemic andhemorrhagic stroke have already been published in the lastfew years [5ndash9]This paper will therefore concentrate only onthemost recent research in this field In addition the primaryfocus will be on those treatments that have shown promise inanimal models or human patients as opposed to those thatto date have only shown protection in vitro or in cell culture

2 Animal Models of Stroke

A significant amount of research on neuroprotection instroke is performed using animal models A large variety ofmethods for inducing stroke in animals have been developed

Hindawi Publishing CorporationISRN NeurologyVolume 2014 Article ID 515716 17 pageshttpdxdoiorg1011552014515716

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and each is unique in its pathology and the effect of variousneuroprotective agents Since the results of experimentsusing a particular neuroprotective strategymay be dependenton the specific model used it is necessary to understandthese models and how they differ The majority of strokemodels use rodents and can be categorized by the typeof stroke that they are designed to replicate Models ofischemic stroke exhibit the greatest diversity in the typesof procedures used however most involve occlusion of oneor more blood vessels In focal ischemia models typicallyonly one vessel is occluded the most common being middlecerebral artery occlusion (MCAO) Global ischemia modelsoften involve bilateral occlusion of the common carotidarteries (CCAO) and may also include bilateral occlusionof another vessel such as the vertebral artery (4 vesselmodels) There are also 3 vessel occlusion models thatcombine bilateral common carotid occlusion with unilateralocclusion of another vessel Models of ischemic stroke canalso involve either permanent ischemia or transient ischemiawith subsequent reperfusion Models of hemorrhagic stroketypically involve the introduction of autologous blood intothe brain by direct injection or procedures that cause ruptureof a cerebral blood vessel Other less common stroke modelsexist but will not be discussed hereMore detailed discussionsof animal stroke models can be found in several reviews[10ndash13]

3 Targets for Neuroprotection in Stroke

31 Inflammation A significant amount of the research beingperformed on neuroprotection following stroke is concen-trated onmitigating the effects of inflammation An overviewof the inflammatory process in the brain after stroke is shownin Figure 1 Following ischemia and reperfusion damagedbrain tissue secretes cytokines and chemokines that recruitinflammatory cells to the injured area [14 15] These cellsrelease their own secretory factors which can build up totoxic levels Inflammatory processes also result in the pro-duction of reactive oxygen species leading to oxidative stressand activation ofmatrixmetalloproteinases (MMPs) causingdisruption of the blood-brain barrier (BBB) and edemaOn the other hand inflammation has beneficial effects aswell such as increasing blood flow to the affected areaand the removal of damaged tissue by phagocytic cells andMMPs The positive versus negative effects of inflammationfollowing stroke and the appropriateness of intervention area topic that is often debated [16] It is generally consideredhowever that inflammation does more harm than goodafter stroke especially in the early stages One importantmolecule resulting in cell damage and death following strokeis tumor necrosis factor alpha (TNF120572) TNF120572 interacts withtwo receptors R1 and R2 that mediate death signals viathe Fas associated death domain (FADD) and inflamma-tion via the nuclear factor kappa-light-chain enhancer ofactivated B cells (NF120581B) respectively [17] Activation ofthe NF120581B pathway is commonly used as an indicator ofinflammation in stroke studies The interleukins are anotherimportant set of molecules in the process of inflammation

Interleukin-1 (IL-1) is proinflammatory whereas IL-10 is anti-inflammatory and IL-6 has both pro- and anti-inflammatoryeffects [17] Antagonists of the IL-1 receptor have been shownto be neuroprotective when administered at reperfusion incomorbid tMCAO rats [18]

As one of the early initiators of inflammation after strokeTNF120572 is an excellent target for neuroprotective treatmentsPerhaps the most straightforward way to block the effects ofTNF120572 is to prevent or reduce its productionThe thalidomideanalog 361015840-dithiothalidomide (361015840-DT) is an inhibitor ofTNF120572 synthesis that has been shown to reduce the numberof activated inflammatory cells in the brain after ischemicstroke in mice as well as the extent of BBB disruption[19] Caffeic acid ester fraction reduces infarct volume andimproves performance on behavioral tests in rats subjectedto MCAO [20] Further experiments with cultured microgliasuggest that this effect is due to inhibition of the productionof TNF120572 as well as nitric oxide (NO) and IL-1120573 Atorvastatinsuppresses TNF120572 levels in a rat model of intracerebralhemorrhage reducing brain water content and activationof microglia [21] Another method of action against TNF120572is the use of decoy receptors Fusion proteins consisting ofTNF receptor linked to a monoclonal antibody are capableof crossing the blood-brain barrier and significantly reduceinfarct volumes after tMCAO in mice [22]

Activation of NF120581B by TNF120572 initiates a signaling cascadethat regulates a number of inflammatory processes makingit a good point of intervention Honokiol has been shown tosuppress the activation of NF120581B in ischemic mice as well aslevels of TNF120572 and significantly reduces brain water content[23] Rosmarinic acid blocks activation of NF120581B by TNF120572after tMCAO in diabetic rats and reduces edema and tissuedamage [24] Suppression of NF120581B activity by angiotensin-(1ndash7) reduces infarct volumes improves neurological deficitsand decreases oxidative stress in rats subjected to pMCAO[25] Kaempferol glycosides inhibit the activation of NF120581B aswell as the signal transducer and activator of transcription3 (STAT3) another proinflammatory transcription factorin tMCAO rats resulting in reduced infarct volume andneurological deficits [26] It should be noted that not allNF120581B activity is harmful and harmful activation of theNF120581Bcomplex is associated with abnormal acetylation of the RelAsubunit Using a combination of an inhibitor of one typeof deacetylase and an activator of another it is possibleto produce a RelA acetylation similar to that seen in thebeneficial phenomenon known as ischemic preconditioningresulting in neuroprotection inmice exposed to tMCAO [27]

The various signaling cascades induced by stroke leadto the activation and recruitment of inflammatory cells tothe site of injury In the early stages of stroke prior tothe infiltration of neutrophils and macrophages from otherlocations resident microglia are the primary inflammatorycells in the brain Microglia continue to be involved wellinto long term recovery and have been observed 28 daysfollowing stroke in MCAO rats [28] Although microgliaserve a beneficial purpose by removing dead tissue theyalso release secretory factors that can accumulate to toxiclevels particularly in cases of excess activation such as strokeAccordingly treatments that limit microglial activation often

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MacrophageNeutrophilBBB disruption

EndotheliumAdhesion molecule

expression(ICAM selectin etc)

Inflammatory cellinfiltration

Edema

Activatedmicroglia

Microglial activation

Restingmicroglia

Proinflammatory cytokinesreactive oxygen species

Oxidative stress

MMP activation

Damaged neuron

Figure 1 Damaging inflammatory mechanisms in stroke Proinflammatory cytokines and reactive oxygen species released by damagedneurons lead to the activation of microglia and the expression of cellular adhesionmolecules on endothelial cells andmigrating inflammatorycells Infiltrating inflammatory cells and activated microglia secrete additional cytokines and oxygen species resulting in further tissuedamage oxidative stress and activation of matrix metalloproteinases leading to disruption of the blood-brain barrier and edema

have neuroprotective effects The ginseng metabolite com-pound K suppresses microglial activation by inhibiting mul-tiple upstream signaling molecules and is neuroprotective inMCAO mice [29] Sesamin is neuroprotective in a mousemodel of ICH and has been shown to prevent an increase inmicroglial cells by keeping them in their resting state [30]Retinoids are also neuroprotective in models of ICH andreduce levels of activated microglia even with posttreatment[31] Alternatively increasing the reactivity of microglia canalso have neuroprotective effects The ATP-dependent potas-sium channel blocker glibenclamide increases the phagocyticcapacity ofmicroglia resulting in improved neurological out-come reduced infarct volume and enhanced neurogenesisin rats subjected to transient or permanent MCAO [32ndash34]Activation of the microglial alpha-7 nicotinic acetylcholinereceptor induces expression of the heme oxygenase-1 (HO-1)gene which is associated with neuroprotection in mice afterphotothrombotic stroke [35]

The processes involved in inflammation may not onlydirectly contribute to brain damage following stroke butmay also activate secondary mechanisms that lead to furtherdamage The activity of large numbers of inflammatory cellsin the affected area combined with low oxygen and ATPlevels leads to the formation of reactive oxygen species andthe onset of oxidative stress Activation of MMPs whileimportant for the removal of dead tissue and the ability of

immune cells to enter the brain may also result in disruptionof the blood-brain barrier and edema due to an influxof water These topics will be discussed separately in thefollowing sections

32 Oxidative Stress The production of reactive oxygenspecies (ROS) and other free radicals during stroke is aconsequence of not only inflammation but also excitotoxicityand the inhibition of cellular respiration in a low oxygenenvironment [36] These molecules such as hydroxyl rad-ical superoxide and peroxynitrite are highly reactive anddamaging to multiple cellular components leading to celldeath One way of reducing oxidative stress is to reducethe production of free radicals Although nitric oxide is anormal signaling molecule in the body and has beneficialeffects in stroke larger amounts resulting from increasedactivity of the induced nitric oxide synthase (iNOS) canlead to aberrant signaling and or react with superoxide toproduce peroxynitrite Nebivolol decreases the expressionof iNOS following bilateral CCAO in rats and increasesexpression of the beneficial endothelial nitric oxide synthase(eNOS) leading to a reduction in histopathological changes[37] Another source of ROS is the nicotinamide adeninedinucleotide phosphate (NADPH) oxidases and inhibitorsof these enzymes could be beneficial in stroke [38] Anothermethod of protection is to induce endogenous mechanisms

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for the removal of free radicals in the body Hydrogensulfide gas increases the activity of superoxide dismutaseand glutathione peroxidase in rats subjected to focal cerebralischemia resulting in decreased injury to neuronal mito-chondria and a subsequent reduction inmarkers of apoptosis[39] Hydrogen-rich saline increases endogenous antioxidantenzyme activity and decreases the amount of oxidativeproducts in pMCAO rats [40] A nucleic acid-based productimproves the antioxidant status of neuronal mitochondriaafter transient ischemia in rats [41] Alternatively exogenouscompounds with free radical scavenging properties can beusedThenovel compoundMnTm4PyPmimics the activity ofendogenous manganese superoxide dismutase and reducesinfarct volume and neurological deficit after MCAO in mice[42] An extract of Ocimum sanctum protects tMCAO ratsby preserving reduced glutathione content and antioxidantenzyme activity [43] Hydrogen gas has been shown toneutralize free radicals and has beneficial effects on severalcontributors to early brain injury after subarachnoid hem-orrhage in rats [44] Furthermore noneffective doses of thefree radical scavenger lipoic acid enhance the neuroprotectiveeffects of the NADPH oxidase inhibitor apocynin whengiven in combination to tMCAO rats [45] Inhibition ofdownstream signaling pathways leading to oxidative stress-induced damage rather than the direct removal of ROSmay also have beneficial effects The antioxidant N-tert-butyl-120572-phenylnitrone suppresses expression of complementcomponent 3 a mediator of inflammation that is induced byoxidative stress inmice after transient focal cerebral ischemia[46]

33 Blood-Brain Barrier Disruption Disruption of the blood-brain barrier following stroke is commonly associated withthe action of two matrix metalloproteinases MMP-2 andMMP-9 MMP-2 is constitutively expressed at low levels innormal brain tissue however stroke increases its expressionand activity and also induces the expression of MMP-9 MMP-2 cleaves and activates MMP-9 which degradescomponents of the basement membrane in vascular wallsand leads to BBB disruption Other factors involved inBBB permeability after stroke include the extent of tightjunction formation between endothelial cells and the effectsof treatment with tissue plasminogen activator The activityof MMPs is regulated endogenously by the tissue inhibitorof matrix metalloproteinase (TIMP) and treatments thatstimulate it may be of significant benefit in protection againststroke-related brain damage Inhibition of the expression andactivity of MMPs by other means may be protective as wellEthanol has been shown to inhibit the increase in MMP-2 and MMP-9 expression after tMCAO in rats and signif-icantly reduces brain edema [47] Apocynum venetum leafextract (AVLE) also alleviates symptoms of BBB disruptionin tMCAO rats by inhibiting the expression and activity ofMMPs [48] Hyperbaric oxygen treatment improved BBBfunction in a rat embolic stroke model through modulationof MMP-9 but displayed reduced effectiveness when admin-istered in combination with tPA [49] It may therefore beof limited benefit in those stroke patients who receive tPA

Treatments that increase the formation of tight junctionsmayalso provide neuroprotection following stroke Doxycyclineincreases the expression of tight junction proteins in tMCAOrats and also inhibits MMPs [50] Kruppel-like factor 2(KLF2) protects against tMCAO in mice by regulation ofthe tight junction component occluding [51] The c-Jun N-terminal kinase (JNK) inhibitor SP600125 restores vasculartight junctions and alleviates BBB disruption in a ratmodel ofsubarachnoid hemorrhage [52] The GTPase RhoA is knownto play an important role in the regulation of endothelialtight junctions and inhibition of RhoA by fibroblast growthfactor preserves BBB integrity in a mouse model of intracere-bral hemorrhage [53] Additional neuroprotective strategiesinclude those that alleviate the negative effects of tPA Highdensity lipoproteins have been shown to reduce hemorrhagictransformation and improve BBB integrity following tPAtreatment in experimental models [54] Neurotrophic factorscan also be used to stimulate repair mechanisms and restoreBBB function Pigment epithelium-derived factor (PEDF)for example has been shown to have beneficial effects onboth BBB permeability and lesion volume after ischemia-reperfusion in rats [55]

34 Excitotoxicity During stroke depletion of neuronaloxygen and energy reserves leads to the release of toxicamounts of the neurotransmitter glutamate into the extra-cellular space [2 17] The subsequent activation of gluta-mate receptors causes an influx of calcium and neuronaldepolarization resulting in aberrant activation of numerouscalcium-dependent pathways in the brain and initiation ofthe processes of necrosis apoptosis and autophagy Gluta-mate excitotoxicity therefore plays a significant role in thepathology of stroke and a large number of research studiesare devoted to suppressing its effects One method of neu-roprotection against excitotoxicity is to reduce the amountof glutamate release during stroke The Ginkgo biloba extractEGb761 has been shown to significantly decrease striatalglutamate levels inmice subjected toMCAO accompanied byreduced neurodegeneration and edema [56] The individualconstituents of EGb761 also have neuroprotective properties[57] Another method of protection is to block the actionof glutamate receptors in the brain The microRNA miR-223 reduces expression of the glutamate receptor subunitsGluR2 and NR2B and is neuroprotective against transientglobal ischemia [58] Activation of the transient receptorpotential vanilloid 4 (TRPV4) is associated with increasedactivity of the NMDA receptor HC-067047 an antagonist ofTRPV4 reduces the extent of infarct after tMCAO in mice[59] Magnesium sulfate is an antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and insome studies has been shown to improve recovery in humanswith acute ischemic stroke [60] On the other hand largescale clinical trials such as the intravenous magnesium effi-cacy in stroke (IMAGES) trial concluded thatmagnesiumdidnot significantly improve outcome in ischemic stroke patientsbut may be beneficial in lacunar stroke [61] It is possiblethat the timing of treatment is critical therefore the fieldadministration of stroke therapy-magnesium (FAST-MAG)

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trial was devised to test the benefits of magnesium givenprior to arrival at a hospital Results from a pilot trialsuggest that early administration of magnesium may havebenefits and phase III trials are currently underway [62]Inhibiting the influx of calcium into cells following glutamatereceptor activation can also be beneficial Overexpressionof the transient receptor potential canonical 6 (TRPC6)suppresses the increase in calcium induced by NMDA andreduces infarct size and mortality in mice [63] Hyperforinan activator of TRPC6 has also been found to be neuro-protective following tMCAO in rats [64] The compoundginsenoside-Rd decreases expression of the calcium channelTRPM7 in MCAO rats which may be partially responsiblefor its neuroprotective effects [65]

35 Apoptosis During stroke the diminished supply ofoxygen and glucose to the brain leads to reduced cellularmetabolism and depletion of energy stores Combined withtissue damage due to mechanisms such as those mentionedabove cell death by either necrosis or apoptosis may be ini-tiated In the context of intervention apoptosis is preferableto necrosis because it can be blocked by various treatmentsallowing damaged tissue to be rescued Cells within thecore infarct typically die by necrosis whereas those in thepenumbra die by apoptosis The primary factor in determin-ing which mechanism of cell death occurs is the level ofATP within the cell [66] ATP is required for the process ofapoptosis and cells with insufficient ATP stores will die bynecrosis instead Apoptosis can occur by several pathways asshown in Figure 2 The mitochondrial pathway can proceedthrough either caspase dependent or caspase independentmechanisms Alternatively apoptosis may be induced by thedeath receptor pathway

In the caspase dependent pathway of mitochondrialapoptosis release of cytochromeC frommitochondria resultsin activation of caspase 3 which initiates a caspase cascadeleading to the degradation of cellular components and celldeath Caspase 3 activity is commonly used as an indicator ofapoptosis Reduction of activated caspase 3 levels is thereforea goal of many neuroprotective treatments Tanshinone IIAdecreases the levels of cleaved caspase 3 in tMCAO ratsresulting in a reduction in infarct volume edema andneurological deficits Diallyl sulfide reduces expression ofcaspase 3 and increases expression of BCL-2 an endogenousantiapoptotic protein in tMCAO rats as well Hypothermiahas been shown to reduce caspase 3 levels for up to 1 weekafter focal cerebral ischemia in rats [67] Pioglitazone anagonist of the peroxisome proliferator-activated receptor 120574(PPAR120574) activates STAT3 in tMCAO rats leading to changesin the expression of antiapoptotic genes and reduced levels ofcaspase 3 [68] Caspase 3 is not the only potential therapeutictarget within this pathway however The cellular inhibitorsof apoptosis (cIAPs) are endogenous molecules that bind tocaspases and block their activation Ischemic preconditioninghas been shown to increase the levels of cIAP1 in neuronsand reduce apoptosis following unilateral CCAO in rats[69]

Although apoptosis is most commonly associated withthe caspase dependent mitochondrial pathway other path-ways also contribute to cell death after stroke and neuropro-tective agents that act upon these pathways are being inves-tigated The caspase independent pathway of apoptosis ischaracterized bymitochondrial release of apoptosis-inducingfactor (AIF) which is stimulated by the activity of poly(ADP-ribose) polymerase (PARP) Several treatments that inhibitthe caspase dependent pathway of apoptosis have also beenshown to inhibit the caspase independent pathway as wellEthanol administration decreases the expression of bothcaspase 3 and AIF up to 24 hours after tMCAO in rats [70]The nitric oxide donor (S)-ZJM-289 suppresses the releaseof both cytochrome C and AIF from mitochondria andsignificantly reduces injury in MCAO rats [71] CyclosporinA has been shown to decrease the expression of caspase3 AIF and cytochrome C in a rat model of SAH [72]Other compounds have been identified that target the caspaseindependent pathway specifically Ginsenoside-Rd has beenshown to inhibit PARP-1 activity and AIF release in ratssubjected to MCAO [73] The death receptor pathway ofapoptosis differs from the other two in that mitochondriaare not required for its induction Similar to the caspasedependent pathway of mitochondrial apoptosis however thedeath receptor pathway also uses caspase 3 as an effectorTreatments that affect the level and activity of caspase 3 maytherefore block this pathway as well Treatments that targetthis pathway directly have also been identified Musconedecreases the expression of the death receptor FAS andreduces apoptosis in MCAO rats [74] Antibodies againstTNF120572 another initiator of the death receptor pathway blockchanges in the expression of caspase 3 after SAH in rats[75]

36 Autophagy The role of autophagy in stroke has onlyrecently begun to be elucidated and is not fully understoodAutophagy appears to have a dual role in the responseto cellular damage absorbing damaged components as aprotective measure in some cells and serving as a mechanismof cell death in others Autophagy is mediated by the ATGfamily of proteins and regulated by a number of nutrient andenergy sensing pathways that converge on the mammaliantarget of rapamycin (mTOR) [76 77] An overview of theprocess of autophagy and its regulation is shown in Figure 3Induction of autophagy prevents cell death by apoptosisand in this respect is considered to be beneficial The drugrapamycin is an inhibitor of mTOR that leads to inductionof autophagy In a rat model of subarachnoid hemorrhagerapamycin suppressed apoptosis and reduced neurologi-cal deficits whereas inhibition of autophagy increased theamount of brain damage [78] Activity of the tuberoussclerosis complex (TSC) also leads to mTOR inhibition andinduction of autophagy Suppression of the TSC1 subunit ofthis complex has been shown to increase the vulnerabilityof hippocampal neurons to cell death after ischemia in vivo[79] Alternatively the inhibition of autophagy can also beneuroprotective In pMCAO rats ischemic postconditioninginhibited the induction of autophagy and reduced infarct

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TRADD FADD

Cytochrome C

MitochondriaAIF

BAXBAKBCL-XL

BCL-2BAD BID

Caspase 9

Caspase 3

APAF-1

Caspase 8

FASL

PARP

TNFR FAS

Cell stressdamage

Apoptosis

TNF-120572

Figure 2 Mechanisms of induction of apoptosis In the classical pathway mitochondria release cytochrome C in response to cell stress anddamage leading to activation of caspase 9 and subsequent activation of caspase 3 and other effectors of apoptosis Alternatively mitochondriamay also release apoptosis-inducing factor (AIF) which leads to apoptosis by a caspase independent mechanismThe death receptor pathwayinvolves the activation of FADDby various cell signal receptors followed by activation of caspase 8 and the subsequent caspase cascade leadingto apoptosis

size and edema [80] A chemical inhibitor of autophagyhad similar effects whereas rapamycin partially reversedthem It is hopeful that further research will determine ifthe overall effect of autophagy in stroke is beneficial orharmful

4 Ischemic Tolerance and the Effects ofPre- and Postconditioning

The brain is highly susceptible to ischemia and numerousendogenous mechanisms exist to protect neural tissue fromits effects Although these mechanisms are naturally stim-ulated in response to stroke they may also be artificiallyinduced by nondamaging techniques to produce a protectivestate known as ischemic tolerance [81 82] Preconditioningis a neuroprotective strategy by which ischemic tolerance isinduced prior to stroke in order to protect the brain fromsubsequent damage and potentially could be used as a pre-ventative measure in high risk individuals or as a precautionagainst secondary stroke following medical procedures suchas aneurysm repair or cardiac surgery In the case of naturally

occurring strokes which cannot be predicted postcondition-ingmay be a therapeutic strategy that could be used afterwardto accelerate or enhance protective mechanisms or as aprecaution against stroke recurrence Preconditioning andischemic tolerance have already been extensively reviewedand will only be covered briefly here [83ndash86] Some evidencesuggests however that although preconditioning may bebeneficial in the short term long term structural changesin the brain indicate that tissue damage is merely beingpostponed [87] Clinical studies are needed to test the safetyand efficacy of these novel strategies in humans

Ischemic tolerance can be induced directly by manyconditioning mechanisms including hypoxiahyperoxia hy-pothermiahyperthermia drug treatments blood vessel oc-clusion and dietary restriction [81] Ischemic precondi-tioning has been shown to downregulate components ofmetabolic pathways such as adenosine 51015840-monophosphate-activated protein kinase (AMPK) [88] Preconditioningby the anesthetics sevoflurane and isoflurane inhibits theexpression of proapoptotic genes and upregulates anti-apoptotic genes in MCAO rats [89] Potential mediatorsof preconditioning include the lymphocyte cell kinase(LCK) and sodiumcalcium exchangers (NCX) [90ndash92]

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Insulin receptorIRS

InsulinCalcium

CaMKK

ATP LKB1 AMPK PI3K

DNA damagehypoxiastress

HIF1 REDD1 TSC1TSC2 AKT PDK1

RHEB

mTORRAPTOR

ATG1ATG13

Amino acid deprivation

RapamycinFKBP12

JNKEndoplasmic reticulum stress

BCL2 ERK

ATG6ATG14

ATG10

ATG5ATG12ATG16 ATG7 ATG4

LC3-II LC3-I LC3

ATG3Induction

Isolation membrane

Nucleation

Phagophore Elongation

Autophagosome

Autolysosome

Lysosome

Fusion

Figure 3 The process of autophagy and its regulation Induction of autophagy is inhibited by mTOR the activity of which is controlledby numerous upstream signaling pathways that respond to metabolic activity energy status and tissue damage Progression of autophagyrequires several members of the ATG protein family leading to the production of a membranous structure that engulfs damaged cellularcomponents to form the autophagosome Subsequent fusion of the autophagosome with a lysosome results in degradation of the damagedcomponents Proteins involved in the regulation of autophagy are shown in shaded boxes Positive interactions are denoted by arrows andnegative interactions by lines with flat ends

Postconditioning inhibits MMP9 expression and subsequentdegradation of the extracellular matrix in MCAO rats [93]Ischemic tolerance in the brain can also be stimulatedremotely for example by application of a tourniquet to oneof the limbs Remote preconditioning is protective in amouseembolic stroke model both by itself and in combination with

tissue plasminogen activator [94] It also provides protectionby upregulation of eNOS in rats subjected to global ischemiaand reperfusion [95] Remote preconditioning has even beenshown to have beneficial effects in human patients withsubarachnoid hemorrhage but further studies are needed[96]

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5 Neuroprotection in Hemorrhagic Stroke

The pathologies of ischemic and hemorrhagic stroke sharemany of the same damaging processes such as inflamma-tion oxidative stress and excitotoxicity Treatments that areneuroprotective in one may also be beneficial in the otherand several examples of protection in models of hemorrhagicstroke have already been given in the previous sectionsProcesses such as cytotoxicity however are unique to hemor-rhagic stroke and are directly related to the accumulation ofblood in the brain Multiple blood components are believedto contribute to tissue damage after hemorrhage particularlyhemoglobin Haptoglobin and hemopexin are endogenousproteins that bind and remove hemoglobin and its degrada-tion products respectively and enhancement of their activitymay be protective [3] Heme oxygenase (HO) is anotherendogenous protein that converts heme to iron and otherproducts Free iron reacts with hydrogen peroxide to formhydroxyl radicals leading to oxidative stress Inhibition ofHO or chelation of iron by agents such as deferoxamine couldhave beneficial effects Valproic acid decreases the expressionof HO-1 following ICH in rats and attenuated cell death[97] Combination treatment of deferoxamine and statinshas been associated with improved results in behavioral testsin rats after ICH [98] In addition to cytotoxicity cerebralvasospasm is a significant contributor to death and disabilityafter subarachnoid hemorrhage Because of its serious naturea considerable amount of research is dedicated to mitigatingits effects Hydrogen-rich saline has been shown to decreasevasospasm in rats after experimental SAH possibly bysuppressing the effects of inflammation and oxidative stress[99] Vasospasm in SAH rats is also reduced by an analog of120572-melanocyte stimulating hormone and is accompanied bychanges in the expression of factors involved in tissue damageand repair [100]

6 Benefits of Combination Therapy forNeuroprotection in Stroke

Thepathology of stroke is complex withmultiple overlappingprocesses leading to either damage or protection Althoughconsiderable neuroprotection can be gained by targeting justone of these processes the potential benefit is even greaterif multiple mechanisms of damage can be suppressed at thesame time Targeting the same pathway with more than oneneuroprotective agent can also be beneficial Consequentlycombination therapy with more than one drug has provento be effective in several experimental studies The additionalbenefit may be small additive or even synergistic in somecases Progesterone plus vitamin D hormone for examplereduces infarct size and neurological deficits in tMCAO ratsto a greater extent than either treatment alone [101] Thecombination of the anti-inflammatory properties of atorvas-tatin and the antioxidant properties of probucol also producesincreased neuroprotection in pMCAO rats [102] Simvastatincombined with granulocyte colony-stimulating factor (G-CSF) reduced recovery time in a rat model of intracerebralhemorrhage and improved outcome [103] Another strategy

for combination therapy is the use of one drug to block thenegative effects of another such as tPA Mild hypothermiahigh-density lipoproteins activated protein C analog andfingolimod have all been shown to reduce the incidence ofhemorrhagic transformation following administration of tPAin several animal models [54 104ndash106]

7 Neuroprotective Treatments withPleiotropic Effects

Although combination therapy can produce additional ben-efits in some cases not all treatments are compatible witheach other Some combinationsmay have antagonistic effectsproducing less benefit than either treatment alone In somecases combination therapies may enhance damage Fur-thermore combination treatment requires significantly moretesting to determine safety and effectiveness than a singlecompound There is therefore considerable interest in thestudy of treatments with beneficial effects on more thanone mechanism of stroke-related damage Some of thesetreatments have only recently been discovered (Table 1) andare still in the early stages of investigation Others howeverhave already been the subject of considerable study and showgreat promise for the treatment of stroke as summarizedbelow

71 Minocycline Minocycline is a broad spectrum antibioticwhich in addition to its antibacterial activity also hasanti-inflammatory and antiapoptotic effects [107] Conse-quently it has been shown to be protective in a numberof diseases including stroke Minocycline is one of thefew neuroprotective agents in animal studies that has alsobeen proven effective in human trials In one recent trialoral administration of minocycline resulted in significantlyimproved outcomes as long as three months after stroke[108] Furthermore animal studies indicate that additionalbenefits are to be gained by combining minocycline withother neuroprotective strategies Minocycline reduces therisk of subsequent hemorrhage following administration oftissue plasminogen activator in diabetic rats subjected tofocal embolic stroke [109] It also reduces infarct size andsuppresses several hallmarks of inflammation Minocyclineplus normobaric hyperoxia has a synergistic effect on thereduction in infarct volume following tMCAO in rats andhas a positive effect on hemispheric swelling that was notseen with either treatment alone [110] This combinationalso resulted in greater inhibition of apoptosis and MMPactivation Minocycline improves recovery after transplanta-tion of bone marrow mononuclear cells into ischemic ratspresumably by inhibition of microglial activation [111 112] Italso preconditions neural stem cells against oxidative stressproducing reduced infarct size and improved neurologicalperformance following transplantation in rats exposed totMCAO [113]

72 Carnosine Carnosine is a naturally occurring dipeptidethat has both antioxidant and antiexcitotoxic properties [114115] It also is an efficient chelator of metal ions such as

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Table 1 Neuroprotective treatments with multiple beneficial effects in stroke

Treatment Species Model Benefits ReferenceITH33IQM921 Mouse Ischemia Antiexcitotoxic antioxidant Lorrio et al 2013 [131]TAT-M9 Mouse Ischemia Antioxidant antiapoptotic Guo et al 2013 [132]Glycyrrhizic acid Rat Ischemia Anti-inflammatory antiexcitotoxic and antioxidant Kim et al 2012 [133]Vitis amurensis extract Rat Ischemia Anti-inflammatory antiexcitotoxic antioxidant and antiapoptotic Kim et al 2012 [134]cis-Hinokiresinols Rat Ischemia Anti-inflammatory antioxidant Ju et al 2013 [135]Berberine Rat Ischemia Anti-inflammatory antiapoptotic Zhang et al 2012 [136]S-Nitrosoglutathione Rat Ischemia Antioxidant BBB integrity Khan et al 2012 [137]Taurine Rat Ischemia Antiexcitotoxic antioxidant and antiapoptotic Gharibani et al 2013 [138]MFG-E8 Rat Ischemia Anti-inflammatory antiapoptotic Cheyuo et al 2012 [139]Nitrone derivatives Rat Ischemia Antiexcitotoxic antioxidant Sun et al 2012 [140]

zinc which is required for the activity of matrix metallo-proteinases Preclinical studies have shown that carnosineis well tolerated and produces robust neuroprotection inanimal models of both transient and permanent ischemia[116] It also readily crosses the intact blood-brain barrierwhich allows it to be administered even in the early stagesof stroke Carnosine reduces glutamate excitotoxicity inpMCAOmice resulting in reduced infarct size and improvedneurologic function [117] In another study carnosine wasshown to decrease infarct size MMP activity and levels ofreactive oxygen species [118] Carnosine can also be cleavedby carnosinase into the amino acids alanine and histidinewhich are neuroprotective as well Bestatin an inhibitor ofcarnosinase increases damage in pMCAOmice [119]

73 Asiatic Acid Asiatic acid is a plant-derived compoundwith effects on oxidative stress inflammation and excitotox-icity that has been shown to be beneficial in the treatmentof wound healing beta-amyloid toxicity and liver injuryRecent evidence suggests that it may be neuroprotective instroke as well In pMCAO mice asiatic acid reduces infarctsize and improves neurologic scores possibly by suppressionof mitochondrial damage and BBB disruption [120] Subse-quently asiatic acid was also found to be neuroprotective inmultiple models of ischemia in rats by inhibiting mitochon-drial damage and MMP-9 activation [121] Asiatic acid alsoblocks the negative effects of excitotoxicity in mice followingexposure to glutamate [122] An extract of Centella asiaticahas been shown to improve several markers of behavioralfunction and improved the antioxidant status in tMCAO rats[123]This extract contains asiatic acid as well as several otherrelated compounds that also have neuroprotective propertiesFurther investigation of this class of molecules is thereforewarranted to determine the extent of their effects

74 Hypothermia The beneficial effects of cooling the bodyafter injury are well known and induction of hypothermiais currently used in clinical practice to prevent secondarybrain injury after cardiac arrest and resuscitation peri-natal or neonatal asphyxia and head trauma [124ndash126]Considerable evidence suggests that hypothermia may bebeneficial in the treatment of stroke as well Microarray

experiments have determined that neuroprotection result-ing from hypothermia in MCAO rats is associated withchanges in the expression of genes involved in the processesof inflammation apoptosis and calcium regulation [127]Hypothermia induction by the neurotensin receptor 1 (NTR1)agonist ABS-201 reduces infarct volume and suppresses celldeath by apoptosis and autophagy in mice subjected to focalischemia [128] A recent meta-analysis of human clinicaltrials on the other hand found no benefit of hypothermiain stroke patients [129] These trials had a limited number ofsubjects however and larger trials are currently in progressfor example EuroHYP-1 and ICTuS23 [130]

75 Flavonoids In some cases whole classes of moleculesare known for having multiple neuroprotective effects Onesuch group of compounds that are currently the subjectof intensive research are the flavonoids These moleculesare naturally occurring compounds that readily cross theblood-brain barrier and are well known for their protectiveeffectsTheflavonoids in cocoa for example have antioxidantproperties and also promote perfusion angiogenesis andneurogenesis in the brain [141] Xanthohumol has beenfound to have anti-inflammatory anti-apoptotic antioxi-dant and antithrombotic properties Following MCAO inrats xanthohumol decreases the levels of TNF120572 hypoxia-inducible factor 1 alpha (HIF-1120572) and inducible nitric oxidesynthase (iNOS) [142] It also reduces expression of activatedcaspase 3 scavenges hydroxyl radicals and inhibits plateletaggregation Treatment with naringenin results in neuropro-tection in tMCAO rats through both antioxidant and anti-inflammatorymechanisms [143] Galangin improves cerebralblood blow inhibits apoptosis and protects mitochondrialfunction after MCAO in rats [144] In tMCAO mice fisetinprotects the brain against ischemic injury by suppressingactivation of cerebral inflammatory cells and inhibiting themigration of macrophages and dendritic cells into the brain[145] In models of intracerebral hemorrhage baicalin hasbeen found to attenuate edema of the brain and inhibitapoptosis [146]

76 Cannabinoids Another major class of molecules withmultiple beneficial effects in stroke are the cannabinoids

10 ISRN Neurology

These compounds are primarily known for their anti-inflammatory effects in many diseases including stroke [147]Recently however evidence suggests that cannabinoids mayalso have antioxidant and antiapoptotic effects [148] Thecannabinoid receptor agonists WIN55212-2 and JWH-133reduce activation of microglia and macrophages after induc-tion of ischemia in mice and rats resulting in reduced infarctsize and neurological impairment as well as protection ofoligodendrocyte precursor cells [149ndash151] Another receptoragonist TAK-937 provides neuroprotection in tMCAO ratsand the neuroprotective effect is increased when given incombinationwith hypothermia [152] Furthermore TAK-937not only is effective in rodent models of stroke but also hasbeen shown to reduce infarct volume in nonhuman primates[153] This specific compound is therefore of considerableinterest for future use in human trials

8 Neuroprotective Agents in HumanClinical Stroke Trials

Perhaps the greatest challenge in the study of neuroprotectionin stroke is the translation of animal studies to humansNumerous treatments that produce robust protection inrodents have failed to provide significant benefit in clinicaltrials The various theories on the reason for this failure havealready been discussed elsewhere and will not be coveredhere [5 154 155] Amid the abundance of discouragingresults however a small number of neuroprotective strategieshave shown promise in human stroke patients A briefsummary of recently completed clinical trials for the studyof neuroprotection in ischemic stroke and subarachnoidhemorrhage is provided below A discussion of recent clinicaltrials for neuroprotection in intracerebral hemorrhage isalready available [8]

81 International Citicoline Trial on Acute Stroke (ICTUS)Citicoline is a nutritional supplement that not only is com-monly used to improve memory retention but also has beenshown to prevent neuronal degeneration and improve visualfunction It has already been approved in some countriesfor the treatment of acute ischemic stroke A randomizedplacebo controlled trial was conducted to evaluate the effi-cacy of citicoline in patients with moderate to severe acuteischemic stroke [156] A total of 2298 patients were admin-istered either citicoline (1000mg every 12 hours) or placebofor up to 6 weeks Outcome was determined at 90 days basedon the National Institute of Health Stroke Scale (NIHSS)modified Rankin Scale (mRS) and modified Barthel Index(mBI scores) plus the occurrence of intracranial hemorrhageneurologic deterioration or death No significant differencein recovery was observed between the citicoline and placebotreatment groups

82 Minocycline Minocycline is an oral antibiotic withproven safety over years of use In addition to its antibioticproperties minocycline also has anti-inflammatory and anti-apoptotic effects that have been shown to be neuroprotectivein animal models of stroke and in previous human trials

The efficacy of oral minocycline was examined in arecent single-blinded open-label study [108] Fifty patientswith acute ischemic stroke were given either minocycline(200mgday) or placebo for five days and assessed for variousindicators of outcome at 1 7 30 and 90 days Patientsreceiving minocycline showed significant improvement after30 days in NIHSS mBI and mRS scores NIHSS scorescontinued to be significantly improved at 90 days Largerphase II and phase III trials are awaited

83 Cerebrolysin Cerebrolysin is a mixture of peptide frag-ments that mimics the action of neurotrophic factors andhas been shown to be neuroprotective in a number of condi-tions such as hyperthermia-induced neurotoxicity vasculardementia Alzheimerrsquos disease traumatic brain injury andstroke A large double-blind clinical trial was conducted totest the efficacy and safety of Cerebrolysin in patients withacute ischemic stroke [157] A total of 1070 patients wereadministered aspirin and either Cerebrolysin (30mLday) orplacebo over a period of 10 days Although no significantdifference between treatment groups was seen after 90 days apositive trendwas seen in those patients with anNIHSS scoregreater than 12

84 Ginsenoside-Rd Ginsenoside-Rd is a calcium channelantagonist that has been previously shown to be neuropro-tective in human trials An extended trial of ginsenoside-Rdwas performed in 390 patients with acute ischemic stroke[158] Subjects were administered ginsenoside-Rd or placebointravenously over a 14-day period and evaluated usingNIHSS and mRS scores for 90 days Significant improvementwas seen with ginsenoside-Rd in NIHSS scores at 15 days andmRS scores at 90 days

85 Granulocyte-Colony Stimulating Factor (G-CSF) G-CSFis a growth factor that stimulates the production and releaseof hematopoietic stem cells in bone marrow and may bebeneficial in the enhancement of recovery after stroke Thesafety of G-CSFwas examined in a randomized phase IIb trial[159] A total of 60 patients with either ischemic or hemor-rhagic stroke were given G-CSF (10 120583gkg) or placebo over 5days and monitored for the frequency of adverse effects G-CSF significantly increased white cell counts and produced atrend toward reduced infarct volume No difference was seenbetween treatment groups in the frequency of adverse effects

86 Evaluating Neuroprotection in Aneurysm Coiling Ther-apy (ENACT) Trial The compound known as NA-1 (Tat-NR2B9c) is an inhibitor of the postsynaptic density-95 (PSD-95) protein that is neuroprotective in primate models ofstroke PSD-95 associates with theNMDAglutamate receptorsubtype and contributes to the process of excitotoxicitywhich is suppressed by treatment with NA-1 The safety andefficacy of NA-1 after endovascular aneurysm repair wereexamined in patients with iatrogenic stroke [160] A totalof 185 patients were treated for a ruptured or unrupturedintracranial aneurysm by endovascular coiling followedby administration of NA-1 or placebo Evaluative criteria

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

[1] S D Reed S C CramerD K Blough KMeyer and J G JarvikldquoTreatment with tissue plasminogen activator and inpatientmortality rates for patients with ischemic stroke treated incommunity hospitalsrdquo Stroke vol 32 no 8 pp 1832ndash1839 2001

[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

ISRN Neurology 3

MacrophageNeutrophilBBB disruption

EndotheliumAdhesion molecule

expression(ICAM selectin etc)

Inflammatory cellinfiltration

Edema

Activatedmicroglia

Microglial activation

Restingmicroglia

Proinflammatory cytokinesreactive oxygen species

Oxidative stress

MMP activation

Damaged neuron

Figure 1 Damaging inflammatory mechanisms in stroke Proinflammatory cytokines and reactive oxygen species released by damagedneurons lead to the activation of microglia and the expression of cellular adhesionmolecules on endothelial cells andmigrating inflammatorycells Infiltrating inflammatory cells and activated microglia secrete additional cytokines and oxygen species resulting in further tissuedamage oxidative stress and activation of matrix metalloproteinases leading to disruption of the blood-brain barrier and edema

have neuroprotective effects The ginseng metabolite com-pound K suppresses microglial activation by inhibiting mul-tiple upstream signaling molecules and is neuroprotective inMCAO mice [29] Sesamin is neuroprotective in a mousemodel of ICH and has been shown to prevent an increase inmicroglial cells by keeping them in their resting state [30]Retinoids are also neuroprotective in models of ICH andreduce levels of activated microglia even with posttreatment[31] Alternatively increasing the reactivity of microglia canalso have neuroprotective effects The ATP-dependent potas-sium channel blocker glibenclamide increases the phagocyticcapacity ofmicroglia resulting in improved neurological out-come reduced infarct volume and enhanced neurogenesisin rats subjected to transient or permanent MCAO [32ndash34]Activation of the microglial alpha-7 nicotinic acetylcholinereceptor induces expression of the heme oxygenase-1 (HO-1)gene which is associated with neuroprotection in mice afterphotothrombotic stroke [35]

The processes involved in inflammation may not onlydirectly contribute to brain damage following stroke butmay also activate secondary mechanisms that lead to furtherdamage The activity of large numbers of inflammatory cellsin the affected area combined with low oxygen and ATPlevels leads to the formation of reactive oxygen species andthe onset of oxidative stress Activation of MMPs whileimportant for the removal of dead tissue and the ability of

immune cells to enter the brain may also result in disruptionof the blood-brain barrier and edema due to an influxof water These topics will be discussed separately in thefollowing sections

32 Oxidative Stress The production of reactive oxygenspecies (ROS) and other free radicals during stroke is aconsequence of not only inflammation but also excitotoxicityand the inhibition of cellular respiration in a low oxygenenvironment [36] These molecules such as hydroxyl rad-ical superoxide and peroxynitrite are highly reactive anddamaging to multiple cellular components leading to celldeath One way of reducing oxidative stress is to reducethe production of free radicals Although nitric oxide is anormal signaling molecule in the body and has beneficialeffects in stroke larger amounts resulting from increasedactivity of the induced nitric oxide synthase (iNOS) canlead to aberrant signaling and or react with superoxide toproduce peroxynitrite Nebivolol decreases the expressionof iNOS following bilateral CCAO in rats and increasesexpression of the beneficial endothelial nitric oxide synthase(eNOS) leading to a reduction in histopathological changes[37] Another source of ROS is the nicotinamide adeninedinucleotide phosphate (NADPH) oxidases and inhibitorsof these enzymes could be beneficial in stroke [38] Anothermethod of protection is to induce endogenous mechanisms

4 ISRN Neurology

for the removal of free radicals in the body Hydrogensulfide gas increases the activity of superoxide dismutaseand glutathione peroxidase in rats subjected to focal cerebralischemia resulting in decreased injury to neuronal mito-chondria and a subsequent reduction inmarkers of apoptosis[39] Hydrogen-rich saline increases endogenous antioxidantenzyme activity and decreases the amount of oxidativeproducts in pMCAO rats [40] A nucleic acid-based productimproves the antioxidant status of neuronal mitochondriaafter transient ischemia in rats [41] Alternatively exogenouscompounds with free radical scavenging properties can beusedThenovel compoundMnTm4PyPmimics the activity ofendogenous manganese superoxide dismutase and reducesinfarct volume and neurological deficit after MCAO in mice[42] An extract of Ocimum sanctum protects tMCAO ratsby preserving reduced glutathione content and antioxidantenzyme activity [43] Hydrogen gas has been shown toneutralize free radicals and has beneficial effects on severalcontributors to early brain injury after subarachnoid hem-orrhage in rats [44] Furthermore noneffective doses of thefree radical scavenger lipoic acid enhance the neuroprotectiveeffects of the NADPH oxidase inhibitor apocynin whengiven in combination to tMCAO rats [45] Inhibition ofdownstream signaling pathways leading to oxidative stress-induced damage rather than the direct removal of ROSmay also have beneficial effects The antioxidant N-tert-butyl-120572-phenylnitrone suppresses expression of complementcomponent 3 a mediator of inflammation that is induced byoxidative stress inmice after transient focal cerebral ischemia[46]

33 Blood-Brain Barrier Disruption Disruption of the blood-brain barrier following stroke is commonly associated withthe action of two matrix metalloproteinases MMP-2 andMMP-9 MMP-2 is constitutively expressed at low levels innormal brain tissue however stroke increases its expressionand activity and also induces the expression of MMP-9 MMP-2 cleaves and activates MMP-9 which degradescomponents of the basement membrane in vascular wallsand leads to BBB disruption Other factors involved inBBB permeability after stroke include the extent of tightjunction formation between endothelial cells and the effectsof treatment with tissue plasminogen activator The activityof MMPs is regulated endogenously by the tissue inhibitorof matrix metalloproteinase (TIMP) and treatments thatstimulate it may be of significant benefit in protection againststroke-related brain damage Inhibition of the expression andactivity of MMPs by other means may be protective as wellEthanol has been shown to inhibit the increase in MMP-2 and MMP-9 expression after tMCAO in rats and signif-icantly reduces brain edema [47] Apocynum venetum leafextract (AVLE) also alleviates symptoms of BBB disruptionin tMCAO rats by inhibiting the expression and activity ofMMPs [48] Hyperbaric oxygen treatment improved BBBfunction in a rat embolic stroke model through modulationof MMP-9 but displayed reduced effectiveness when admin-istered in combination with tPA [49] It may therefore beof limited benefit in those stroke patients who receive tPA

Treatments that increase the formation of tight junctionsmayalso provide neuroprotection following stroke Doxycyclineincreases the expression of tight junction proteins in tMCAOrats and also inhibits MMPs [50] Kruppel-like factor 2(KLF2) protects against tMCAO in mice by regulation ofthe tight junction component occluding [51] The c-Jun N-terminal kinase (JNK) inhibitor SP600125 restores vasculartight junctions and alleviates BBB disruption in a ratmodel ofsubarachnoid hemorrhage [52] The GTPase RhoA is knownto play an important role in the regulation of endothelialtight junctions and inhibition of RhoA by fibroblast growthfactor preserves BBB integrity in a mouse model of intracere-bral hemorrhage [53] Additional neuroprotective strategiesinclude those that alleviate the negative effects of tPA Highdensity lipoproteins have been shown to reduce hemorrhagictransformation and improve BBB integrity following tPAtreatment in experimental models [54] Neurotrophic factorscan also be used to stimulate repair mechanisms and restoreBBB function Pigment epithelium-derived factor (PEDF)for example has been shown to have beneficial effects onboth BBB permeability and lesion volume after ischemia-reperfusion in rats [55]

34 Excitotoxicity During stroke depletion of neuronaloxygen and energy reserves leads to the release of toxicamounts of the neurotransmitter glutamate into the extra-cellular space [2 17] The subsequent activation of gluta-mate receptors causes an influx of calcium and neuronaldepolarization resulting in aberrant activation of numerouscalcium-dependent pathways in the brain and initiation ofthe processes of necrosis apoptosis and autophagy Gluta-mate excitotoxicity therefore plays a significant role in thepathology of stroke and a large number of research studiesare devoted to suppressing its effects One method of neu-roprotection against excitotoxicity is to reduce the amountof glutamate release during stroke The Ginkgo biloba extractEGb761 has been shown to significantly decrease striatalglutamate levels inmice subjected toMCAO accompanied byreduced neurodegeneration and edema [56] The individualconstituents of EGb761 also have neuroprotective properties[57] Another method of protection is to block the actionof glutamate receptors in the brain The microRNA miR-223 reduces expression of the glutamate receptor subunitsGluR2 and NR2B and is neuroprotective against transientglobal ischemia [58] Activation of the transient receptorpotential vanilloid 4 (TRPV4) is associated with increasedactivity of the NMDA receptor HC-067047 an antagonist ofTRPV4 reduces the extent of infarct after tMCAO in mice[59] Magnesium sulfate is an antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and insome studies has been shown to improve recovery in humanswith acute ischemic stroke [60] On the other hand largescale clinical trials such as the intravenous magnesium effi-cacy in stroke (IMAGES) trial concluded thatmagnesiumdidnot significantly improve outcome in ischemic stroke patientsbut may be beneficial in lacunar stroke [61] It is possiblethat the timing of treatment is critical therefore the fieldadministration of stroke therapy-magnesium (FAST-MAG)

ISRN Neurology 5

trial was devised to test the benefits of magnesium givenprior to arrival at a hospital Results from a pilot trialsuggest that early administration of magnesium may havebenefits and phase III trials are currently underway [62]Inhibiting the influx of calcium into cells following glutamatereceptor activation can also be beneficial Overexpressionof the transient receptor potential canonical 6 (TRPC6)suppresses the increase in calcium induced by NMDA andreduces infarct size and mortality in mice [63] Hyperforinan activator of TRPC6 has also been found to be neuro-protective following tMCAO in rats [64] The compoundginsenoside-Rd decreases expression of the calcium channelTRPM7 in MCAO rats which may be partially responsiblefor its neuroprotective effects [65]

35 Apoptosis During stroke the diminished supply ofoxygen and glucose to the brain leads to reduced cellularmetabolism and depletion of energy stores Combined withtissue damage due to mechanisms such as those mentionedabove cell death by either necrosis or apoptosis may be ini-tiated In the context of intervention apoptosis is preferableto necrosis because it can be blocked by various treatmentsallowing damaged tissue to be rescued Cells within thecore infarct typically die by necrosis whereas those in thepenumbra die by apoptosis The primary factor in determin-ing which mechanism of cell death occurs is the level ofATP within the cell [66] ATP is required for the process ofapoptosis and cells with insufficient ATP stores will die bynecrosis instead Apoptosis can occur by several pathways asshown in Figure 2 The mitochondrial pathway can proceedthrough either caspase dependent or caspase independentmechanisms Alternatively apoptosis may be induced by thedeath receptor pathway

In the caspase dependent pathway of mitochondrialapoptosis release of cytochromeC frommitochondria resultsin activation of caspase 3 which initiates a caspase cascadeleading to the degradation of cellular components and celldeath Caspase 3 activity is commonly used as an indicator ofapoptosis Reduction of activated caspase 3 levels is thereforea goal of many neuroprotective treatments Tanshinone IIAdecreases the levels of cleaved caspase 3 in tMCAO ratsresulting in a reduction in infarct volume edema andneurological deficits Diallyl sulfide reduces expression ofcaspase 3 and increases expression of BCL-2 an endogenousantiapoptotic protein in tMCAO rats as well Hypothermiahas been shown to reduce caspase 3 levels for up to 1 weekafter focal cerebral ischemia in rats [67] Pioglitazone anagonist of the peroxisome proliferator-activated receptor 120574(PPAR120574) activates STAT3 in tMCAO rats leading to changesin the expression of antiapoptotic genes and reduced levels ofcaspase 3 [68] Caspase 3 is not the only potential therapeutictarget within this pathway however The cellular inhibitorsof apoptosis (cIAPs) are endogenous molecules that bind tocaspases and block their activation Ischemic preconditioninghas been shown to increase the levels of cIAP1 in neuronsand reduce apoptosis following unilateral CCAO in rats[69]

Although apoptosis is most commonly associated withthe caspase dependent mitochondrial pathway other path-ways also contribute to cell death after stroke and neuropro-tective agents that act upon these pathways are being inves-tigated The caspase independent pathway of apoptosis ischaracterized bymitochondrial release of apoptosis-inducingfactor (AIF) which is stimulated by the activity of poly(ADP-ribose) polymerase (PARP) Several treatments that inhibitthe caspase dependent pathway of apoptosis have also beenshown to inhibit the caspase independent pathway as wellEthanol administration decreases the expression of bothcaspase 3 and AIF up to 24 hours after tMCAO in rats [70]The nitric oxide donor (S)-ZJM-289 suppresses the releaseof both cytochrome C and AIF from mitochondria andsignificantly reduces injury in MCAO rats [71] CyclosporinA has been shown to decrease the expression of caspase3 AIF and cytochrome C in a rat model of SAH [72]Other compounds have been identified that target the caspaseindependent pathway specifically Ginsenoside-Rd has beenshown to inhibit PARP-1 activity and AIF release in ratssubjected to MCAO [73] The death receptor pathway ofapoptosis differs from the other two in that mitochondriaare not required for its induction Similar to the caspasedependent pathway of mitochondrial apoptosis however thedeath receptor pathway also uses caspase 3 as an effectorTreatments that affect the level and activity of caspase 3 maytherefore block this pathway as well Treatments that targetthis pathway directly have also been identified Musconedecreases the expression of the death receptor FAS andreduces apoptosis in MCAO rats [74] Antibodies againstTNF120572 another initiator of the death receptor pathway blockchanges in the expression of caspase 3 after SAH in rats[75]

36 Autophagy The role of autophagy in stroke has onlyrecently begun to be elucidated and is not fully understoodAutophagy appears to have a dual role in the responseto cellular damage absorbing damaged components as aprotective measure in some cells and serving as a mechanismof cell death in others Autophagy is mediated by the ATGfamily of proteins and regulated by a number of nutrient andenergy sensing pathways that converge on the mammaliantarget of rapamycin (mTOR) [76 77] An overview of theprocess of autophagy and its regulation is shown in Figure 3Induction of autophagy prevents cell death by apoptosisand in this respect is considered to be beneficial The drugrapamycin is an inhibitor of mTOR that leads to inductionof autophagy In a rat model of subarachnoid hemorrhagerapamycin suppressed apoptosis and reduced neurologi-cal deficits whereas inhibition of autophagy increased theamount of brain damage [78] Activity of the tuberoussclerosis complex (TSC) also leads to mTOR inhibition andinduction of autophagy Suppression of the TSC1 subunit ofthis complex has been shown to increase the vulnerabilityof hippocampal neurons to cell death after ischemia in vivo[79] Alternatively the inhibition of autophagy can also beneuroprotective In pMCAO rats ischemic postconditioninginhibited the induction of autophagy and reduced infarct

6 ISRN Neurology

TRADD FADD

Cytochrome C

MitochondriaAIF

BAXBAKBCL-XL

BCL-2BAD BID

Caspase 9

Caspase 3

APAF-1

Caspase 8

FASL

PARP

TNFR FAS

Cell stressdamage

Apoptosis

TNF-120572

Figure 2 Mechanisms of induction of apoptosis In the classical pathway mitochondria release cytochrome C in response to cell stress anddamage leading to activation of caspase 9 and subsequent activation of caspase 3 and other effectors of apoptosis Alternatively mitochondriamay also release apoptosis-inducing factor (AIF) which leads to apoptosis by a caspase independent mechanismThe death receptor pathwayinvolves the activation of FADDby various cell signal receptors followed by activation of caspase 8 and the subsequent caspase cascade leadingto apoptosis

size and edema [80] A chemical inhibitor of autophagyhad similar effects whereas rapamycin partially reversedthem It is hopeful that further research will determine ifthe overall effect of autophagy in stroke is beneficial orharmful

4 Ischemic Tolerance and the Effects ofPre- and Postconditioning

The brain is highly susceptible to ischemia and numerousendogenous mechanisms exist to protect neural tissue fromits effects Although these mechanisms are naturally stim-ulated in response to stroke they may also be artificiallyinduced by nondamaging techniques to produce a protectivestate known as ischemic tolerance [81 82] Preconditioningis a neuroprotective strategy by which ischemic tolerance isinduced prior to stroke in order to protect the brain fromsubsequent damage and potentially could be used as a pre-ventative measure in high risk individuals or as a precautionagainst secondary stroke following medical procedures suchas aneurysm repair or cardiac surgery In the case of naturally

occurring strokes which cannot be predicted postcondition-ingmay be a therapeutic strategy that could be used afterwardto accelerate or enhance protective mechanisms or as aprecaution against stroke recurrence Preconditioning andischemic tolerance have already been extensively reviewedand will only be covered briefly here [83ndash86] Some evidencesuggests however that although preconditioning may bebeneficial in the short term long term structural changesin the brain indicate that tissue damage is merely beingpostponed [87] Clinical studies are needed to test the safetyand efficacy of these novel strategies in humans

Ischemic tolerance can be induced directly by manyconditioning mechanisms including hypoxiahyperoxia hy-pothermiahyperthermia drug treatments blood vessel oc-clusion and dietary restriction [81] Ischemic precondi-tioning has been shown to downregulate components ofmetabolic pathways such as adenosine 51015840-monophosphate-activated protein kinase (AMPK) [88] Preconditioningby the anesthetics sevoflurane and isoflurane inhibits theexpression of proapoptotic genes and upregulates anti-apoptotic genes in MCAO rats [89] Potential mediatorsof preconditioning include the lymphocyte cell kinase(LCK) and sodiumcalcium exchangers (NCX) [90ndash92]

ISRN Neurology 7

Insulin receptorIRS

InsulinCalcium

CaMKK

ATP LKB1 AMPK PI3K

DNA damagehypoxiastress

HIF1 REDD1 TSC1TSC2 AKT PDK1

RHEB

mTORRAPTOR

ATG1ATG13

Amino acid deprivation

RapamycinFKBP12

JNKEndoplasmic reticulum stress

BCL2 ERK

ATG6ATG14

ATG10

ATG5ATG12ATG16 ATG7 ATG4

LC3-II LC3-I LC3

ATG3Induction

Isolation membrane

Nucleation

Phagophore Elongation

Autophagosome

Autolysosome

Lysosome

Fusion

Figure 3 The process of autophagy and its regulation Induction of autophagy is inhibited by mTOR the activity of which is controlledby numerous upstream signaling pathways that respond to metabolic activity energy status and tissue damage Progression of autophagyrequires several members of the ATG protein family leading to the production of a membranous structure that engulfs damaged cellularcomponents to form the autophagosome Subsequent fusion of the autophagosome with a lysosome results in degradation of the damagedcomponents Proteins involved in the regulation of autophagy are shown in shaded boxes Positive interactions are denoted by arrows andnegative interactions by lines with flat ends

Postconditioning inhibits MMP9 expression and subsequentdegradation of the extracellular matrix in MCAO rats [93]Ischemic tolerance in the brain can also be stimulatedremotely for example by application of a tourniquet to oneof the limbs Remote preconditioning is protective in amouseembolic stroke model both by itself and in combination with

tissue plasminogen activator [94] It also provides protectionby upregulation of eNOS in rats subjected to global ischemiaand reperfusion [95] Remote preconditioning has even beenshown to have beneficial effects in human patients withsubarachnoid hemorrhage but further studies are needed[96]

8 ISRN Neurology

5 Neuroprotection in Hemorrhagic Stroke

The pathologies of ischemic and hemorrhagic stroke sharemany of the same damaging processes such as inflamma-tion oxidative stress and excitotoxicity Treatments that areneuroprotective in one may also be beneficial in the otherand several examples of protection in models of hemorrhagicstroke have already been given in the previous sectionsProcesses such as cytotoxicity however are unique to hemor-rhagic stroke and are directly related to the accumulation ofblood in the brain Multiple blood components are believedto contribute to tissue damage after hemorrhage particularlyhemoglobin Haptoglobin and hemopexin are endogenousproteins that bind and remove hemoglobin and its degrada-tion products respectively and enhancement of their activitymay be protective [3] Heme oxygenase (HO) is anotherendogenous protein that converts heme to iron and otherproducts Free iron reacts with hydrogen peroxide to formhydroxyl radicals leading to oxidative stress Inhibition ofHO or chelation of iron by agents such as deferoxamine couldhave beneficial effects Valproic acid decreases the expressionof HO-1 following ICH in rats and attenuated cell death[97] Combination treatment of deferoxamine and statinshas been associated with improved results in behavioral testsin rats after ICH [98] In addition to cytotoxicity cerebralvasospasm is a significant contributor to death and disabilityafter subarachnoid hemorrhage Because of its serious naturea considerable amount of research is dedicated to mitigatingits effects Hydrogen-rich saline has been shown to decreasevasospasm in rats after experimental SAH possibly bysuppressing the effects of inflammation and oxidative stress[99] Vasospasm in SAH rats is also reduced by an analog of120572-melanocyte stimulating hormone and is accompanied bychanges in the expression of factors involved in tissue damageand repair [100]

6 Benefits of Combination Therapy forNeuroprotection in Stroke

Thepathology of stroke is complex withmultiple overlappingprocesses leading to either damage or protection Althoughconsiderable neuroprotection can be gained by targeting justone of these processes the potential benefit is even greaterif multiple mechanisms of damage can be suppressed at thesame time Targeting the same pathway with more than oneneuroprotective agent can also be beneficial Consequentlycombination therapy with more than one drug has provento be effective in several experimental studies The additionalbenefit may be small additive or even synergistic in somecases Progesterone plus vitamin D hormone for examplereduces infarct size and neurological deficits in tMCAO ratsto a greater extent than either treatment alone [101] Thecombination of the anti-inflammatory properties of atorvas-tatin and the antioxidant properties of probucol also producesincreased neuroprotection in pMCAO rats [102] Simvastatincombined with granulocyte colony-stimulating factor (G-CSF) reduced recovery time in a rat model of intracerebralhemorrhage and improved outcome [103] Another strategy

for combination therapy is the use of one drug to block thenegative effects of another such as tPA Mild hypothermiahigh-density lipoproteins activated protein C analog andfingolimod have all been shown to reduce the incidence ofhemorrhagic transformation following administration of tPAin several animal models [54 104ndash106]

7 Neuroprotective Treatments withPleiotropic Effects

Although combination therapy can produce additional ben-efits in some cases not all treatments are compatible witheach other Some combinationsmay have antagonistic effectsproducing less benefit than either treatment alone In somecases combination therapies may enhance damage Fur-thermore combination treatment requires significantly moretesting to determine safety and effectiveness than a singlecompound There is therefore considerable interest in thestudy of treatments with beneficial effects on more thanone mechanism of stroke-related damage Some of thesetreatments have only recently been discovered (Table 1) andare still in the early stages of investigation Others howeverhave already been the subject of considerable study and showgreat promise for the treatment of stroke as summarizedbelow

71 Minocycline Minocycline is a broad spectrum antibioticwhich in addition to its antibacterial activity also hasanti-inflammatory and antiapoptotic effects [107] Conse-quently it has been shown to be protective in a numberof diseases including stroke Minocycline is one of thefew neuroprotective agents in animal studies that has alsobeen proven effective in human trials In one recent trialoral administration of minocycline resulted in significantlyimproved outcomes as long as three months after stroke[108] Furthermore animal studies indicate that additionalbenefits are to be gained by combining minocycline withother neuroprotective strategies Minocycline reduces therisk of subsequent hemorrhage following administration oftissue plasminogen activator in diabetic rats subjected tofocal embolic stroke [109] It also reduces infarct size andsuppresses several hallmarks of inflammation Minocyclineplus normobaric hyperoxia has a synergistic effect on thereduction in infarct volume following tMCAO in rats andhas a positive effect on hemispheric swelling that was notseen with either treatment alone [110] This combinationalso resulted in greater inhibition of apoptosis and MMPactivation Minocycline improves recovery after transplanta-tion of bone marrow mononuclear cells into ischemic ratspresumably by inhibition of microglial activation [111 112] Italso preconditions neural stem cells against oxidative stressproducing reduced infarct size and improved neurologicalperformance following transplantation in rats exposed totMCAO [113]

72 Carnosine Carnosine is a naturally occurring dipeptidethat has both antioxidant and antiexcitotoxic properties [114115] It also is an efficient chelator of metal ions such as

ISRN Neurology 9

Table 1 Neuroprotective treatments with multiple beneficial effects in stroke

Treatment Species Model Benefits ReferenceITH33IQM921 Mouse Ischemia Antiexcitotoxic antioxidant Lorrio et al 2013 [131]TAT-M9 Mouse Ischemia Antioxidant antiapoptotic Guo et al 2013 [132]Glycyrrhizic acid Rat Ischemia Anti-inflammatory antiexcitotoxic and antioxidant Kim et al 2012 [133]Vitis amurensis extract Rat Ischemia Anti-inflammatory antiexcitotoxic antioxidant and antiapoptotic Kim et al 2012 [134]cis-Hinokiresinols Rat Ischemia Anti-inflammatory antioxidant Ju et al 2013 [135]Berberine Rat Ischemia Anti-inflammatory antiapoptotic Zhang et al 2012 [136]S-Nitrosoglutathione Rat Ischemia Antioxidant BBB integrity Khan et al 2012 [137]Taurine Rat Ischemia Antiexcitotoxic antioxidant and antiapoptotic Gharibani et al 2013 [138]MFG-E8 Rat Ischemia Anti-inflammatory antiapoptotic Cheyuo et al 2012 [139]Nitrone derivatives Rat Ischemia Antiexcitotoxic antioxidant Sun et al 2012 [140]

zinc which is required for the activity of matrix metallo-proteinases Preclinical studies have shown that carnosineis well tolerated and produces robust neuroprotection inanimal models of both transient and permanent ischemia[116] It also readily crosses the intact blood-brain barrierwhich allows it to be administered even in the early stagesof stroke Carnosine reduces glutamate excitotoxicity inpMCAOmice resulting in reduced infarct size and improvedneurologic function [117] In another study carnosine wasshown to decrease infarct size MMP activity and levels ofreactive oxygen species [118] Carnosine can also be cleavedby carnosinase into the amino acids alanine and histidinewhich are neuroprotective as well Bestatin an inhibitor ofcarnosinase increases damage in pMCAOmice [119]

73 Asiatic Acid Asiatic acid is a plant-derived compoundwith effects on oxidative stress inflammation and excitotox-icity that has been shown to be beneficial in the treatmentof wound healing beta-amyloid toxicity and liver injuryRecent evidence suggests that it may be neuroprotective instroke as well In pMCAO mice asiatic acid reduces infarctsize and improves neurologic scores possibly by suppressionof mitochondrial damage and BBB disruption [120] Subse-quently asiatic acid was also found to be neuroprotective inmultiple models of ischemia in rats by inhibiting mitochon-drial damage and MMP-9 activation [121] Asiatic acid alsoblocks the negative effects of excitotoxicity in mice followingexposure to glutamate [122] An extract of Centella asiaticahas been shown to improve several markers of behavioralfunction and improved the antioxidant status in tMCAO rats[123]This extract contains asiatic acid as well as several otherrelated compounds that also have neuroprotective propertiesFurther investigation of this class of molecules is thereforewarranted to determine the extent of their effects

74 Hypothermia The beneficial effects of cooling the bodyafter injury are well known and induction of hypothermiais currently used in clinical practice to prevent secondarybrain injury after cardiac arrest and resuscitation peri-natal or neonatal asphyxia and head trauma [124ndash126]Considerable evidence suggests that hypothermia may bebeneficial in the treatment of stroke as well Microarray

experiments have determined that neuroprotection result-ing from hypothermia in MCAO rats is associated withchanges in the expression of genes involved in the processesof inflammation apoptosis and calcium regulation [127]Hypothermia induction by the neurotensin receptor 1 (NTR1)agonist ABS-201 reduces infarct volume and suppresses celldeath by apoptosis and autophagy in mice subjected to focalischemia [128] A recent meta-analysis of human clinicaltrials on the other hand found no benefit of hypothermiain stroke patients [129] These trials had a limited number ofsubjects however and larger trials are currently in progressfor example EuroHYP-1 and ICTuS23 [130]

75 Flavonoids In some cases whole classes of moleculesare known for having multiple neuroprotective effects Onesuch group of compounds that are currently the subjectof intensive research are the flavonoids These moleculesare naturally occurring compounds that readily cross theblood-brain barrier and are well known for their protectiveeffectsTheflavonoids in cocoa for example have antioxidantproperties and also promote perfusion angiogenesis andneurogenesis in the brain [141] Xanthohumol has beenfound to have anti-inflammatory anti-apoptotic antioxi-dant and antithrombotic properties Following MCAO inrats xanthohumol decreases the levels of TNF120572 hypoxia-inducible factor 1 alpha (HIF-1120572) and inducible nitric oxidesynthase (iNOS) [142] It also reduces expression of activatedcaspase 3 scavenges hydroxyl radicals and inhibits plateletaggregation Treatment with naringenin results in neuropro-tection in tMCAO rats through both antioxidant and anti-inflammatorymechanisms [143] Galangin improves cerebralblood blow inhibits apoptosis and protects mitochondrialfunction after MCAO in rats [144] In tMCAO mice fisetinprotects the brain against ischemic injury by suppressingactivation of cerebral inflammatory cells and inhibiting themigration of macrophages and dendritic cells into the brain[145] In models of intracerebral hemorrhage baicalin hasbeen found to attenuate edema of the brain and inhibitapoptosis [146]

76 Cannabinoids Another major class of molecules withmultiple beneficial effects in stroke are the cannabinoids

10 ISRN Neurology

These compounds are primarily known for their anti-inflammatory effects in many diseases including stroke [147]Recently however evidence suggests that cannabinoids mayalso have antioxidant and antiapoptotic effects [148] Thecannabinoid receptor agonists WIN55212-2 and JWH-133reduce activation of microglia and macrophages after induc-tion of ischemia in mice and rats resulting in reduced infarctsize and neurological impairment as well as protection ofoligodendrocyte precursor cells [149ndash151] Another receptoragonist TAK-937 provides neuroprotection in tMCAO ratsand the neuroprotective effect is increased when given incombinationwith hypothermia [152] Furthermore TAK-937not only is effective in rodent models of stroke but also hasbeen shown to reduce infarct volume in nonhuman primates[153] This specific compound is therefore of considerableinterest for future use in human trials

8 Neuroprotective Agents in HumanClinical Stroke Trials

Perhaps the greatest challenge in the study of neuroprotectionin stroke is the translation of animal studies to humansNumerous treatments that produce robust protection inrodents have failed to provide significant benefit in clinicaltrials The various theories on the reason for this failure havealready been discussed elsewhere and will not be coveredhere [5 154 155] Amid the abundance of discouragingresults however a small number of neuroprotective strategieshave shown promise in human stroke patients A briefsummary of recently completed clinical trials for the studyof neuroprotection in ischemic stroke and subarachnoidhemorrhage is provided below A discussion of recent clinicaltrials for neuroprotection in intracerebral hemorrhage isalready available [8]

81 International Citicoline Trial on Acute Stroke (ICTUS)Citicoline is a nutritional supplement that not only is com-monly used to improve memory retention but also has beenshown to prevent neuronal degeneration and improve visualfunction It has already been approved in some countriesfor the treatment of acute ischemic stroke A randomizedplacebo controlled trial was conducted to evaluate the effi-cacy of citicoline in patients with moderate to severe acuteischemic stroke [156] A total of 2298 patients were admin-istered either citicoline (1000mg every 12 hours) or placebofor up to 6 weeks Outcome was determined at 90 days basedon the National Institute of Health Stroke Scale (NIHSS)modified Rankin Scale (mRS) and modified Barthel Index(mBI scores) plus the occurrence of intracranial hemorrhageneurologic deterioration or death No significant differencein recovery was observed between the citicoline and placebotreatment groups

82 Minocycline Minocycline is an oral antibiotic withproven safety over years of use In addition to its antibioticproperties minocycline also has anti-inflammatory and anti-apoptotic effects that have been shown to be neuroprotectivein animal models of stroke and in previous human trials

The efficacy of oral minocycline was examined in arecent single-blinded open-label study [108] Fifty patientswith acute ischemic stroke were given either minocycline(200mgday) or placebo for five days and assessed for variousindicators of outcome at 1 7 30 and 90 days Patientsreceiving minocycline showed significant improvement after30 days in NIHSS mBI and mRS scores NIHSS scorescontinued to be significantly improved at 90 days Largerphase II and phase III trials are awaited

83 Cerebrolysin Cerebrolysin is a mixture of peptide frag-ments that mimics the action of neurotrophic factors andhas been shown to be neuroprotective in a number of condi-tions such as hyperthermia-induced neurotoxicity vasculardementia Alzheimerrsquos disease traumatic brain injury andstroke A large double-blind clinical trial was conducted totest the efficacy and safety of Cerebrolysin in patients withacute ischemic stroke [157] A total of 1070 patients wereadministered aspirin and either Cerebrolysin (30mLday) orplacebo over a period of 10 days Although no significantdifference between treatment groups was seen after 90 days apositive trendwas seen in those patients with anNIHSS scoregreater than 12

84 Ginsenoside-Rd Ginsenoside-Rd is a calcium channelantagonist that has been previously shown to be neuropro-tective in human trials An extended trial of ginsenoside-Rdwas performed in 390 patients with acute ischemic stroke[158] Subjects were administered ginsenoside-Rd or placebointravenously over a 14-day period and evaluated usingNIHSS and mRS scores for 90 days Significant improvementwas seen with ginsenoside-Rd in NIHSS scores at 15 days andmRS scores at 90 days

85 Granulocyte-Colony Stimulating Factor (G-CSF) G-CSFis a growth factor that stimulates the production and releaseof hematopoietic stem cells in bone marrow and may bebeneficial in the enhancement of recovery after stroke Thesafety of G-CSFwas examined in a randomized phase IIb trial[159] A total of 60 patients with either ischemic or hemor-rhagic stroke were given G-CSF (10 120583gkg) or placebo over 5days and monitored for the frequency of adverse effects G-CSF significantly increased white cell counts and produced atrend toward reduced infarct volume No difference was seenbetween treatment groups in the frequency of adverse effects

86 Evaluating Neuroprotection in Aneurysm Coiling Ther-apy (ENACT) Trial The compound known as NA-1 (Tat-NR2B9c) is an inhibitor of the postsynaptic density-95 (PSD-95) protein that is neuroprotective in primate models ofstroke PSD-95 associates with theNMDAglutamate receptorsubtype and contributes to the process of excitotoxicitywhich is suppressed by treatment with NA-1 The safety andefficacy of NA-1 after endovascular aneurysm repair wereexamined in patients with iatrogenic stroke [160] A totalof 185 patients were treated for a ruptured or unrupturedintracranial aneurysm by endovascular coiling followedby administration of NA-1 or placebo Evaluative criteria

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

[1] S D Reed S C CramerD K Blough KMeyer and J G JarvikldquoTreatment with tissue plasminogen activator and inpatientmortality rates for patients with ischemic stroke treated incommunity hospitalsrdquo Stroke vol 32 no 8 pp 1832ndash1839 2001

[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

4 ISRN Neurology

for the removal of free radicals in the body Hydrogensulfide gas increases the activity of superoxide dismutaseand glutathione peroxidase in rats subjected to focal cerebralischemia resulting in decreased injury to neuronal mito-chondria and a subsequent reduction inmarkers of apoptosis[39] Hydrogen-rich saline increases endogenous antioxidantenzyme activity and decreases the amount of oxidativeproducts in pMCAO rats [40] A nucleic acid-based productimproves the antioxidant status of neuronal mitochondriaafter transient ischemia in rats [41] Alternatively exogenouscompounds with free radical scavenging properties can beusedThenovel compoundMnTm4PyPmimics the activity ofendogenous manganese superoxide dismutase and reducesinfarct volume and neurological deficit after MCAO in mice[42] An extract of Ocimum sanctum protects tMCAO ratsby preserving reduced glutathione content and antioxidantenzyme activity [43] Hydrogen gas has been shown toneutralize free radicals and has beneficial effects on severalcontributors to early brain injury after subarachnoid hem-orrhage in rats [44] Furthermore noneffective doses of thefree radical scavenger lipoic acid enhance the neuroprotectiveeffects of the NADPH oxidase inhibitor apocynin whengiven in combination to tMCAO rats [45] Inhibition ofdownstream signaling pathways leading to oxidative stress-induced damage rather than the direct removal of ROSmay also have beneficial effects The antioxidant N-tert-butyl-120572-phenylnitrone suppresses expression of complementcomponent 3 a mediator of inflammation that is induced byoxidative stress inmice after transient focal cerebral ischemia[46]

33 Blood-Brain Barrier Disruption Disruption of the blood-brain barrier following stroke is commonly associated withthe action of two matrix metalloproteinases MMP-2 andMMP-9 MMP-2 is constitutively expressed at low levels innormal brain tissue however stroke increases its expressionand activity and also induces the expression of MMP-9 MMP-2 cleaves and activates MMP-9 which degradescomponents of the basement membrane in vascular wallsand leads to BBB disruption Other factors involved inBBB permeability after stroke include the extent of tightjunction formation between endothelial cells and the effectsof treatment with tissue plasminogen activator The activityof MMPs is regulated endogenously by the tissue inhibitorof matrix metalloproteinase (TIMP) and treatments thatstimulate it may be of significant benefit in protection againststroke-related brain damage Inhibition of the expression andactivity of MMPs by other means may be protective as wellEthanol has been shown to inhibit the increase in MMP-2 and MMP-9 expression after tMCAO in rats and signif-icantly reduces brain edema [47] Apocynum venetum leafextract (AVLE) also alleviates symptoms of BBB disruptionin tMCAO rats by inhibiting the expression and activity ofMMPs [48] Hyperbaric oxygen treatment improved BBBfunction in a rat embolic stroke model through modulationof MMP-9 but displayed reduced effectiveness when admin-istered in combination with tPA [49] It may therefore beof limited benefit in those stroke patients who receive tPA

Treatments that increase the formation of tight junctionsmayalso provide neuroprotection following stroke Doxycyclineincreases the expression of tight junction proteins in tMCAOrats and also inhibits MMPs [50] Kruppel-like factor 2(KLF2) protects against tMCAO in mice by regulation ofthe tight junction component occluding [51] The c-Jun N-terminal kinase (JNK) inhibitor SP600125 restores vasculartight junctions and alleviates BBB disruption in a ratmodel ofsubarachnoid hemorrhage [52] The GTPase RhoA is knownto play an important role in the regulation of endothelialtight junctions and inhibition of RhoA by fibroblast growthfactor preserves BBB integrity in a mouse model of intracere-bral hemorrhage [53] Additional neuroprotective strategiesinclude those that alleviate the negative effects of tPA Highdensity lipoproteins have been shown to reduce hemorrhagictransformation and improve BBB integrity following tPAtreatment in experimental models [54] Neurotrophic factorscan also be used to stimulate repair mechanisms and restoreBBB function Pigment epithelium-derived factor (PEDF)for example has been shown to have beneficial effects onboth BBB permeability and lesion volume after ischemia-reperfusion in rats [55]

34 Excitotoxicity During stroke depletion of neuronaloxygen and energy reserves leads to the release of toxicamounts of the neurotransmitter glutamate into the extra-cellular space [2 17] The subsequent activation of gluta-mate receptors causes an influx of calcium and neuronaldepolarization resulting in aberrant activation of numerouscalcium-dependent pathways in the brain and initiation ofthe processes of necrosis apoptosis and autophagy Gluta-mate excitotoxicity therefore plays a significant role in thepathology of stroke and a large number of research studiesare devoted to suppressing its effects One method of neu-roprotection against excitotoxicity is to reduce the amountof glutamate release during stroke The Ginkgo biloba extractEGb761 has been shown to significantly decrease striatalglutamate levels inmice subjected toMCAO accompanied byreduced neurodegeneration and edema [56] The individualconstituents of EGb761 also have neuroprotective properties[57] Another method of protection is to block the actionof glutamate receptors in the brain The microRNA miR-223 reduces expression of the glutamate receptor subunitsGluR2 and NR2B and is neuroprotective against transientglobal ischemia [58] Activation of the transient receptorpotential vanilloid 4 (TRPV4) is associated with increasedactivity of the NMDA receptor HC-067047 an antagonist ofTRPV4 reduces the extent of infarct after tMCAO in mice[59] Magnesium sulfate is an antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and insome studies has been shown to improve recovery in humanswith acute ischemic stroke [60] On the other hand largescale clinical trials such as the intravenous magnesium effi-cacy in stroke (IMAGES) trial concluded thatmagnesiumdidnot significantly improve outcome in ischemic stroke patientsbut may be beneficial in lacunar stroke [61] It is possiblethat the timing of treatment is critical therefore the fieldadministration of stroke therapy-magnesium (FAST-MAG)

ISRN Neurology 5

trial was devised to test the benefits of magnesium givenprior to arrival at a hospital Results from a pilot trialsuggest that early administration of magnesium may havebenefits and phase III trials are currently underway [62]Inhibiting the influx of calcium into cells following glutamatereceptor activation can also be beneficial Overexpressionof the transient receptor potential canonical 6 (TRPC6)suppresses the increase in calcium induced by NMDA andreduces infarct size and mortality in mice [63] Hyperforinan activator of TRPC6 has also been found to be neuro-protective following tMCAO in rats [64] The compoundginsenoside-Rd decreases expression of the calcium channelTRPM7 in MCAO rats which may be partially responsiblefor its neuroprotective effects [65]

35 Apoptosis During stroke the diminished supply ofoxygen and glucose to the brain leads to reduced cellularmetabolism and depletion of energy stores Combined withtissue damage due to mechanisms such as those mentionedabove cell death by either necrosis or apoptosis may be ini-tiated In the context of intervention apoptosis is preferableto necrosis because it can be blocked by various treatmentsallowing damaged tissue to be rescued Cells within thecore infarct typically die by necrosis whereas those in thepenumbra die by apoptosis The primary factor in determin-ing which mechanism of cell death occurs is the level ofATP within the cell [66] ATP is required for the process ofapoptosis and cells with insufficient ATP stores will die bynecrosis instead Apoptosis can occur by several pathways asshown in Figure 2 The mitochondrial pathway can proceedthrough either caspase dependent or caspase independentmechanisms Alternatively apoptosis may be induced by thedeath receptor pathway

In the caspase dependent pathway of mitochondrialapoptosis release of cytochromeC frommitochondria resultsin activation of caspase 3 which initiates a caspase cascadeleading to the degradation of cellular components and celldeath Caspase 3 activity is commonly used as an indicator ofapoptosis Reduction of activated caspase 3 levels is thereforea goal of many neuroprotective treatments Tanshinone IIAdecreases the levels of cleaved caspase 3 in tMCAO ratsresulting in a reduction in infarct volume edema andneurological deficits Diallyl sulfide reduces expression ofcaspase 3 and increases expression of BCL-2 an endogenousantiapoptotic protein in tMCAO rats as well Hypothermiahas been shown to reduce caspase 3 levels for up to 1 weekafter focal cerebral ischemia in rats [67] Pioglitazone anagonist of the peroxisome proliferator-activated receptor 120574(PPAR120574) activates STAT3 in tMCAO rats leading to changesin the expression of antiapoptotic genes and reduced levels ofcaspase 3 [68] Caspase 3 is not the only potential therapeutictarget within this pathway however The cellular inhibitorsof apoptosis (cIAPs) are endogenous molecules that bind tocaspases and block their activation Ischemic preconditioninghas been shown to increase the levels of cIAP1 in neuronsand reduce apoptosis following unilateral CCAO in rats[69]

Although apoptosis is most commonly associated withthe caspase dependent mitochondrial pathway other path-ways also contribute to cell death after stroke and neuropro-tective agents that act upon these pathways are being inves-tigated The caspase independent pathway of apoptosis ischaracterized bymitochondrial release of apoptosis-inducingfactor (AIF) which is stimulated by the activity of poly(ADP-ribose) polymerase (PARP) Several treatments that inhibitthe caspase dependent pathway of apoptosis have also beenshown to inhibit the caspase independent pathway as wellEthanol administration decreases the expression of bothcaspase 3 and AIF up to 24 hours after tMCAO in rats [70]The nitric oxide donor (S)-ZJM-289 suppresses the releaseof both cytochrome C and AIF from mitochondria andsignificantly reduces injury in MCAO rats [71] CyclosporinA has been shown to decrease the expression of caspase3 AIF and cytochrome C in a rat model of SAH [72]Other compounds have been identified that target the caspaseindependent pathway specifically Ginsenoside-Rd has beenshown to inhibit PARP-1 activity and AIF release in ratssubjected to MCAO [73] The death receptor pathway ofapoptosis differs from the other two in that mitochondriaare not required for its induction Similar to the caspasedependent pathway of mitochondrial apoptosis however thedeath receptor pathway also uses caspase 3 as an effectorTreatments that affect the level and activity of caspase 3 maytherefore block this pathway as well Treatments that targetthis pathway directly have also been identified Musconedecreases the expression of the death receptor FAS andreduces apoptosis in MCAO rats [74] Antibodies againstTNF120572 another initiator of the death receptor pathway blockchanges in the expression of caspase 3 after SAH in rats[75]

36 Autophagy The role of autophagy in stroke has onlyrecently begun to be elucidated and is not fully understoodAutophagy appears to have a dual role in the responseto cellular damage absorbing damaged components as aprotective measure in some cells and serving as a mechanismof cell death in others Autophagy is mediated by the ATGfamily of proteins and regulated by a number of nutrient andenergy sensing pathways that converge on the mammaliantarget of rapamycin (mTOR) [76 77] An overview of theprocess of autophagy and its regulation is shown in Figure 3Induction of autophagy prevents cell death by apoptosisand in this respect is considered to be beneficial The drugrapamycin is an inhibitor of mTOR that leads to inductionof autophagy In a rat model of subarachnoid hemorrhagerapamycin suppressed apoptosis and reduced neurologi-cal deficits whereas inhibition of autophagy increased theamount of brain damage [78] Activity of the tuberoussclerosis complex (TSC) also leads to mTOR inhibition andinduction of autophagy Suppression of the TSC1 subunit ofthis complex has been shown to increase the vulnerabilityof hippocampal neurons to cell death after ischemia in vivo[79] Alternatively the inhibition of autophagy can also beneuroprotective In pMCAO rats ischemic postconditioninginhibited the induction of autophagy and reduced infarct

6 ISRN Neurology

TRADD FADD

Cytochrome C

MitochondriaAIF

BAXBAKBCL-XL

BCL-2BAD BID

Caspase 9

Caspase 3

APAF-1

Caspase 8

FASL

PARP

TNFR FAS

Cell stressdamage

Apoptosis

TNF-120572

Figure 2 Mechanisms of induction of apoptosis In the classical pathway mitochondria release cytochrome C in response to cell stress anddamage leading to activation of caspase 9 and subsequent activation of caspase 3 and other effectors of apoptosis Alternatively mitochondriamay also release apoptosis-inducing factor (AIF) which leads to apoptosis by a caspase independent mechanismThe death receptor pathwayinvolves the activation of FADDby various cell signal receptors followed by activation of caspase 8 and the subsequent caspase cascade leadingto apoptosis

size and edema [80] A chemical inhibitor of autophagyhad similar effects whereas rapamycin partially reversedthem It is hopeful that further research will determine ifthe overall effect of autophagy in stroke is beneficial orharmful

4 Ischemic Tolerance and the Effects ofPre- and Postconditioning

The brain is highly susceptible to ischemia and numerousendogenous mechanisms exist to protect neural tissue fromits effects Although these mechanisms are naturally stim-ulated in response to stroke they may also be artificiallyinduced by nondamaging techniques to produce a protectivestate known as ischemic tolerance [81 82] Preconditioningis a neuroprotective strategy by which ischemic tolerance isinduced prior to stroke in order to protect the brain fromsubsequent damage and potentially could be used as a pre-ventative measure in high risk individuals or as a precautionagainst secondary stroke following medical procedures suchas aneurysm repair or cardiac surgery In the case of naturally

occurring strokes which cannot be predicted postcondition-ingmay be a therapeutic strategy that could be used afterwardto accelerate or enhance protective mechanisms or as aprecaution against stroke recurrence Preconditioning andischemic tolerance have already been extensively reviewedand will only be covered briefly here [83ndash86] Some evidencesuggests however that although preconditioning may bebeneficial in the short term long term structural changesin the brain indicate that tissue damage is merely beingpostponed [87] Clinical studies are needed to test the safetyand efficacy of these novel strategies in humans

Ischemic tolerance can be induced directly by manyconditioning mechanisms including hypoxiahyperoxia hy-pothermiahyperthermia drug treatments blood vessel oc-clusion and dietary restriction [81] Ischemic precondi-tioning has been shown to downregulate components ofmetabolic pathways such as adenosine 51015840-monophosphate-activated protein kinase (AMPK) [88] Preconditioningby the anesthetics sevoflurane and isoflurane inhibits theexpression of proapoptotic genes and upregulates anti-apoptotic genes in MCAO rats [89] Potential mediatorsof preconditioning include the lymphocyte cell kinase(LCK) and sodiumcalcium exchangers (NCX) [90ndash92]

ISRN Neurology 7

Insulin receptorIRS

InsulinCalcium

CaMKK

ATP LKB1 AMPK PI3K

DNA damagehypoxiastress

HIF1 REDD1 TSC1TSC2 AKT PDK1

RHEB

mTORRAPTOR

ATG1ATG13

Amino acid deprivation

RapamycinFKBP12

JNKEndoplasmic reticulum stress

BCL2 ERK

ATG6ATG14

ATG10

ATG5ATG12ATG16 ATG7 ATG4

LC3-II LC3-I LC3

ATG3Induction

Isolation membrane

Nucleation

Phagophore Elongation

Autophagosome

Autolysosome

Lysosome

Fusion

Figure 3 The process of autophagy and its regulation Induction of autophagy is inhibited by mTOR the activity of which is controlledby numerous upstream signaling pathways that respond to metabolic activity energy status and tissue damage Progression of autophagyrequires several members of the ATG protein family leading to the production of a membranous structure that engulfs damaged cellularcomponents to form the autophagosome Subsequent fusion of the autophagosome with a lysosome results in degradation of the damagedcomponents Proteins involved in the regulation of autophagy are shown in shaded boxes Positive interactions are denoted by arrows andnegative interactions by lines with flat ends

Postconditioning inhibits MMP9 expression and subsequentdegradation of the extracellular matrix in MCAO rats [93]Ischemic tolerance in the brain can also be stimulatedremotely for example by application of a tourniquet to oneof the limbs Remote preconditioning is protective in amouseembolic stroke model both by itself and in combination with

tissue plasminogen activator [94] It also provides protectionby upregulation of eNOS in rats subjected to global ischemiaand reperfusion [95] Remote preconditioning has even beenshown to have beneficial effects in human patients withsubarachnoid hemorrhage but further studies are needed[96]

8 ISRN Neurology

5 Neuroprotection in Hemorrhagic Stroke

The pathologies of ischemic and hemorrhagic stroke sharemany of the same damaging processes such as inflamma-tion oxidative stress and excitotoxicity Treatments that areneuroprotective in one may also be beneficial in the otherand several examples of protection in models of hemorrhagicstroke have already been given in the previous sectionsProcesses such as cytotoxicity however are unique to hemor-rhagic stroke and are directly related to the accumulation ofblood in the brain Multiple blood components are believedto contribute to tissue damage after hemorrhage particularlyhemoglobin Haptoglobin and hemopexin are endogenousproteins that bind and remove hemoglobin and its degrada-tion products respectively and enhancement of their activitymay be protective [3] Heme oxygenase (HO) is anotherendogenous protein that converts heme to iron and otherproducts Free iron reacts with hydrogen peroxide to formhydroxyl radicals leading to oxidative stress Inhibition ofHO or chelation of iron by agents such as deferoxamine couldhave beneficial effects Valproic acid decreases the expressionof HO-1 following ICH in rats and attenuated cell death[97] Combination treatment of deferoxamine and statinshas been associated with improved results in behavioral testsin rats after ICH [98] In addition to cytotoxicity cerebralvasospasm is a significant contributor to death and disabilityafter subarachnoid hemorrhage Because of its serious naturea considerable amount of research is dedicated to mitigatingits effects Hydrogen-rich saline has been shown to decreasevasospasm in rats after experimental SAH possibly bysuppressing the effects of inflammation and oxidative stress[99] Vasospasm in SAH rats is also reduced by an analog of120572-melanocyte stimulating hormone and is accompanied bychanges in the expression of factors involved in tissue damageand repair [100]

6 Benefits of Combination Therapy forNeuroprotection in Stroke

Thepathology of stroke is complex withmultiple overlappingprocesses leading to either damage or protection Althoughconsiderable neuroprotection can be gained by targeting justone of these processes the potential benefit is even greaterif multiple mechanisms of damage can be suppressed at thesame time Targeting the same pathway with more than oneneuroprotective agent can also be beneficial Consequentlycombination therapy with more than one drug has provento be effective in several experimental studies The additionalbenefit may be small additive or even synergistic in somecases Progesterone plus vitamin D hormone for examplereduces infarct size and neurological deficits in tMCAO ratsto a greater extent than either treatment alone [101] Thecombination of the anti-inflammatory properties of atorvas-tatin and the antioxidant properties of probucol also producesincreased neuroprotection in pMCAO rats [102] Simvastatincombined with granulocyte colony-stimulating factor (G-CSF) reduced recovery time in a rat model of intracerebralhemorrhage and improved outcome [103] Another strategy

for combination therapy is the use of one drug to block thenegative effects of another such as tPA Mild hypothermiahigh-density lipoproteins activated protein C analog andfingolimod have all been shown to reduce the incidence ofhemorrhagic transformation following administration of tPAin several animal models [54 104ndash106]

7 Neuroprotective Treatments withPleiotropic Effects

Although combination therapy can produce additional ben-efits in some cases not all treatments are compatible witheach other Some combinationsmay have antagonistic effectsproducing less benefit than either treatment alone In somecases combination therapies may enhance damage Fur-thermore combination treatment requires significantly moretesting to determine safety and effectiveness than a singlecompound There is therefore considerable interest in thestudy of treatments with beneficial effects on more thanone mechanism of stroke-related damage Some of thesetreatments have only recently been discovered (Table 1) andare still in the early stages of investigation Others howeverhave already been the subject of considerable study and showgreat promise for the treatment of stroke as summarizedbelow

71 Minocycline Minocycline is a broad spectrum antibioticwhich in addition to its antibacterial activity also hasanti-inflammatory and antiapoptotic effects [107] Conse-quently it has been shown to be protective in a numberof diseases including stroke Minocycline is one of thefew neuroprotective agents in animal studies that has alsobeen proven effective in human trials In one recent trialoral administration of minocycline resulted in significantlyimproved outcomes as long as three months after stroke[108] Furthermore animal studies indicate that additionalbenefits are to be gained by combining minocycline withother neuroprotective strategies Minocycline reduces therisk of subsequent hemorrhage following administration oftissue plasminogen activator in diabetic rats subjected tofocal embolic stroke [109] It also reduces infarct size andsuppresses several hallmarks of inflammation Minocyclineplus normobaric hyperoxia has a synergistic effect on thereduction in infarct volume following tMCAO in rats andhas a positive effect on hemispheric swelling that was notseen with either treatment alone [110] This combinationalso resulted in greater inhibition of apoptosis and MMPactivation Minocycline improves recovery after transplanta-tion of bone marrow mononuclear cells into ischemic ratspresumably by inhibition of microglial activation [111 112] Italso preconditions neural stem cells against oxidative stressproducing reduced infarct size and improved neurologicalperformance following transplantation in rats exposed totMCAO [113]

72 Carnosine Carnosine is a naturally occurring dipeptidethat has both antioxidant and antiexcitotoxic properties [114115] It also is an efficient chelator of metal ions such as

ISRN Neurology 9

Table 1 Neuroprotective treatments with multiple beneficial effects in stroke

Treatment Species Model Benefits ReferenceITH33IQM921 Mouse Ischemia Antiexcitotoxic antioxidant Lorrio et al 2013 [131]TAT-M9 Mouse Ischemia Antioxidant antiapoptotic Guo et al 2013 [132]Glycyrrhizic acid Rat Ischemia Anti-inflammatory antiexcitotoxic and antioxidant Kim et al 2012 [133]Vitis amurensis extract Rat Ischemia Anti-inflammatory antiexcitotoxic antioxidant and antiapoptotic Kim et al 2012 [134]cis-Hinokiresinols Rat Ischemia Anti-inflammatory antioxidant Ju et al 2013 [135]Berberine Rat Ischemia Anti-inflammatory antiapoptotic Zhang et al 2012 [136]S-Nitrosoglutathione Rat Ischemia Antioxidant BBB integrity Khan et al 2012 [137]Taurine Rat Ischemia Antiexcitotoxic antioxidant and antiapoptotic Gharibani et al 2013 [138]MFG-E8 Rat Ischemia Anti-inflammatory antiapoptotic Cheyuo et al 2012 [139]Nitrone derivatives Rat Ischemia Antiexcitotoxic antioxidant Sun et al 2012 [140]

zinc which is required for the activity of matrix metallo-proteinases Preclinical studies have shown that carnosineis well tolerated and produces robust neuroprotection inanimal models of both transient and permanent ischemia[116] It also readily crosses the intact blood-brain barrierwhich allows it to be administered even in the early stagesof stroke Carnosine reduces glutamate excitotoxicity inpMCAOmice resulting in reduced infarct size and improvedneurologic function [117] In another study carnosine wasshown to decrease infarct size MMP activity and levels ofreactive oxygen species [118] Carnosine can also be cleavedby carnosinase into the amino acids alanine and histidinewhich are neuroprotective as well Bestatin an inhibitor ofcarnosinase increases damage in pMCAOmice [119]

73 Asiatic Acid Asiatic acid is a plant-derived compoundwith effects on oxidative stress inflammation and excitotox-icity that has been shown to be beneficial in the treatmentof wound healing beta-amyloid toxicity and liver injuryRecent evidence suggests that it may be neuroprotective instroke as well In pMCAO mice asiatic acid reduces infarctsize and improves neurologic scores possibly by suppressionof mitochondrial damage and BBB disruption [120] Subse-quently asiatic acid was also found to be neuroprotective inmultiple models of ischemia in rats by inhibiting mitochon-drial damage and MMP-9 activation [121] Asiatic acid alsoblocks the negative effects of excitotoxicity in mice followingexposure to glutamate [122] An extract of Centella asiaticahas been shown to improve several markers of behavioralfunction and improved the antioxidant status in tMCAO rats[123]This extract contains asiatic acid as well as several otherrelated compounds that also have neuroprotective propertiesFurther investigation of this class of molecules is thereforewarranted to determine the extent of their effects

74 Hypothermia The beneficial effects of cooling the bodyafter injury are well known and induction of hypothermiais currently used in clinical practice to prevent secondarybrain injury after cardiac arrest and resuscitation peri-natal or neonatal asphyxia and head trauma [124ndash126]Considerable evidence suggests that hypothermia may bebeneficial in the treatment of stroke as well Microarray

experiments have determined that neuroprotection result-ing from hypothermia in MCAO rats is associated withchanges in the expression of genes involved in the processesof inflammation apoptosis and calcium regulation [127]Hypothermia induction by the neurotensin receptor 1 (NTR1)agonist ABS-201 reduces infarct volume and suppresses celldeath by apoptosis and autophagy in mice subjected to focalischemia [128] A recent meta-analysis of human clinicaltrials on the other hand found no benefit of hypothermiain stroke patients [129] These trials had a limited number ofsubjects however and larger trials are currently in progressfor example EuroHYP-1 and ICTuS23 [130]

75 Flavonoids In some cases whole classes of moleculesare known for having multiple neuroprotective effects Onesuch group of compounds that are currently the subjectof intensive research are the flavonoids These moleculesare naturally occurring compounds that readily cross theblood-brain barrier and are well known for their protectiveeffectsTheflavonoids in cocoa for example have antioxidantproperties and also promote perfusion angiogenesis andneurogenesis in the brain [141] Xanthohumol has beenfound to have anti-inflammatory anti-apoptotic antioxi-dant and antithrombotic properties Following MCAO inrats xanthohumol decreases the levels of TNF120572 hypoxia-inducible factor 1 alpha (HIF-1120572) and inducible nitric oxidesynthase (iNOS) [142] It also reduces expression of activatedcaspase 3 scavenges hydroxyl radicals and inhibits plateletaggregation Treatment with naringenin results in neuropro-tection in tMCAO rats through both antioxidant and anti-inflammatorymechanisms [143] Galangin improves cerebralblood blow inhibits apoptosis and protects mitochondrialfunction after MCAO in rats [144] In tMCAO mice fisetinprotects the brain against ischemic injury by suppressingactivation of cerebral inflammatory cells and inhibiting themigration of macrophages and dendritic cells into the brain[145] In models of intracerebral hemorrhage baicalin hasbeen found to attenuate edema of the brain and inhibitapoptosis [146]

76 Cannabinoids Another major class of molecules withmultiple beneficial effects in stroke are the cannabinoids

10 ISRN Neurology

These compounds are primarily known for their anti-inflammatory effects in many diseases including stroke [147]Recently however evidence suggests that cannabinoids mayalso have antioxidant and antiapoptotic effects [148] Thecannabinoid receptor agonists WIN55212-2 and JWH-133reduce activation of microglia and macrophages after induc-tion of ischemia in mice and rats resulting in reduced infarctsize and neurological impairment as well as protection ofoligodendrocyte precursor cells [149ndash151] Another receptoragonist TAK-937 provides neuroprotection in tMCAO ratsand the neuroprotective effect is increased when given incombinationwith hypothermia [152] Furthermore TAK-937not only is effective in rodent models of stroke but also hasbeen shown to reduce infarct volume in nonhuman primates[153] This specific compound is therefore of considerableinterest for future use in human trials

8 Neuroprotective Agents in HumanClinical Stroke Trials

Perhaps the greatest challenge in the study of neuroprotectionin stroke is the translation of animal studies to humansNumerous treatments that produce robust protection inrodents have failed to provide significant benefit in clinicaltrials The various theories on the reason for this failure havealready been discussed elsewhere and will not be coveredhere [5 154 155] Amid the abundance of discouragingresults however a small number of neuroprotective strategieshave shown promise in human stroke patients A briefsummary of recently completed clinical trials for the studyof neuroprotection in ischemic stroke and subarachnoidhemorrhage is provided below A discussion of recent clinicaltrials for neuroprotection in intracerebral hemorrhage isalready available [8]

81 International Citicoline Trial on Acute Stroke (ICTUS)Citicoline is a nutritional supplement that not only is com-monly used to improve memory retention but also has beenshown to prevent neuronal degeneration and improve visualfunction It has already been approved in some countriesfor the treatment of acute ischemic stroke A randomizedplacebo controlled trial was conducted to evaluate the effi-cacy of citicoline in patients with moderate to severe acuteischemic stroke [156] A total of 2298 patients were admin-istered either citicoline (1000mg every 12 hours) or placebofor up to 6 weeks Outcome was determined at 90 days basedon the National Institute of Health Stroke Scale (NIHSS)modified Rankin Scale (mRS) and modified Barthel Index(mBI scores) plus the occurrence of intracranial hemorrhageneurologic deterioration or death No significant differencein recovery was observed between the citicoline and placebotreatment groups

82 Minocycline Minocycline is an oral antibiotic withproven safety over years of use In addition to its antibioticproperties minocycline also has anti-inflammatory and anti-apoptotic effects that have been shown to be neuroprotectivein animal models of stroke and in previous human trials

The efficacy of oral minocycline was examined in arecent single-blinded open-label study [108] Fifty patientswith acute ischemic stroke were given either minocycline(200mgday) or placebo for five days and assessed for variousindicators of outcome at 1 7 30 and 90 days Patientsreceiving minocycline showed significant improvement after30 days in NIHSS mBI and mRS scores NIHSS scorescontinued to be significantly improved at 90 days Largerphase II and phase III trials are awaited

83 Cerebrolysin Cerebrolysin is a mixture of peptide frag-ments that mimics the action of neurotrophic factors andhas been shown to be neuroprotective in a number of condi-tions such as hyperthermia-induced neurotoxicity vasculardementia Alzheimerrsquos disease traumatic brain injury andstroke A large double-blind clinical trial was conducted totest the efficacy and safety of Cerebrolysin in patients withacute ischemic stroke [157] A total of 1070 patients wereadministered aspirin and either Cerebrolysin (30mLday) orplacebo over a period of 10 days Although no significantdifference between treatment groups was seen after 90 days apositive trendwas seen in those patients with anNIHSS scoregreater than 12

84 Ginsenoside-Rd Ginsenoside-Rd is a calcium channelantagonist that has been previously shown to be neuropro-tective in human trials An extended trial of ginsenoside-Rdwas performed in 390 patients with acute ischemic stroke[158] Subjects were administered ginsenoside-Rd or placebointravenously over a 14-day period and evaluated usingNIHSS and mRS scores for 90 days Significant improvementwas seen with ginsenoside-Rd in NIHSS scores at 15 days andmRS scores at 90 days

85 Granulocyte-Colony Stimulating Factor (G-CSF) G-CSFis a growth factor that stimulates the production and releaseof hematopoietic stem cells in bone marrow and may bebeneficial in the enhancement of recovery after stroke Thesafety of G-CSFwas examined in a randomized phase IIb trial[159] A total of 60 patients with either ischemic or hemor-rhagic stroke were given G-CSF (10 120583gkg) or placebo over 5days and monitored for the frequency of adverse effects G-CSF significantly increased white cell counts and produced atrend toward reduced infarct volume No difference was seenbetween treatment groups in the frequency of adverse effects

86 Evaluating Neuroprotection in Aneurysm Coiling Ther-apy (ENACT) Trial The compound known as NA-1 (Tat-NR2B9c) is an inhibitor of the postsynaptic density-95 (PSD-95) protein that is neuroprotective in primate models ofstroke PSD-95 associates with theNMDAglutamate receptorsubtype and contributes to the process of excitotoxicitywhich is suppressed by treatment with NA-1 The safety andefficacy of NA-1 after endovascular aneurysm repair wereexamined in patients with iatrogenic stroke [160] A totalof 185 patients were treated for a ruptured or unrupturedintracranial aneurysm by endovascular coiling followedby administration of NA-1 or placebo Evaluative criteria

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

[1] S D Reed S C CramerD K Blough KMeyer and J G JarvikldquoTreatment with tissue plasminogen activator and inpatientmortality rates for patients with ischemic stroke treated incommunity hospitalsrdquo Stroke vol 32 no 8 pp 1832ndash1839 2001

[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

ISRN Neurology 5

trial was devised to test the benefits of magnesium givenprior to arrival at a hospital Results from a pilot trialsuggest that early administration of magnesium may havebenefits and phase III trials are currently underway [62]Inhibiting the influx of calcium into cells following glutamatereceptor activation can also be beneficial Overexpressionof the transient receptor potential canonical 6 (TRPC6)suppresses the increase in calcium induced by NMDA andreduces infarct size and mortality in mice [63] Hyperforinan activator of TRPC6 has also been found to be neuro-protective following tMCAO in rats [64] The compoundginsenoside-Rd decreases expression of the calcium channelTRPM7 in MCAO rats which may be partially responsiblefor its neuroprotective effects [65]

35 Apoptosis During stroke the diminished supply ofoxygen and glucose to the brain leads to reduced cellularmetabolism and depletion of energy stores Combined withtissue damage due to mechanisms such as those mentionedabove cell death by either necrosis or apoptosis may be ini-tiated In the context of intervention apoptosis is preferableto necrosis because it can be blocked by various treatmentsallowing damaged tissue to be rescued Cells within thecore infarct typically die by necrosis whereas those in thepenumbra die by apoptosis The primary factor in determin-ing which mechanism of cell death occurs is the level ofATP within the cell [66] ATP is required for the process ofapoptosis and cells with insufficient ATP stores will die bynecrosis instead Apoptosis can occur by several pathways asshown in Figure 2 The mitochondrial pathway can proceedthrough either caspase dependent or caspase independentmechanisms Alternatively apoptosis may be induced by thedeath receptor pathway

In the caspase dependent pathway of mitochondrialapoptosis release of cytochromeC frommitochondria resultsin activation of caspase 3 which initiates a caspase cascadeleading to the degradation of cellular components and celldeath Caspase 3 activity is commonly used as an indicator ofapoptosis Reduction of activated caspase 3 levels is thereforea goal of many neuroprotective treatments Tanshinone IIAdecreases the levels of cleaved caspase 3 in tMCAO ratsresulting in a reduction in infarct volume edema andneurological deficits Diallyl sulfide reduces expression ofcaspase 3 and increases expression of BCL-2 an endogenousantiapoptotic protein in tMCAO rats as well Hypothermiahas been shown to reduce caspase 3 levels for up to 1 weekafter focal cerebral ischemia in rats [67] Pioglitazone anagonist of the peroxisome proliferator-activated receptor 120574(PPAR120574) activates STAT3 in tMCAO rats leading to changesin the expression of antiapoptotic genes and reduced levels ofcaspase 3 [68] Caspase 3 is not the only potential therapeutictarget within this pathway however The cellular inhibitorsof apoptosis (cIAPs) are endogenous molecules that bind tocaspases and block their activation Ischemic preconditioninghas been shown to increase the levels of cIAP1 in neuronsand reduce apoptosis following unilateral CCAO in rats[69]

Although apoptosis is most commonly associated withthe caspase dependent mitochondrial pathway other path-ways also contribute to cell death after stroke and neuropro-tective agents that act upon these pathways are being inves-tigated The caspase independent pathway of apoptosis ischaracterized bymitochondrial release of apoptosis-inducingfactor (AIF) which is stimulated by the activity of poly(ADP-ribose) polymerase (PARP) Several treatments that inhibitthe caspase dependent pathway of apoptosis have also beenshown to inhibit the caspase independent pathway as wellEthanol administration decreases the expression of bothcaspase 3 and AIF up to 24 hours after tMCAO in rats [70]The nitric oxide donor (S)-ZJM-289 suppresses the releaseof both cytochrome C and AIF from mitochondria andsignificantly reduces injury in MCAO rats [71] CyclosporinA has been shown to decrease the expression of caspase3 AIF and cytochrome C in a rat model of SAH [72]Other compounds have been identified that target the caspaseindependent pathway specifically Ginsenoside-Rd has beenshown to inhibit PARP-1 activity and AIF release in ratssubjected to MCAO [73] The death receptor pathway ofapoptosis differs from the other two in that mitochondriaare not required for its induction Similar to the caspasedependent pathway of mitochondrial apoptosis however thedeath receptor pathway also uses caspase 3 as an effectorTreatments that affect the level and activity of caspase 3 maytherefore block this pathway as well Treatments that targetthis pathway directly have also been identified Musconedecreases the expression of the death receptor FAS andreduces apoptosis in MCAO rats [74] Antibodies againstTNF120572 another initiator of the death receptor pathway blockchanges in the expression of caspase 3 after SAH in rats[75]

36 Autophagy The role of autophagy in stroke has onlyrecently begun to be elucidated and is not fully understoodAutophagy appears to have a dual role in the responseto cellular damage absorbing damaged components as aprotective measure in some cells and serving as a mechanismof cell death in others Autophagy is mediated by the ATGfamily of proteins and regulated by a number of nutrient andenergy sensing pathways that converge on the mammaliantarget of rapamycin (mTOR) [76 77] An overview of theprocess of autophagy and its regulation is shown in Figure 3Induction of autophagy prevents cell death by apoptosisand in this respect is considered to be beneficial The drugrapamycin is an inhibitor of mTOR that leads to inductionof autophagy In a rat model of subarachnoid hemorrhagerapamycin suppressed apoptosis and reduced neurologi-cal deficits whereas inhibition of autophagy increased theamount of brain damage [78] Activity of the tuberoussclerosis complex (TSC) also leads to mTOR inhibition andinduction of autophagy Suppression of the TSC1 subunit ofthis complex has been shown to increase the vulnerabilityof hippocampal neurons to cell death after ischemia in vivo[79] Alternatively the inhibition of autophagy can also beneuroprotective In pMCAO rats ischemic postconditioninginhibited the induction of autophagy and reduced infarct

6 ISRN Neurology

TRADD FADD

Cytochrome C

MitochondriaAIF

BAXBAKBCL-XL

BCL-2BAD BID

Caspase 9

Caspase 3

APAF-1

Caspase 8

FASL

PARP

TNFR FAS

Cell stressdamage

Apoptosis

TNF-120572

Figure 2 Mechanisms of induction of apoptosis In the classical pathway mitochondria release cytochrome C in response to cell stress anddamage leading to activation of caspase 9 and subsequent activation of caspase 3 and other effectors of apoptosis Alternatively mitochondriamay also release apoptosis-inducing factor (AIF) which leads to apoptosis by a caspase independent mechanismThe death receptor pathwayinvolves the activation of FADDby various cell signal receptors followed by activation of caspase 8 and the subsequent caspase cascade leadingto apoptosis

size and edema [80] A chemical inhibitor of autophagyhad similar effects whereas rapamycin partially reversedthem It is hopeful that further research will determine ifthe overall effect of autophagy in stroke is beneficial orharmful

4 Ischemic Tolerance and the Effects ofPre- and Postconditioning

The brain is highly susceptible to ischemia and numerousendogenous mechanisms exist to protect neural tissue fromits effects Although these mechanisms are naturally stim-ulated in response to stroke they may also be artificiallyinduced by nondamaging techniques to produce a protectivestate known as ischemic tolerance [81 82] Preconditioningis a neuroprotective strategy by which ischemic tolerance isinduced prior to stroke in order to protect the brain fromsubsequent damage and potentially could be used as a pre-ventative measure in high risk individuals or as a precautionagainst secondary stroke following medical procedures suchas aneurysm repair or cardiac surgery In the case of naturally

occurring strokes which cannot be predicted postcondition-ingmay be a therapeutic strategy that could be used afterwardto accelerate or enhance protective mechanisms or as aprecaution against stroke recurrence Preconditioning andischemic tolerance have already been extensively reviewedand will only be covered briefly here [83ndash86] Some evidencesuggests however that although preconditioning may bebeneficial in the short term long term structural changesin the brain indicate that tissue damage is merely beingpostponed [87] Clinical studies are needed to test the safetyand efficacy of these novel strategies in humans

Ischemic tolerance can be induced directly by manyconditioning mechanisms including hypoxiahyperoxia hy-pothermiahyperthermia drug treatments blood vessel oc-clusion and dietary restriction [81] Ischemic precondi-tioning has been shown to downregulate components ofmetabolic pathways such as adenosine 51015840-monophosphate-activated protein kinase (AMPK) [88] Preconditioningby the anesthetics sevoflurane and isoflurane inhibits theexpression of proapoptotic genes and upregulates anti-apoptotic genes in MCAO rats [89] Potential mediatorsof preconditioning include the lymphocyte cell kinase(LCK) and sodiumcalcium exchangers (NCX) [90ndash92]

ISRN Neurology 7

Insulin receptorIRS

InsulinCalcium

CaMKK

ATP LKB1 AMPK PI3K

DNA damagehypoxiastress

HIF1 REDD1 TSC1TSC2 AKT PDK1

RHEB

mTORRAPTOR

ATG1ATG13

Amino acid deprivation

RapamycinFKBP12

JNKEndoplasmic reticulum stress

BCL2 ERK

ATG6ATG14

ATG10

ATG5ATG12ATG16 ATG7 ATG4

LC3-II LC3-I LC3

ATG3Induction

Isolation membrane

Nucleation

Phagophore Elongation

Autophagosome

Autolysosome

Lysosome

Fusion

Figure 3 The process of autophagy and its regulation Induction of autophagy is inhibited by mTOR the activity of which is controlledby numerous upstream signaling pathways that respond to metabolic activity energy status and tissue damage Progression of autophagyrequires several members of the ATG protein family leading to the production of a membranous structure that engulfs damaged cellularcomponents to form the autophagosome Subsequent fusion of the autophagosome with a lysosome results in degradation of the damagedcomponents Proteins involved in the regulation of autophagy are shown in shaded boxes Positive interactions are denoted by arrows andnegative interactions by lines with flat ends

Postconditioning inhibits MMP9 expression and subsequentdegradation of the extracellular matrix in MCAO rats [93]Ischemic tolerance in the brain can also be stimulatedremotely for example by application of a tourniquet to oneof the limbs Remote preconditioning is protective in amouseembolic stroke model both by itself and in combination with

tissue plasminogen activator [94] It also provides protectionby upregulation of eNOS in rats subjected to global ischemiaand reperfusion [95] Remote preconditioning has even beenshown to have beneficial effects in human patients withsubarachnoid hemorrhage but further studies are needed[96]

8 ISRN Neurology

5 Neuroprotection in Hemorrhagic Stroke

The pathologies of ischemic and hemorrhagic stroke sharemany of the same damaging processes such as inflamma-tion oxidative stress and excitotoxicity Treatments that areneuroprotective in one may also be beneficial in the otherand several examples of protection in models of hemorrhagicstroke have already been given in the previous sectionsProcesses such as cytotoxicity however are unique to hemor-rhagic stroke and are directly related to the accumulation ofblood in the brain Multiple blood components are believedto contribute to tissue damage after hemorrhage particularlyhemoglobin Haptoglobin and hemopexin are endogenousproteins that bind and remove hemoglobin and its degrada-tion products respectively and enhancement of their activitymay be protective [3] Heme oxygenase (HO) is anotherendogenous protein that converts heme to iron and otherproducts Free iron reacts with hydrogen peroxide to formhydroxyl radicals leading to oxidative stress Inhibition ofHO or chelation of iron by agents such as deferoxamine couldhave beneficial effects Valproic acid decreases the expressionof HO-1 following ICH in rats and attenuated cell death[97] Combination treatment of deferoxamine and statinshas been associated with improved results in behavioral testsin rats after ICH [98] In addition to cytotoxicity cerebralvasospasm is a significant contributor to death and disabilityafter subarachnoid hemorrhage Because of its serious naturea considerable amount of research is dedicated to mitigatingits effects Hydrogen-rich saline has been shown to decreasevasospasm in rats after experimental SAH possibly bysuppressing the effects of inflammation and oxidative stress[99] Vasospasm in SAH rats is also reduced by an analog of120572-melanocyte stimulating hormone and is accompanied bychanges in the expression of factors involved in tissue damageand repair [100]

6 Benefits of Combination Therapy forNeuroprotection in Stroke

Thepathology of stroke is complex withmultiple overlappingprocesses leading to either damage or protection Althoughconsiderable neuroprotection can be gained by targeting justone of these processes the potential benefit is even greaterif multiple mechanisms of damage can be suppressed at thesame time Targeting the same pathway with more than oneneuroprotective agent can also be beneficial Consequentlycombination therapy with more than one drug has provento be effective in several experimental studies The additionalbenefit may be small additive or even synergistic in somecases Progesterone plus vitamin D hormone for examplereduces infarct size and neurological deficits in tMCAO ratsto a greater extent than either treatment alone [101] Thecombination of the anti-inflammatory properties of atorvas-tatin and the antioxidant properties of probucol also producesincreased neuroprotection in pMCAO rats [102] Simvastatincombined with granulocyte colony-stimulating factor (G-CSF) reduced recovery time in a rat model of intracerebralhemorrhage and improved outcome [103] Another strategy

for combination therapy is the use of one drug to block thenegative effects of another such as tPA Mild hypothermiahigh-density lipoproteins activated protein C analog andfingolimod have all been shown to reduce the incidence ofhemorrhagic transformation following administration of tPAin several animal models [54 104ndash106]

7 Neuroprotective Treatments withPleiotropic Effects

Although combination therapy can produce additional ben-efits in some cases not all treatments are compatible witheach other Some combinationsmay have antagonistic effectsproducing less benefit than either treatment alone In somecases combination therapies may enhance damage Fur-thermore combination treatment requires significantly moretesting to determine safety and effectiveness than a singlecompound There is therefore considerable interest in thestudy of treatments with beneficial effects on more thanone mechanism of stroke-related damage Some of thesetreatments have only recently been discovered (Table 1) andare still in the early stages of investigation Others howeverhave already been the subject of considerable study and showgreat promise for the treatment of stroke as summarizedbelow

71 Minocycline Minocycline is a broad spectrum antibioticwhich in addition to its antibacterial activity also hasanti-inflammatory and antiapoptotic effects [107] Conse-quently it has been shown to be protective in a numberof diseases including stroke Minocycline is one of thefew neuroprotective agents in animal studies that has alsobeen proven effective in human trials In one recent trialoral administration of minocycline resulted in significantlyimproved outcomes as long as three months after stroke[108] Furthermore animal studies indicate that additionalbenefits are to be gained by combining minocycline withother neuroprotective strategies Minocycline reduces therisk of subsequent hemorrhage following administration oftissue plasminogen activator in diabetic rats subjected tofocal embolic stroke [109] It also reduces infarct size andsuppresses several hallmarks of inflammation Minocyclineplus normobaric hyperoxia has a synergistic effect on thereduction in infarct volume following tMCAO in rats andhas a positive effect on hemispheric swelling that was notseen with either treatment alone [110] This combinationalso resulted in greater inhibition of apoptosis and MMPactivation Minocycline improves recovery after transplanta-tion of bone marrow mononuclear cells into ischemic ratspresumably by inhibition of microglial activation [111 112] Italso preconditions neural stem cells against oxidative stressproducing reduced infarct size and improved neurologicalperformance following transplantation in rats exposed totMCAO [113]

72 Carnosine Carnosine is a naturally occurring dipeptidethat has both antioxidant and antiexcitotoxic properties [114115] It also is an efficient chelator of metal ions such as

ISRN Neurology 9

Table 1 Neuroprotective treatments with multiple beneficial effects in stroke

Treatment Species Model Benefits ReferenceITH33IQM921 Mouse Ischemia Antiexcitotoxic antioxidant Lorrio et al 2013 [131]TAT-M9 Mouse Ischemia Antioxidant antiapoptotic Guo et al 2013 [132]Glycyrrhizic acid Rat Ischemia Anti-inflammatory antiexcitotoxic and antioxidant Kim et al 2012 [133]Vitis amurensis extract Rat Ischemia Anti-inflammatory antiexcitotoxic antioxidant and antiapoptotic Kim et al 2012 [134]cis-Hinokiresinols Rat Ischemia Anti-inflammatory antioxidant Ju et al 2013 [135]Berberine Rat Ischemia Anti-inflammatory antiapoptotic Zhang et al 2012 [136]S-Nitrosoglutathione Rat Ischemia Antioxidant BBB integrity Khan et al 2012 [137]Taurine Rat Ischemia Antiexcitotoxic antioxidant and antiapoptotic Gharibani et al 2013 [138]MFG-E8 Rat Ischemia Anti-inflammatory antiapoptotic Cheyuo et al 2012 [139]Nitrone derivatives Rat Ischemia Antiexcitotoxic antioxidant Sun et al 2012 [140]

zinc which is required for the activity of matrix metallo-proteinases Preclinical studies have shown that carnosineis well tolerated and produces robust neuroprotection inanimal models of both transient and permanent ischemia[116] It also readily crosses the intact blood-brain barrierwhich allows it to be administered even in the early stagesof stroke Carnosine reduces glutamate excitotoxicity inpMCAOmice resulting in reduced infarct size and improvedneurologic function [117] In another study carnosine wasshown to decrease infarct size MMP activity and levels ofreactive oxygen species [118] Carnosine can also be cleavedby carnosinase into the amino acids alanine and histidinewhich are neuroprotective as well Bestatin an inhibitor ofcarnosinase increases damage in pMCAOmice [119]

73 Asiatic Acid Asiatic acid is a plant-derived compoundwith effects on oxidative stress inflammation and excitotox-icity that has been shown to be beneficial in the treatmentof wound healing beta-amyloid toxicity and liver injuryRecent evidence suggests that it may be neuroprotective instroke as well In pMCAO mice asiatic acid reduces infarctsize and improves neurologic scores possibly by suppressionof mitochondrial damage and BBB disruption [120] Subse-quently asiatic acid was also found to be neuroprotective inmultiple models of ischemia in rats by inhibiting mitochon-drial damage and MMP-9 activation [121] Asiatic acid alsoblocks the negative effects of excitotoxicity in mice followingexposure to glutamate [122] An extract of Centella asiaticahas been shown to improve several markers of behavioralfunction and improved the antioxidant status in tMCAO rats[123]This extract contains asiatic acid as well as several otherrelated compounds that also have neuroprotective propertiesFurther investigation of this class of molecules is thereforewarranted to determine the extent of their effects

74 Hypothermia The beneficial effects of cooling the bodyafter injury are well known and induction of hypothermiais currently used in clinical practice to prevent secondarybrain injury after cardiac arrest and resuscitation peri-natal or neonatal asphyxia and head trauma [124ndash126]Considerable evidence suggests that hypothermia may bebeneficial in the treatment of stroke as well Microarray

experiments have determined that neuroprotection result-ing from hypothermia in MCAO rats is associated withchanges in the expression of genes involved in the processesof inflammation apoptosis and calcium regulation [127]Hypothermia induction by the neurotensin receptor 1 (NTR1)agonist ABS-201 reduces infarct volume and suppresses celldeath by apoptosis and autophagy in mice subjected to focalischemia [128] A recent meta-analysis of human clinicaltrials on the other hand found no benefit of hypothermiain stroke patients [129] These trials had a limited number ofsubjects however and larger trials are currently in progressfor example EuroHYP-1 and ICTuS23 [130]

75 Flavonoids In some cases whole classes of moleculesare known for having multiple neuroprotective effects Onesuch group of compounds that are currently the subjectof intensive research are the flavonoids These moleculesare naturally occurring compounds that readily cross theblood-brain barrier and are well known for their protectiveeffectsTheflavonoids in cocoa for example have antioxidantproperties and also promote perfusion angiogenesis andneurogenesis in the brain [141] Xanthohumol has beenfound to have anti-inflammatory anti-apoptotic antioxi-dant and antithrombotic properties Following MCAO inrats xanthohumol decreases the levels of TNF120572 hypoxia-inducible factor 1 alpha (HIF-1120572) and inducible nitric oxidesynthase (iNOS) [142] It also reduces expression of activatedcaspase 3 scavenges hydroxyl radicals and inhibits plateletaggregation Treatment with naringenin results in neuropro-tection in tMCAO rats through both antioxidant and anti-inflammatorymechanisms [143] Galangin improves cerebralblood blow inhibits apoptosis and protects mitochondrialfunction after MCAO in rats [144] In tMCAO mice fisetinprotects the brain against ischemic injury by suppressingactivation of cerebral inflammatory cells and inhibiting themigration of macrophages and dendritic cells into the brain[145] In models of intracerebral hemorrhage baicalin hasbeen found to attenuate edema of the brain and inhibitapoptosis [146]

76 Cannabinoids Another major class of molecules withmultiple beneficial effects in stroke are the cannabinoids

10 ISRN Neurology

These compounds are primarily known for their anti-inflammatory effects in many diseases including stroke [147]Recently however evidence suggests that cannabinoids mayalso have antioxidant and antiapoptotic effects [148] Thecannabinoid receptor agonists WIN55212-2 and JWH-133reduce activation of microglia and macrophages after induc-tion of ischemia in mice and rats resulting in reduced infarctsize and neurological impairment as well as protection ofoligodendrocyte precursor cells [149ndash151] Another receptoragonist TAK-937 provides neuroprotection in tMCAO ratsand the neuroprotective effect is increased when given incombinationwith hypothermia [152] Furthermore TAK-937not only is effective in rodent models of stroke but also hasbeen shown to reduce infarct volume in nonhuman primates[153] This specific compound is therefore of considerableinterest for future use in human trials

8 Neuroprotective Agents in HumanClinical Stroke Trials

Perhaps the greatest challenge in the study of neuroprotectionin stroke is the translation of animal studies to humansNumerous treatments that produce robust protection inrodents have failed to provide significant benefit in clinicaltrials The various theories on the reason for this failure havealready been discussed elsewhere and will not be coveredhere [5 154 155] Amid the abundance of discouragingresults however a small number of neuroprotective strategieshave shown promise in human stroke patients A briefsummary of recently completed clinical trials for the studyof neuroprotection in ischemic stroke and subarachnoidhemorrhage is provided below A discussion of recent clinicaltrials for neuroprotection in intracerebral hemorrhage isalready available [8]

81 International Citicoline Trial on Acute Stroke (ICTUS)Citicoline is a nutritional supplement that not only is com-monly used to improve memory retention but also has beenshown to prevent neuronal degeneration and improve visualfunction It has already been approved in some countriesfor the treatment of acute ischemic stroke A randomizedplacebo controlled trial was conducted to evaluate the effi-cacy of citicoline in patients with moderate to severe acuteischemic stroke [156] A total of 2298 patients were admin-istered either citicoline (1000mg every 12 hours) or placebofor up to 6 weeks Outcome was determined at 90 days basedon the National Institute of Health Stroke Scale (NIHSS)modified Rankin Scale (mRS) and modified Barthel Index(mBI scores) plus the occurrence of intracranial hemorrhageneurologic deterioration or death No significant differencein recovery was observed between the citicoline and placebotreatment groups

82 Minocycline Minocycline is an oral antibiotic withproven safety over years of use In addition to its antibioticproperties minocycline also has anti-inflammatory and anti-apoptotic effects that have been shown to be neuroprotectivein animal models of stroke and in previous human trials

The efficacy of oral minocycline was examined in arecent single-blinded open-label study [108] Fifty patientswith acute ischemic stroke were given either minocycline(200mgday) or placebo for five days and assessed for variousindicators of outcome at 1 7 30 and 90 days Patientsreceiving minocycline showed significant improvement after30 days in NIHSS mBI and mRS scores NIHSS scorescontinued to be significantly improved at 90 days Largerphase II and phase III trials are awaited

83 Cerebrolysin Cerebrolysin is a mixture of peptide frag-ments that mimics the action of neurotrophic factors andhas been shown to be neuroprotective in a number of condi-tions such as hyperthermia-induced neurotoxicity vasculardementia Alzheimerrsquos disease traumatic brain injury andstroke A large double-blind clinical trial was conducted totest the efficacy and safety of Cerebrolysin in patients withacute ischemic stroke [157] A total of 1070 patients wereadministered aspirin and either Cerebrolysin (30mLday) orplacebo over a period of 10 days Although no significantdifference between treatment groups was seen after 90 days apositive trendwas seen in those patients with anNIHSS scoregreater than 12

84 Ginsenoside-Rd Ginsenoside-Rd is a calcium channelantagonist that has been previously shown to be neuropro-tective in human trials An extended trial of ginsenoside-Rdwas performed in 390 patients with acute ischemic stroke[158] Subjects were administered ginsenoside-Rd or placebointravenously over a 14-day period and evaluated usingNIHSS and mRS scores for 90 days Significant improvementwas seen with ginsenoside-Rd in NIHSS scores at 15 days andmRS scores at 90 days

85 Granulocyte-Colony Stimulating Factor (G-CSF) G-CSFis a growth factor that stimulates the production and releaseof hematopoietic stem cells in bone marrow and may bebeneficial in the enhancement of recovery after stroke Thesafety of G-CSFwas examined in a randomized phase IIb trial[159] A total of 60 patients with either ischemic or hemor-rhagic stroke were given G-CSF (10 120583gkg) or placebo over 5days and monitored for the frequency of adverse effects G-CSF significantly increased white cell counts and produced atrend toward reduced infarct volume No difference was seenbetween treatment groups in the frequency of adverse effects

86 Evaluating Neuroprotection in Aneurysm Coiling Ther-apy (ENACT) Trial The compound known as NA-1 (Tat-NR2B9c) is an inhibitor of the postsynaptic density-95 (PSD-95) protein that is neuroprotective in primate models ofstroke PSD-95 associates with theNMDAglutamate receptorsubtype and contributes to the process of excitotoxicitywhich is suppressed by treatment with NA-1 The safety andefficacy of NA-1 after endovascular aneurysm repair wereexamined in patients with iatrogenic stroke [160] A totalof 185 patients were treated for a ruptured or unrupturedintracranial aneurysm by endovascular coiling followedby administration of NA-1 or placebo Evaluative criteria

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

[1] S D Reed S C CramerD K Blough KMeyer and J G JarvikldquoTreatment with tissue plasminogen activator and inpatientmortality rates for patients with ischemic stroke treated incommunity hospitalsrdquo Stroke vol 32 no 8 pp 1832ndash1839 2001

[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

6 ISRN Neurology

TRADD FADD

Cytochrome C

MitochondriaAIF

BAXBAKBCL-XL

BCL-2BAD BID

Caspase 9

Caspase 3

APAF-1

Caspase 8

FASL

PARP

TNFR FAS

Cell stressdamage

Apoptosis

TNF-120572

Figure 2 Mechanisms of induction of apoptosis In the classical pathway mitochondria release cytochrome C in response to cell stress anddamage leading to activation of caspase 9 and subsequent activation of caspase 3 and other effectors of apoptosis Alternatively mitochondriamay also release apoptosis-inducing factor (AIF) which leads to apoptosis by a caspase independent mechanismThe death receptor pathwayinvolves the activation of FADDby various cell signal receptors followed by activation of caspase 8 and the subsequent caspase cascade leadingto apoptosis

size and edema [80] A chemical inhibitor of autophagyhad similar effects whereas rapamycin partially reversedthem It is hopeful that further research will determine ifthe overall effect of autophagy in stroke is beneficial orharmful

4 Ischemic Tolerance and the Effects ofPre- and Postconditioning

The brain is highly susceptible to ischemia and numerousendogenous mechanisms exist to protect neural tissue fromits effects Although these mechanisms are naturally stim-ulated in response to stroke they may also be artificiallyinduced by nondamaging techniques to produce a protectivestate known as ischemic tolerance [81 82] Preconditioningis a neuroprotective strategy by which ischemic tolerance isinduced prior to stroke in order to protect the brain fromsubsequent damage and potentially could be used as a pre-ventative measure in high risk individuals or as a precautionagainst secondary stroke following medical procedures suchas aneurysm repair or cardiac surgery In the case of naturally

occurring strokes which cannot be predicted postcondition-ingmay be a therapeutic strategy that could be used afterwardto accelerate or enhance protective mechanisms or as aprecaution against stroke recurrence Preconditioning andischemic tolerance have already been extensively reviewedand will only be covered briefly here [83ndash86] Some evidencesuggests however that although preconditioning may bebeneficial in the short term long term structural changesin the brain indicate that tissue damage is merely beingpostponed [87] Clinical studies are needed to test the safetyand efficacy of these novel strategies in humans

Ischemic tolerance can be induced directly by manyconditioning mechanisms including hypoxiahyperoxia hy-pothermiahyperthermia drug treatments blood vessel oc-clusion and dietary restriction [81] Ischemic precondi-tioning has been shown to downregulate components ofmetabolic pathways such as adenosine 51015840-monophosphate-activated protein kinase (AMPK) [88] Preconditioningby the anesthetics sevoflurane and isoflurane inhibits theexpression of proapoptotic genes and upregulates anti-apoptotic genes in MCAO rats [89] Potential mediatorsof preconditioning include the lymphocyte cell kinase(LCK) and sodiumcalcium exchangers (NCX) [90ndash92]

ISRN Neurology 7

Insulin receptorIRS

InsulinCalcium

CaMKK

ATP LKB1 AMPK PI3K

DNA damagehypoxiastress

HIF1 REDD1 TSC1TSC2 AKT PDK1

RHEB

mTORRAPTOR

ATG1ATG13

Amino acid deprivation

RapamycinFKBP12

JNKEndoplasmic reticulum stress

BCL2 ERK

ATG6ATG14

ATG10

ATG5ATG12ATG16 ATG7 ATG4

LC3-II LC3-I LC3

ATG3Induction

Isolation membrane

Nucleation

Phagophore Elongation

Autophagosome

Autolysosome

Lysosome

Fusion

Figure 3 The process of autophagy and its regulation Induction of autophagy is inhibited by mTOR the activity of which is controlledby numerous upstream signaling pathways that respond to metabolic activity energy status and tissue damage Progression of autophagyrequires several members of the ATG protein family leading to the production of a membranous structure that engulfs damaged cellularcomponents to form the autophagosome Subsequent fusion of the autophagosome with a lysosome results in degradation of the damagedcomponents Proteins involved in the regulation of autophagy are shown in shaded boxes Positive interactions are denoted by arrows andnegative interactions by lines with flat ends

Postconditioning inhibits MMP9 expression and subsequentdegradation of the extracellular matrix in MCAO rats [93]Ischemic tolerance in the brain can also be stimulatedremotely for example by application of a tourniquet to oneof the limbs Remote preconditioning is protective in amouseembolic stroke model both by itself and in combination with

tissue plasminogen activator [94] It also provides protectionby upregulation of eNOS in rats subjected to global ischemiaand reperfusion [95] Remote preconditioning has even beenshown to have beneficial effects in human patients withsubarachnoid hemorrhage but further studies are needed[96]

8 ISRN Neurology

5 Neuroprotection in Hemorrhagic Stroke

The pathologies of ischemic and hemorrhagic stroke sharemany of the same damaging processes such as inflamma-tion oxidative stress and excitotoxicity Treatments that areneuroprotective in one may also be beneficial in the otherand several examples of protection in models of hemorrhagicstroke have already been given in the previous sectionsProcesses such as cytotoxicity however are unique to hemor-rhagic stroke and are directly related to the accumulation ofblood in the brain Multiple blood components are believedto contribute to tissue damage after hemorrhage particularlyhemoglobin Haptoglobin and hemopexin are endogenousproteins that bind and remove hemoglobin and its degrada-tion products respectively and enhancement of their activitymay be protective [3] Heme oxygenase (HO) is anotherendogenous protein that converts heme to iron and otherproducts Free iron reacts with hydrogen peroxide to formhydroxyl radicals leading to oxidative stress Inhibition ofHO or chelation of iron by agents such as deferoxamine couldhave beneficial effects Valproic acid decreases the expressionof HO-1 following ICH in rats and attenuated cell death[97] Combination treatment of deferoxamine and statinshas been associated with improved results in behavioral testsin rats after ICH [98] In addition to cytotoxicity cerebralvasospasm is a significant contributor to death and disabilityafter subarachnoid hemorrhage Because of its serious naturea considerable amount of research is dedicated to mitigatingits effects Hydrogen-rich saline has been shown to decreasevasospasm in rats after experimental SAH possibly bysuppressing the effects of inflammation and oxidative stress[99] Vasospasm in SAH rats is also reduced by an analog of120572-melanocyte stimulating hormone and is accompanied bychanges in the expression of factors involved in tissue damageand repair [100]

6 Benefits of Combination Therapy forNeuroprotection in Stroke

Thepathology of stroke is complex withmultiple overlappingprocesses leading to either damage or protection Althoughconsiderable neuroprotection can be gained by targeting justone of these processes the potential benefit is even greaterif multiple mechanisms of damage can be suppressed at thesame time Targeting the same pathway with more than oneneuroprotective agent can also be beneficial Consequentlycombination therapy with more than one drug has provento be effective in several experimental studies The additionalbenefit may be small additive or even synergistic in somecases Progesterone plus vitamin D hormone for examplereduces infarct size and neurological deficits in tMCAO ratsto a greater extent than either treatment alone [101] Thecombination of the anti-inflammatory properties of atorvas-tatin and the antioxidant properties of probucol also producesincreased neuroprotection in pMCAO rats [102] Simvastatincombined with granulocyte colony-stimulating factor (G-CSF) reduced recovery time in a rat model of intracerebralhemorrhage and improved outcome [103] Another strategy

for combination therapy is the use of one drug to block thenegative effects of another such as tPA Mild hypothermiahigh-density lipoproteins activated protein C analog andfingolimod have all been shown to reduce the incidence ofhemorrhagic transformation following administration of tPAin several animal models [54 104ndash106]

7 Neuroprotective Treatments withPleiotropic Effects

Although combination therapy can produce additional ben-efits in some cases not all treatments are compatible witheach other Some combinationsmay have antagonistic effectsproducing less benefit than either treatment alone In somecases combination therapies may enhance damage Fur-thermore combination treatment requires significantly moretesting to determine safety and effectiveness than a singlecompound There is therefore considerable interest in thestudy of treatments with beneficial effects on more thanone mechanism of stroke-related damage Some of thesetreatments have only recently been discovered (Table 1) andare still in the early stages of investigation Others howeverhave already been the subject of considerable study and showgreat promise for the treatment of stroke as summarizedbelow

71 Minocycline Minocycline is a broad spectrum antibioticwhich in addition to its antibacterial activity also hasanti-inflammatory and antiapoptotic effects [107] Conse-quently it has been shown to be protective in a numberof diseases including stroke Minocycline is one of thefew neuroprotective agents in animal studies that has alsobeen proven effective in human trials In one recent trialoral administration of minocycline resulted in significantlyimproved outcomes as long as three months after stroke[108] Furthermore animal studies indicate that additionalbenefits are to be gained by combining minocycline withother neuroprotective strategies Minocycline reduces therisk of subsequent hemorrhage following administration oftissue plasminogen activator in diabetic rats subjected tofocal embolic stroke [109] It also reduces infarct size andsuppresses several hallmarks of inflammation Minocyclineplus normobaric hyperoxia has a synergistic effect on thereduction in infarct volume following tMCAO in rats andhas a positive effect on hemispheric swelling that was notseen with either treatment alone [110] This combinationalso resulted in greater inhibition of apoptosis and MMPactivation Minocycline improves recovery after transplanta-tion of bone marrow mononuclear cells into ischemic ratspresumably by inhibition of microglial activation [111 112] Italso preconditions neural stem cells against oxidative stressproducing reduced infarct size and improved neurologicalperformance following transplantation in rats exposed totMCAO [113]

72 Carnosine Carnosine is a naturally occurring dipeptidethat has both antioxidant and antiexcitotoxic properties [114115] It also is an efficient chelator of metal ions such as

ISRN Neurology 9

Table 1 Neuroprotective treatments with multiple beneficial effects in stroke

Treatment Species Model Benefits ReferenceITH33IQM921 Mouse Ischemia Antiexcitotoxic antioxidant Lorrio et al 2013 [131]TAT-M9 Mouse Ischemia Antioxidant antiapoptotic Guo et al 2013 [132]Glycyrrhizic acid Rat Ischemia Anti-inflammatory antiexcitotoxic and antioxidant Kim et al 2012 [133]Vitis amurensis extract Rat Ischemia Anti-inflammatory antiexcitotoxic antioxidant and antiapoptotic Kim et al 2012 [134]cis-Hinokiresinols Rat Ischemia Anti-inflammatory antioxidant Ju et al 2013 [135]Berberine Rat Ischemia Anti-inflammatory antiapoptotic Zhang et al 2012 [136]S-Nitrosoglutathione Rat Ischemia Antioxidant BBB integrity Khan et al 2012 [137]Taurine Rat Ischemia Antiexcitotoxic antioxidant and antiapoptotic Gharibani et al 2013 [138]MFG-E8 Rat Ischemia Anti-inflammatory antiapoptotic Cheyuo et al 2012 [139]Nitrone derivatives Rat Ischemia Antiexcitotoxic antioxidant Sun et al 2012 [140]

zinc which is required for the activity of matrix metallo-proteinases Preclinical studies have shown that carnosineis well tolerated and produces robust neuroprotection inanimal models of both transient and permanent ischemia[116] It also readily crosses the intact blood-brain barrierwhich allows it to be administered even in the early stagesof stroke Carnosine reduces glutamate excitotoxicity inpMCAOmice resulting in reduced infarct size and improvedneurologic function [117] In another study carnosine wasshown to decrease infarct size MMP activity and levels ofreactive oxygen species [118] Carnosine can also be cleavedby carnosinase into the amino acids alanine and histidinewhich are neuroprotective as well Bestatin an inhibitor ofcarnosinase increases damage in pMCAOmice [119]

73 Asiatic Acid Asiatic acid is a plant-derived compoundwith effects on oxidative stress inflammation and excitotox-icity that has been shown to be beneficial in the treatmentof wound healing beta-amyloid toxicity and liver injuryRecent evidence suggests that it may be neuroprotective instroke as well In pMCAO mice asiatic acid reduces infarctsize and improves neurologic scores possibly by suppressionof mitochondrial damage and BBB disruption [120] Subse-quently asiatic acid was also found to be neuroprotective inmultiple models of ischemia in rats by inhibiting mitochon-drial damage and MMP-9 activation [121] Asiatic acid alsoblocks the negative effects of excitotoxicity in mice followingexposure to glutamate [122] An extract of Centella asiaticahas been shown to improve several markers of behavioralfunction and improved the antioxidant status in tMCAO rats[123]This extract contains asiatic acid as well as several otherrelated compounds that also have neuroprotective propertiesFurther investigation of this class of molecules is thereforewarranted to determine the extent of their effects

74 Hypothermia The beneficial effects of cooling the bodyafter injury are well known and induction of hypothermiais currently used in clinical practice to prevent secondarybrain injury after cardiac arrest and resuscitation peri-natal or neonatal asphyxia and head trauma [124ndash126]Considerable evidence suggests that hypothermia may bebeneficial in the treatment of stroke as well Microarray

experiments have determined that neuroprotection result-ing from hypothermia in MCAO rats is associated withchanges in the expression of genes involved in the processesof inflammation apoptosis and calcium regulation [127]Hypothermia induction by the neurotensin receptor 1 (NTR1)agonist ABS-201 reduces infarct volume and suppresses celldeath by apoptosis and autophagy in mice subjected to focalischemia [128] A recent meta-analysis of human clinicaltrials on the other hand found no benefit of hypothermiain stroke patients [129] These trials had a limited number ofsubjects however and larger trials are currently in progressfor example EuroHYP-1 and ICTuS23 [130]

75 Flavonoids In some cases whole classes of moleculesare known for having multiple neuroprotective effects Onesuch group of compounds that are currently the subjectof intensive research are the flavonoids These moleculesare naturally occurring compounds that readily cross theblood-brain barrier and are well known for their protectiveeffectsTheflavonoids in cocoa for example have antioxidantproperties and also promote perfusion angiogenesis andneurogenesis in the brain [141] Xanthohumol has beenfound to have anti-inflammatory anti-apoptotic antioxi-dant and antithrombotic properties Following MCAO inrats xanthohumol decreases the levels of TNF120572 hypoxia-inducible factor 1 alpha (HIF-1120572) and inducible nitric oxidesynthase (iNOS) [142] It also reduces expression of activatedcaspase 3 scavenges hydroxyl radicals and inhibits plateletaggregation Treatment with naringenin results in neuropro-tection in tMCAO rats through both antioxidant and anti-inflammatorymechanisms [143] Galangin improves cerebralblood blow inhibits apoptosis and protects mitochondrialfunction after MCAO in rats [144] In tMCAO mice fisetinprotects the brain against ischemic injury by suppressingactivation of cerebral inflammatory cells and inhibiting themigration of macrophages and dendritic cells into the brain[145] In models of intracerebral hemorrhage baicalin hasbeen found to attenuate edema of the brain and inhibitapoptosis [146]

76 Cannabinoids Another major class of molecules withmultiple beneficial effects in stroke are the cannabinoids

10 ISRN Neurology

These compounds are primarily known for their anti-inflammatory effects in many diseases including stroke [147]Recently however evidence suggests that cannabinoids mayalso have antioxidant and antiapoptotic effects [148] Thecannabinoid receptor agonists WIN55212-2 and JWH-133reduce activation of microglia and macrophages after induc-tion of ischemia in mice and rats resulting in reduced infarctsize and neurological impairment as well as protection ofoligodendrocyte precursor cells [149ndash151] Another receptoragonist TAK-937 provides neuroprotection in tMCAO ratsand the neuroprotective effect is increased when given incombinationwith hypothermia [152] Furthermore TAK-937not only is effective in rodent models of stroke but also hasbeen shown to reduce infarct volume in nonhuman primates[153] This specific compound is therefore of considerableinterest for future use in human trials

8 Neuroprotective Agents in HumanClinical Stroke Trials

Perhaps the greatest challenge in the study of neuroprotectionin stroke is the translation of animal studies to humansNumerous treatments that produce robust protection inrodents have failed to provide significant benefit in clinicaltrials The various theories on the reason for this failure havealready been discussed elsewhere and will not be coveredhere [5 154 155] Amid the abundance of discouragingresults however a small number of neuroprotective strategieshave shown promise in human stroke patients A briefsummary of recently completed clinical trials for the studyof neuroprotection in ischemic stroke and subarachnoidhemorrhage is provided below A discussion of recent clinicaltrials for neuroprotection in intracerebral hemorrhage isalready available [8]

81 International Citicoline Trial on Acute Stroke (ICTUS)Citicoline is a nutritional supplement that not only is com-monly used to improve memory retention but also has beenshown to prevent neuronal degeneration and improve visualfunction It has already been approved in some countriesfor the treatment of acute ischemic stroke A randomizedplacebo controlled trial was conducted to evaluate the effi-cacy of citicoline in patients with moderate to severe acuteischemic stroke [156] A total of 2298 patients were admin-istered either citicoline (1000mg every 12 hours) or placebofor up to 6 weeks Outcome was determined at 90 days basedon the National Institute of Health Stroke Scale (NIHSS)modified Rankin Scale (mRS) and modified Barthel Index(mBI scores) plus the occurrence of intracranial hemorrhageneurologic deterioration or death No significant differencein recovery was observed between the citicoline and placebotreatment groups

82 Minocycline Minocycline is an oral antibiotic withproven safety over years of use In addition to its antibioticproperties minocycline also has anti-inflammatory and anti-apoptotic effects that have been shown to be neuroprotectivein animal models of stroke and in previous human trials

The efficacy of oral minocycline was examined in arecent single-blinded open-label study [108] Fifty patientswith acute ischemic stroke were given either minocycline(200mgday) or placebo for five days and assessed for variousindicators of outcome at 1 7 30 and 90 days Patientsreceiving minocycline showed significant improvement after30 days in NIHSS mBI and mRS scores NIHSS scorescontinued to be significantly improved at 90 days Largerphase II and phase III trials are awaited

83 Cerebrolysin Cerebrolysin is a mixture of peptide frag-ments that mimics the action of neurotrophic factors andhas been shown to be neuroprotective in a number of condi-tions such as hyperthermia-induced neurotoxicity vasculardementia Alzheimerrsquos disease traumatic brain injury andstroke A large double-blind clinical trial was conducted totest the efficacy and safety of Cerebrolysin in patients withacute ischemic stroke [157] A total of 1070 patients wereadministered aspirin and either Cerebrolysin (30mLday) orplacebo over a period of 10 days Although no significantdifference between treatment groups was seen after 90 days apositive trendwas seen in those patients with anNIHSS scoregreater than 12

84 Ginsenoside-Rd Ginsenoside-Rd is a calcium channelantagonist that has been previously shown to be neuropro-tective in human trials An extended trial of ginsenoside-Rdwas performed in 390 patients with acute ischemic stroke[158] Subjects were administered ginsenoside-Rd or placebointravenously over a 14-day period and evaluated usingNIHSS and mRS scores for 90 days Significant improvementwas seen with ginsenoside-Rd in NIHSS scores at 15 days andmRS scores at 90 days

85 Granulocyte-Colony Stimulating Factor (G-CSF) G-CSFis a growth factor that stimulates the production and releaseof hematopoietic stem cells in bone marrow and may bebeneficial in the enhancement of recovery after stroke Thesafety of G-CSFwas examined in a randomized phase IIb trial[159] A total of 60 patients with either ischemic or hemor-rhagic stroke were given G-CSF (10 120583gkg) or placebo over 5days and monitored for the frequency of adverse effects G-CSF significantly increased white cell counts and produced atrend toward reduced infarct volume No difference was seenbetween treatment groups in the frequency of adverse effects

86 Evaluating Neuroprotection in Aneurysm Coiling Ther-apy (ENACT) Trial The compound known as NA-1 (Tat-NR2B9c) is an inhibitor of the postsynaptic density-95 (PSD-95) protein that is neuroprotective in primate models ofstroke PSD-95 associates with theNMDAglutamate receptorsubtype and contributes to the process of excitotoxicitywhich is suppressed by treatment with NA-1 The safety andefficacy of NA-1 after endovascular aneurysm repair wereexamined in patients with iatrogenic stroke [160] A totalof 185 patients were treated for a ruptured or unrupturedintracranial aneurysm by endovascular coiling followedby administration of NA-1 or placebo Evaluative criteria

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

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[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

ISRN Neurology 7

Insulin receptorIRS

InsulinCalcium

CaMKK

ATP LKB1 AMPK PI3K

DNA damagehypoxiastress

HIF1 REDD1 TSC1TSC2 AKT PDK1

RHEB

mTORRAPTOR

ATG1ATG13

Amino acid deprivation

RapamycinFKBP12

JNKEndoplasmic reticulum stress

BCL2 ERK

ATG6ATG14

ATG10

ATG5ATG12ATG16 ATG7 ATG4

LC3-II LC3-I LC3

ATG3Induction

Isolation membrane

Nucleation

Phagophore Elongation

Autophagosome

Autolysosome

Lysosome

Fusion

Figure 3 The process of autophagy and its regulation Induction of autophagy is inhibited by mTOR the activity of which is controlledby numerous upstream signaling pathways that respond to metabolic activity energy status and tissue damage Progression of autophagyrequires several members of the ATG protein family leading to the production of a membranous structure that engulfs damaged cellularcomponents to form the autophagosome Subsequent fusion of the autophagosome with a lysosome results in degradation of the damagedcomponents Proteins involved in the regulation of autophagy are shown in shaded boxes Positive interactions are denoted by arrows andnegative interactions by lines with flat ends

Postconditioning inhibits MMP9 expression and subsequentdegradation of the extracellular matrix in MCAO rats [93]Ischemic tolerance in the brain can also be stimulatedremotely for example by application of a tourniquet to oneof the limbs Remote preconditioning is protective in amouseembolic stroke model both by itself and in combination with

tissue plasminogen activator [94] It also provides protectionby upregulation of eNOS in rats subjected to global ischemiaand reperfusion [95] Remote preconditioning has even beenshown to have beneficial effects in human patients withsubarachnoid hemorrhage but further studies are needed[96]

8 ISRN Neurology

5 Neuroprotection in Hemorrhagic Stroke

The pathologies of ischemic and hemorrhagic stroke sharemany of the same damaging processes such as inflamma-tion oxidative stress and excitotoxicity Treatments that areneuroprotective in one may also be beneficial in the otherand several examples of protection in models of hemorrhagicstroke have already been given in the previous sectionsProcesses such as cytotoxicity however are unique to hemor-rhagic stroke and are directly related to the accumulation ofblood in the brain Multiple blood components are believedto contribute to tissue damage after hemorrhage particularlyhemoglobin Haptoglobin and hemopexin are endogenousproteins that bind and remove hemoglobin and its degrada-tion products respectively and enhancement of their activitymay be protective [3] Heme oxygenase (HO) is anotherendogenous protein that converts heme to iron and otherproducts Free iron reacts with hydrogen peroxide to formhydroxyl radicals leading to oxidative stress Inhibition ofHO or chelation of iron by agents such as deferoxamine couldhave beneficial effects Valproic acid decreases the expressionof HO-1 following ICH in rats and attenuated cell death[97] Combination treatment of deferoxamine and statinshas been associated with improved results in behavioral testsin rats after ICH [98] In addition to cytotoxicity cerebralvasospasm is a significant contributor to death and disabilityafter subarachnoid hemorrhage Because of its serious naturea considerable amount of research is dedicated to mitigatingits effects Hydrogen-rich saline has been shown to decreasevasospasm in rats after experimental SAH possibly bysuppressing the effects of inflammation and oxidative stress[99] Vasospasm in SAH rats is also reduced by an analog of120572-melanocyte stimulating hormone and is accompanied bychanges in the expression of factors involved in tissue damageand repair [100]

6 Benefits of Combination Therapy forNeuroprotection in Stroke

Thepathology of stroke is complex withmultiple overlappingprocesses leading to either damage or protection Althoughconsiderable neuroprotection can be gained by targeting justone of these processes the potential benefit is even greaterif multiple mechanisms of damage can be suppressed at thesame time Targeting the same pathway with more than oneneuroprotective agent can also be beneficial Consequentlycombination therapy with more than one drug has provento be effective in several experimental studies The additionalbenefit may be small additive or even synergistic in somecases Progesterone plus vitamin D hormone for examplereduces infarct size and neurological deficits in tMCAO ratsto a greater extent than either treatment alone [101] Thecombination of the anti-inflammatory properties of atorvas-tatin and the antioxidant properties of probucol also producesincreased neuroprotection in pMCAO rats [102] Simvastatincombined with granulocyte colony-stimulating factor (G-CSF) reduced recovery time in a rat model of intracerebralhemorrhage and improved outcome [103] Another strategy

for combination therapy is the use of one drug to block thenegative effects of another such as tPA Mild hypothermiahigh-density lipoproteins activated protein C analog andfingolimod have all been shown to reduce the incidence ofhemorrhagic transformation following administration of tPAin several animal models [54 104ndash106]

7 Neuroprotective Treatments withPleiotropic Effects

Although combination therapy can produce additional ben-efits in some cases not all treatments are compatible witheach other Some combinationsmay have antagonistic effectsproducing less benefit than either treatment alone In somecases combination therapies may enhance damage Fur-thermore combination treatment requires significantly moretesting to determine safety and effectiveness than a singlecompound There is therefore considerable interest in thestudy of treatments with beneficial effects on more thanone mechanism of stroke-related damage Some of thesetreatments have only recently been discovered (Table 1) andare still in the early stages of investigation Others howeverhave already been the subject of considerable study and showgreat promise for the treatment of stroke as summarizedbelow

71 Minocycline Minocycline is a broad spectrum antibioticwhich in addition to its antibacterial activity also hasanti-inflammatory and antiapoptotic effects [107] Conse-quently it has been shown to be protective in a numberof diseases including stroke Minocycline is one of thefew neuroprotective agents in animal studies that has alsobeen proven effective in human trials In one recent trialoral administration of minocycline resulted in significantlyimproved outcomes as long as three months after stroke[108] Furthermore animal studies indicate that additionalbenefits are to be gained by combining minocycline withother neuroprotective strategies Minocycline reduces therisk of subsequent hemorrhage following administration oftissue plasminogen activator in diabetic rats subjected tofocal embolic stroke [109] It also reduces infarct size andsuppresses several hallmarks of inflammation Minocyclineplus normobaric hyperoxia has a synergistic effect on thereduction in infarct volume following tMCAO in rats andhas a positive effect on hemispheric swelling that was notseen with either treatment alone [110] This combinationalso resulted in greater inhibition of apoptosis and MMPactivation Minocycline improves recovery after transplanta-tion of bone marrow mononuclear cells into ischemic ratspresumably by inhibition of microglial activation [111 112] Italso preconditions neural stem cells against oxidative stressproducing reduced infarct size and improved neurologicalperformance following transplantation in rats exposed totMCAO [113]

72 Carnosine Carnosine is a naturally occurring dipeptidethat has both antioxidant and antiexcitotoxic properties [114115] It also is an efficient chelator of metal ions such as

ISRN Neurology 9

Table 1 Neuroprotective treatments with multiple beneficial effects in stroke

Treatment Species Model Benefits ReferenceITH33IQM921 Mouse Ischemia Antiexcitotoxic antioxidant Lorrio et al 2013 [131]TAT-M9 Mouse Ischemia Antioxidant antiapoptotic Guo et al 2013 [132]Glycyrrhizic acid Rat Ischemia Anti-inflammatory antiexcitotoxic and antioxidant Kim et al 2012 [133]Vitis amurensis extract Rat Ischemia Anti-inflammatory antiexcitotoxic antioxidant and antiapoptotic Kim et al 2012 [134]cis-Hinokiresinols Rat Ischemia Anti-inflammatory antioxidant Ju et al 2013 [135]Berberine Rat Ischemia Anti-inflammatory antiapoptotic Zhang et al 2012 [136]S-Nitrosoglutathione Rat Ischemia Antioxidant BBB integrity Khan et al 2012 [137]Taurine Rat Ischemia Antiexcitotoxic antioxidant and antiapoptotic Gharibani et al 2013 [138]MFG-E8 Rat Ischemia Anti-inflammatory antiapoptotic Cheyuo et al 2012 [139]Nitrone derivatives Rat Ischemia Antiexcitotoxic antioxidant Sun et al 2012 [140]

zinc which is required for the activity of matrix metallo-proteinases Preclinical studies have shown that carnosineis well tolerated and produces robust neuroprotection inanimal models of both transient and permanent ischemia[116] It also readily crosses the intact blood-brain barrierwhich allows it to be administered even in the early stagesof stroke Carnosine reduces glutamate excitotoxicity inpMCAOmice resulting in reduced infarct size and improvedneurologic function [117] In another study carnosine wasshown to decrease infarct size MMP activity and levels ofreactive oxygen species [118] Carnosine can also be cleavedby carnosinase into the amino acids alanine and histidinewhich are neuroprotective as well Bestatin an inhibitor ofcarnosinase increases damage in pMCAOmice [119]

73 Asiatic Acid Asiatic acid is a plant-derived compoundwith effects on oxidative stress inflammation and excitotox-icity that has been shown to be beneficial in the treatmentof wound healing beta-amyloid toxicity and liver injuryRecent evidence suggests that it may be neuroprotective instroke as well In pMCAO mice asiatic acid reduces infarctsize and improves neurologic scores possibly by suppressionof mitochondrial damage and BBB disruption [120] Subse-quently asiatic acid was also found to be neuroprotective inmultiple models of ischemia in rats by inhibiting mitochon-drial damage and MMP-9 activation [121] Asiatic acid alsoblocks the negative effects of excitotoxicity in mice followingexposure to glutamate [122] An extract of Centella asiaticahas been shown to improve several markers of behavioralfunction and improved the antioxidant status in tMCAO rats[123]This extract contains asiatic acid as well as several otherrelated compounds that also have neuroprotective propertiesFurther investigation of this class of molecules is thereforewarranted to determine the extent of their effects

74 Hypothermia The beneficial effects of cooling the bodyafter injury are well known and induction of hypothermiais currently used in clinical practice to prevent secondarybrain injury after cardiac arrest and resuscitation peri-natal or neonatal asphyxia and head trauma [124ndash126]Considerable evidence suggests that hypothermia may bebeneficial in the treatment of stroke as well Microarray

experiments have determined that neuroprotection result-ing from hypothermia in MCAO rats is associated withchanges in the expression of genes involved in the processesof inflammation apoptosis and calcium regulation [127]Hypothermia induction by the neurotensin receptor 1 (NTR1)agonist ABS-201 reduces infarct volume and suppresses celldeath by apoptosis and autophagy in mice subjected to focalischemia [128] A recent meta-analysis of human clinicaltrials on the other hand found no benefit of hypothermiain stroke patients [129] These trials had a limited number ofsubjects however and larger trials are currently in progressfor example EuroHYP-1 and ICTuS23 [130]

75 Flavonoids In some cases whole classes of moleculesare known for having multiple neuroprotective effects Onesuch group of compounds that are currently the subjectof intensive research are the flavonoids These moleculesare naturally occurring compounds that readily cross theblood-brain barrier and are well known for their protectiveeffectsTheflavonoids in cocoa for example have antioxidantproperties and also promote perfusion angiogenesis andneurogenesis in the brain [141] Xanthohumol has beenfound to have anti-inflammatory anti-apoptotic antioxi-dant and antithrombotic properties Following MCAO inrats xanthohumol decreases the levels of TNF120572 hypoxia-inducible factor 1 alpha (HIF-1120572) and inducible nitric oxidesynthase (iNOS) [142] It also reduces expression of activatedcaspase 3 scavenges hydroxyl radicals and inhibits plateletaggregation Treatment with naringenin results in neuropro-tection in tMCAO rats through both antioxidant and anti-inflammatorymechanisms [143] Galangin improves cerebralblood blow inhibits apoptosis and protects mitochondrialfunction after MCAO in rats [144] In tMCAO mice fisetinprotects the brain against ischemic injury by suppressingactivation of cerebral inflammatory cells and inhibiting themigration of macrophages and dendritic cells into the brain[145] In models of intracerebral hemorrhage baicalin hasbeen found to attenuate edema of the brain and inhibitapoptosis [146]

76 Cannabinoids Another major class of molecules withmultiple beneficial effects in stroke are the cannabinoids

10 ISRN Neurology

These compounds are primarily known for their anti-inflammatory effects in many diseases including stroke [147]Recently however evidence suggests that cannabinoids mayalso have antioxidant and antiapoptotic effects [148] Thecannabinoid receptor agonists WIN55212-2 and JWH-133reduce activation of microglia and macrophages after induc-tion of ischemia in mice and rats resulting in reduced infarctsize and neurological impairment as well as protection ofoligodendrocyte precursor cells [149ndash151] Another receptoragonist TAK-937 provides neuroprotection in tMCAO ratsand the neuroprotective effect is increased when given incombinationwith hypothermia [152] Furthermore TAK-937not only is effective in rodent models of stroke but also hasbeen shown to reduce infarct volume in nonhuman primates[153] This specific compound is therefore of considerableinterest for future use in human trials

8 Neuroprotective Agents in HumanClinical Stroke Trials

Perhaps the greatest challenge in the study of neuroprotectionin stroke is the translation of animal studies to humansNumerous treatments that produce robust protection inrodents have failed to provide significant benefit in clinicaltrials The various theories on the reason for this failure havealready been discussed elsewhere and will not be coveredhere [5 154 155] Amid the abundance of discouragingresults however a small number of neuroprotective strategieshave shown promise in human stroke patients A briefsummary of recently completed clinical trials for the studyof neuroprotection in ischemic stroke and subarachnoidhemorrhage is provided below A discussion of recent clinicaltrials for neuroprotection in intracerebral hemorrhage isalready available [8]

81 International Citicoline Trial on Acute Stroke (ICTUS)Citicoline is a nutritional supplement that not only is com-monly used to improve memory retention but also has beenshown to prevent neuronal degeneration and improve visualfunction It has already been approved in some countriesfor the treatment of acute ischemic stroke A randomizedplacebo controlled trial was conducted to evaluate the effi-cacy of citicoline in patients with moderate to severe acuteischemic stroke [156] A total of 2298 patients were admin-istered either citicoline (1000mg every 12 hours) or placebofor up to 6 weeks Outcome was determined at 90 days basedon the National Institute of Health Stroke Scale (NIHSS)modified Rankin Scale (mRS) and modified Barthel Index(mBI scores) plus the occurrence of intracranial hemorrhageneurologic deterioration or death No significant differencein recovery was observed between the citicoline and placebotreatment groups

82 Minocycline Minocycline is an oral antibiotic withproven safety over years of use In addition to its antibioticproperties minocycline also has anti-inflammatory and anti-apoptotic effects that have been shown to be neuroprotectivein animal models of stroke and in previous human trials

The efficacy of oral minocycline was examined in arecent single-blinded open-label study [108] Fifty patientswith acute ischemic stroke were given either minocycline(200mgday) or placebo for five days and assessed for variousindicators of outcome at 1 7 30 and 90 days Patientsreceiving minocycline showed significant improvement after30 days in NIHSS mBI and mRS scores NIHSS scorescontinued to be significantly improved at 90 days Largerphase II and phase III trials are awaited

83 Cerebrolysin Cerebrolysin is a mixture of peptide frag-ments that mimics the action of neurotrophic factors andhas been shown to be neuroprotective in a number of condi-tions such as hyperthermia-induced neurotoxicity vasculardementia Alzheimerrsquos disease traumatic brain injury andstroke A large double-blind clinical trial was conducted totest the efficacy and safety of Cerebrolysin in patients withacute ischemic stroke [157] A total of 1070 patients wereadministered aspirin and either Cerebrolysin (30mLday) orplacebo over a period of 10 days Although no significantdifference between treatment groups was seen after 90 days apositive trendwas seen in those patients with anNIHSS scoregreater than 12

84 Ginsenoside-Rd Ginsenoside-Rd is a calcium channelantagonist that has been previously shown to be neuropro-tective in human trials An extended trial of ginsenoside-Rdwas performed in 390 patients with acute ischemic stroke[158] Subjects were administered ginsenoside-Rd or placebointravenously over a 14-day period and evaluated usingNIHSS and mRS scores for 90 days Significant improvementwas seen with ginsenoside-Rd in NIHSS scores at 15 days andmRS scores at 90 days

85 Granulocyte-Colony Stimulating Factor (G-CSF) G-CSFis a growth factor that stimulates the production and releaseof hematopoietic stem cells in bone marrow and may bebeneficial in the enhancement of recovery after stroke Thesafety of G-CSFwas examined in a randomized phase IIb trial[159] A total of 60 patients with either ischemic or hemor-rhagic stroke were given G-CSF (10 120583gkg) or placebo over 5days and monitored for the frequency of adverse effects G-CSF significantly increased white cell counts and produced atrend toward reduced infarct volume No difference was seenbetween treatment groups in the frequency of adverse effects

86 Evaluating Neuroprotection in Aneurysm Coiling Ther-apy (ENACT) Trial The compound known as NA-1 (Tat-NR2B9c) is an inhibitor of the postsynaptic density-95 (PSD-95) protein that is neuroprotective in primate models ofstroke PSD-95 associates with theNMDAglutamate receptorsubtype and contributes to the process of excitotoxicitywhich is suppressed by treatment with NA-1 The safety andefficacy of NA-1 after endovascular aneurysm repair wereexamined in patients with iatrogenic stroke [160] A totalof 185 patients were treated for a ruptured or unrupturedintracranial aneurysm by endovascular coiling followedby administration of NA-1 or placebo Evaluative criteria

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

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[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

8 ISRN Neurology

5 Neuroprotection in Hemorrhagic Stroke

The pathologies of ischemic and hemorrhagic stroke sharemany of the same damaging processes such as inflamma-tion oxidative stress and excitotoxicity Treatments that areneuroprotective in one may also be beneficial in the otherand several examples of protection in models of hemorrhagicstroke have already been given in the previous sectionsProcesses such as cytotoxicity however are unique to hemor-rhagic stroke and are directly related to the accumulation ofblood in the brain Multiple blood components are believedto contribute to tissue damage after hemorrhage particularlyhemoglobin Haptoglobin and hemopexin are endogenousproteins that bind and remove hemoglobin and its degrada-tion products respectively and enhancement of their activitymay be protective [3] Heme oxygenase (HO) is anotherendogenous protein that converts heme to iron and otherproducts Free iron reacts with hydrogen peroxide to formhydroxyl radicals leading to oxidative stress Inhibition ofHO or chelation of iron by agents such as deferoxamine couldhave beneficial effects Valproic acid decreases the expressionof HO-1 following ICH in rats and attenuated cell death[97] Combination treatment of deferoxamine and statinshas been associated with improved results in behavioral testsin rats after ICH [98] In addition to cytotoxicity cerebralvasospasm is a significant contributor to death and disabilityafter subarachnoid hemorrhage Because of its serious naturea considerable amount of research is dedicated to mitigatingits effects Hydrogen-rich saline has been shown to decreasevasospasm in rats after experimental SAH possibly bysuppressing the effects of inflammation and oxidative stress[99] Vasospasm in SAH rats is also reduced by an analog of120572-melanocyte stimulating hormone and is accompanied bychanges in the expression of factors involved in tissue damageand repair [100]

6 Benefits of Combination Therapy forNeuroprotection in Stroke

Thepathology of stroke is complex withmultiple overlappingprocesses leading to either damage or protection Althoughconsiderable neuroprotection can be gained by targeting justone of these processes the potential benefit is even greaterif multiple mechanisms of damage can be suppressed at thesame time Targeting the same pathway with more than oneneuroprotective agent can also be beneficial Consequentlycombination therapy with more than one drug has provento be effective in several experimental studies The additionalbenefit may be small additive or even synergistic in somecases Progesterone plus vitamin D hormone for examplereduces infarct size and neurological deficits in tMCAO ratsto a greater extent than either treatment alone [101] Thecombination of the anti-inflammatory properties of atorvas-tatin and the antioxidant properties of probucol also producesincreased neuroprotection in pMCAO rats [102] Simvastatincombined with granulocyte colony-stimulating factor (G-CSF) reduced recovery time in a rat model of intracerebralhemorrhage and improved outcome [103] Another strategy

for combination therapy is the use of one drug to block thenegative effects of another such as tPA Mild hypothermiahigh-density lipoproteins activated protein C analog andfingolimod have all been shown to reduce the incidence ofhemorrhagic transformation following administration of tPAin several animal models [54 104ndash106]

7 Neuroprotective Treatments withPleiotropic Effects

Although combination therapy can produce additional ben-efits in some cases not all treatments are compatible witheach other Some combinationsmay have antagonistic effectsproducing less benefit than either treatment alone In somecases combination therapies may enhance damage Fur-thermore combination treatment requires significantly moretesting to determine safety and effectiveness than a singlecompound There is therefore considerable interest in thestudy of treatments with beneficial effects on more thanone mechanism of stroke-related damage Some of thesetreatments have only recently been discovered (Table 1) andare still in the early stages of investigation Others howeverhave already been the subject of considerable study and showgreat promise for the treatment of stroke as summarizedbelow

71 Minocycline Minocycline is a broad spectrum antibioticwhich in addition to its antibacterial activity also hasanti-inflammatory and antiapoptotic effects [107] Conse-quently it has been shown to be protective in a numberof diseases including stroke Minocycline is one of thefew neuroprotective agents in animal studies that has alsobeen proven effective in human trials In one recent trialoral administration of minocycline resulted in significantlyimproved outcomes as long as three months after stroke[108] Furthermore animal studies indicate that additionalbenefits are to be gained by combining minocycline withother neuroprotective strategies Minocycline reduces therisk of subsequent hemorrhage following administration oftissue plasminogen activator in diabetic rats subjected tofocal embolic stroke [109] It also reduces infarct size andsuppresses several hallmarks of inflammation Minocyclineplus normobaric hyperoxia has a synergistic effect on thereduction in infarct volume following tMCAO in rats andhas a positive effect on hemispheric swelling that was notseen with either treatment alone [110] This combinationalso resulted in greater inhibition of apoptosis and MMPactivation Minocycline improves recovery after transplanta-tion of bone marrow mononuclear cells into ischemic ratspresumably by inhibition of microglial activation [111 112] Italso preconditions neural stem cells against oxidative stressproducing reduced infarct size and improved neurologicalperformance following transplantation in rats exposed totMCAO [113]

72 Carnosine Carnosine is a naturally occurring dipeptidethat has both antioxidant and antiexcitotoxic properties [114115] It also is an efficient chelator of metal ions such as

ISRN Neurology 9

Table 1 Neuroprotective treatments with multiple beneficial effects in stroke

Treatment Species Model Benefits ReferenceITH33IQM921 Mouse Ischemia Antiexcitotoxic antioxidant Lorrio et al 2013 [131]TAT-M9 Mouse Ischemia Antioxidant antiapoptotic Guo et al 2013 [132]Glycyrrhizic acid Rat Ischemia Anti-inflammatory antiexcitotoxic and antioxidant Kim et al 2012 [133]Vitis amurensis extract Rat Ischemia Anti-inflammatory antiexcitotoxic antioxidant and antiapoptotic Kim et al 2012 [134]cis-Hinokiresinols Rat Ischemia Anti-inflammatory antioxidant Ju et al 2013 [135]Berberine Rat Ischemia Anti-inflammatory antiapoptotic Zhang et al 2012 [136]S-Nitrosoglutathione Rat Ischemia Antioxidant BBB integrity Khan et al 2012 [137]Taurine Rat Ischemia Antiexcitotoxic antioxidant and antiapoptotic Gharibani et al 2013 [138]MFG-E8 Rat Ischemia Anti-inflammatory antiapoptotic Cheyuo et al 2012 [139]Nitrone derivatives Rat Ischemia Antiexcitotoxic antioxidant Sun et al 2012 [140]

zinc which is required for the activity of matrix metallo-proteinases Preclinical studies have shown that carnosineis well tolerated and produces robust neuroprotection inanimal models of both transient and permanent ischemia[116] It also readily crosses the intact blood-brain barrierwhich allows it to be administered even in the early stagesof stroke Carnosine reduces glutamate excitotoxicity inpMCAOmice resulting in reduced infarct size and improvedneurologic function [117] In another study carnosine wasshown to decrease infarct size MMP activity and levels ofreactive oxygen species [118] Carnosine can also be cleavedby carnosinase into the amino acids alanine and histidinewhich are neuroprotective as well Bestatin an inhibitor ofcarnosinase increases damage in pMCAOmice [119]

73 Asiatic Acid Asiatic acid is a plant-derived compoundwith effects on oxidative stress inflammation and excitotox-icity that has been shown to be beneficial in the treatmentof wound healing beta-amyloid toxicity and liver injuryRecent evidence suggests that it may be neuroprotective instroke as well In pMCAO mice asiatic acid reduces infarctsize and improves neurologic scores possibly by suppressionof mitochondrial damage and BBB disruption [120] Subse-quently asiatic acid was also found to be neuroprotective inmultiple models of ischemia in rats by inhibiting mitochon-drial damage and MMP-9 activation [121] Asiatic acid alsoblocks the negative effects of excitotoxicity in mice followingexposure to glutamate [122] An extract of Centella asiaticahas been shown to improve several markers of behavioralfunction and improved the antioxidant status in tMCAO rats[123]This extract contains asiatic acid as well as several otherrelated compounds that also have neuroprotective propertiesFurther investigation of this class of molecules is thereforewarranted to determine the extent of their effects

74 Hypothermia The beneficial effects of cooling the bodyafter injury are well known and induction of hypothermiais currently used in clinical practice to prevent secondarybrain injury after cardiac arrest and resuscitation peri-natal or neonatal asphyxia and head trauma [124ndash126]Considerable evidence suggests that hypothermia may bebeneficial in the treatment of stroke as well Microarray

experiments have determined that neuroprotection result-ing from hypothermia in MCAO rats is associated withchanges in the expression of genes involved in the processesof inflammation apoptosis and calcium regulation [127]Hypothermia induction by the neurotensin receptor 1 (NTR1)agonist ABS-201 reduces infarct volume and suppresses celldeath by apoptosis and autophagy in mice subjected to focalischemia [128] A recent meta-analysis of human clinicaltrials on the other hand found no benefit of hypothermiain stroke patients [129] These trials had a limited number ofsubjects however and larger trials are currently in progressfor example EuroHYP-1 and ICTuS23 [130]

75 Flavonoids In some cases whole classes of moleculesare known for having multiple neuroprotective effects Onesuch group of compounds that are currently the subjectof intensive research are the flavonoids These moleculesare naturally occurring compounds that readily cross theblood-brain barrier and are well known for their protectiveeffectsTheflavonoids in cocoa for example have antioxidantproperties and also promote perfusion angiogenesis andneurogenesis in the brain [141] Xanthohumol has beenfound to have anti-inflammatory anti-apoptotic antioxi-dant and antithrombotic properties Following MCAO inrats xanthohumol decreases the levels of TNF120572 hypoxia-inducible factor 1 alpha (HIF-1120572) and inducible nitric oxidesynthase (iNOS) [142] It also reduces expression of activatedcaspase 3 scavenges hydroxyl radicals and inhibits plateletaggregation Treatment with naringenin results in neuropro-tection in tMCAO rats through both antioxidant and anti-inflammatorymechanisms [143] Galangin improves cerebralblood blow inhibits apoptosis and protects mitochondrialfunction after MCAO in rats [144] In tMCAO mice fisetinprotects the brain against ischemic injury by suppressingactivation of cerebral inflammatory cells and inhibiting themigration of macrophages and dendritic cells into the brain[145] In models of intracerebral hemorrhage baicalin hasbeen found to attenuate edema of the brain and inhibitapoptosis [146]

76 Cannabinoids Another major class of molecules withmultiple beneficial effects in stroke are the cannabinoids

10 ISRN Neurology

These compounds are primarily known for their anti-inflammatory effects in many diseases including stroke [147]Recently however evidence suggests that cannabinoids mayalso have antioxidant and antiapoptotic effects [148] Thecannabinoid receptor agonists WIN55212-2 and JWH-133reduce activation of microglia and macrophages after induc-tion of ischemia in mice and rats resulting in reduced infarctsize and neurological impairment as well as protection ofoligodendrocyte precursor cells [149ndash151] Another receptoragonist TAK-937 provides neuroprotection in tMCAO ratsand the neuroprotective effect is increased when given incombinationwith hypothermia [152] Furthermore TAK-937not only is effective in rodent models of stroke but also hasbeen shown to reduce infarct volume in nonhuman primates[153] This specific compound is therefore of considerableinterest for future use in human trials

8 Neuroprotective Agents in HumanClinical Stroke Trials

Perhaps the greatest challenge in the study of neuroprotectionin stroke is the translation of animal studies to humansNumerous treatments that produce robust protection inrodents have failed to provide significant benefit in clinicaltrials The various theories on the reason for this failure havealready been discussed elsewhere and will not be coveredhere [5 154 155] Amid the abundance of discouragingresults however a small number of neuroprotective strategieshave shown promise in human stroke patients A briefsummary of recently completed clinical trials for the studyof neuroprotection in ischemic stroke and subarachnoidhemorrhage is provided below A discussion of recent clinicaltrials for neuroprotection in intracerebral hemorrhage isalready available [8]

81 International Citicoline Trial on Acute Stroke (ICTUS)Citicoline is a nutritional supplement that not only is com-monly used to improve memory retention but also has beenshown to prevent neuronal degeneration and improve visualfunction It has already been approved in some countriesfor the treatment of acute ischemic stroke A randomizedplacebo controlled trial was conducted to evaluate the effi-cacy of citicoline in patients with moderate to severe acuteischemic stroke [156] A total of 2298 patients were admin-istered either citicoline (1000mg every 12 hours) or placebofor up to 6 weeks Outcome was determined at 90 days basedon the National Institute of Health Stroke Scale (NIHSS)modified Rankin Scale (mRS) and modified Barthel Index(mBI scores) plus the occurrence of intracranial hemorrhageneurologic deterioration or death No significant differencein recovery was observed between the citicoline and placebotreatment groups

82 Minocycline Minocycline is an oral antibiotic withproven safety over years of use In addition to its antibioticproperties minocycline also has anti-inflammatory and anti-apoptotic effects that have been shown to be neuroprotectivein animal models of stroke and in previous human trials

The efficacy of oral minocycline was examined in arecent single-blinded open-label study [108] Fifty patientswith acute ischemic stroke were given either minocycline(200mgday) or placebo for five days and assessed for variousindicators of outcome at 1 7 30 and 90 days Patientsreceiving minocycline showed significant improvement after30 days in NIHSS mBI and mRS scores NIHSS scorescontinued to be significantly improved at 90 days Largerphase II and phase III trials are awaited

83 Cerebrolysin Cerebrolysin is a mixture of peptide frag-ments that mimics the action of neurotrophic factors andhas been shown to be neuroprotective in a number of condi-tions such as hyperthermia-induced neurotoxicity vasculardementia Alzheimerrsquos disease traumatic brain injury andstroke A large double-blind clinical trial was conducted totest the efficacy and safety of Cerebrolysin in patients withacute ischemic stroke [157] A total of 1070 patients wereadministered aspirin and either Cerebrolysin (30mLday) orplacebo over a period of 10 days Although no significantdifference between treatment groups was seen after 90 days apositive trendwas seen in those patients with anNIHSS scoregreater than 12

84 Ginsenoside-Rd Ginsenoside-Rd is a calcium channelantagonist that has been previously shown to be neuropro-tective in human trials An extended trial of ginsenoside-Rdwas performed in 390 patients with acute ischemic stroke[158] Subjects were administered ginsenoside-Rd or placebointravenously over a 14-day period and evaluated usingNIHSS and mRS scores for 90 days Significant improvementwas seen with ginsenoside-Rd in NIHSS scores at 15 days andmRS scores at 90 days

85 Granulocyte-Colony Stimulating Factor (G-CSF) G-CSFis a growth factor that stimulates the production and releaseof hematopoietic stem cells in bone marrow and may bebeneficial in the enhancement of recovery after stroke Thesafety of G-CSFwas examined in a randomized phase IIb trial[159] A total of 60 patients with either ischemic or hemor-rhagic stroke were given G-CSF (10 120583gkg) or placebo over 5days and monitored for the frequency of adverse effects G-CSF significantly increased white cell counts and produced atrend toward reduced infarct volume No difference was seenbetween treatment groups in the frequency of adverse effects

86 Evaluating Neuroprotection in Aneurysm Coiling Ther-apy (ENACT) Trial The compound known as NA-1 (Tat-NR2B9c) is an inhibitor of the postsynaptic density-95 (PSD-95) protein that is neuroprotective in primate models ofstroke PSD-95 associates with theNMDAglutamate receptorsubtype and contributes to the process of excitotoxicitywhich is suppressed by treatment with NA-1 The safety andefficacy of NA-1 after endovascular aneurysm repair wereexamined in patients with iatrogenic stroke [160] A totalof 185 patients were treated for a ruptured or unrupturedintracranial aneurysm by endovascular coiling followedby administration of NA-1 or placebo Evaluative criteria

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

[1] S D Reed S C CramerD K Blough KMeyer and J G JarvikldquoTreatment with tissue plasminogen activator and inpatientmortality rates for patients with ischemic stroke treated incommunity hospitalsrdquo Stroke vol 32 no 8 pp 1832ndash1839 2001

[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

ISRN Neurology 9

Table 1 Neuroprotective treatments with multiple beneficial effects in stroke

Treatment Species Model Benefits ReferenceITH33IQM921 Mouse Ischemia Antiexcitotoxic antioxidant Lorrio et al 2013 [131]TAT-M9 Mouse Ischemia Antioxidant antiapoptotic Guo et al 2013 [132]Glycyrrhizic acid Rat Ischemia Anti-inflammatory antiexcitotoxic and antioxidant Kim et al 2012 [133]Vitis amurensis extract Rat Ischemia Anti-inflammatory antiexcitotoxic antioxidant and antiapoptotic Kim et al 2012 [134]cis-Hinokiresinols Rat Ischemia Anti-inflammatory antioxidant Ju et al 2013 [135]Berberine Rat Ischemia Anti-inflammatory antiapoptotic Zhang et al 2012 [136]S-Nitrosoglutathione Rat Ischemia Antioxidant BBB integrity Khan et al 2012 [137]Taurine Rat Ischemia Antiexcitotoxic antioxidant and antiapoptotic Gharibani et al 2013 [138]MFG-E8 Rat Ischemia Anti-inflammatory antiapoptotic Cheyuo et al 2012 [139]Nitrone derivatives Rat Ischemia Antiexcitotoxic antioxidant Sun et al 2012 [140]

zinc which is required for the activity of matrix metallo-proteinases Preclinical studies have shown that carnosineis well tolerated and produces robust neuroprotection inanimal models of both transient and permanent ischemia[116] It also readily crosses the intact blood-brain barrierwhich allows it to be administered even in the early stagesof stroke Carnosine reduces glutamate excitotoxicity inpMCAOmice resulting in reduced infarct size and improvedneurologic function [117] In another study carnosine wasshown to decrease infarct size MMP activity and levels ofreactive oxygen species [118] Carnosine can also be cleavedby carnosinase into the amino acids alanine and histidinewhich are neuroprotective as well Bestatin an inhibitor ofcarnosinase increases damage in pMCAOmice [119]

73 Asiatic Acid Asiatic acid is a plant-derived compoundwith effects on oxidative stress inflammation and excitotox-icity that has been shown to be beneficial in the treatmentof wound healing beta-amyloid toxicity and liver injuryRecent evidence suggests that it may be neuroprotective instroke as well In pMCAO mice asiatic acid reduces infarctsize and improves neurologic scores possibly by suppressionof mitochondrial damage and BBB disruption [120] Subse-quently asiatic acid was also found to be neuroprotective inmultiple models of ischemia in rats by inhibiting mitochon-drial damage and MMP-9 activation [121] Asiatic acid alsoblocks the negative effects of excitotoxicity in mice followingexposure to glutamate [122] An extract of Centella asiaticahas been shown to improve several markers of behavioralfunction and improved the antioxidant status in tMCAO rats[123]This extract contains asiatic acid as well as several otherrelated compounds that also have neuroprotective propertiesFurther investigation of this class of molecules is thereforewarranted to determine the extent of their effects

74 Hypothermia The beneficial effects of cooling the bodyafter injury are well known and induction of hypothermiais currently used in clinical practice to prevent secondarybrain injury after cardiac arrest and resuscitation peri-natal or neonatal asphyxia and head trauma [124ndash126]Considerable evidence suggests that hypothermia may bebeneficial in the treatment of stroke as well Microarray

experiments have determined that neuroprotection result-ing from hypothermia in MCAO rats is associated withchanges in the expression of genes involved in the processesof inflammation apoptosis and calcium regulation [127]Hypothermia induction by the neurotensin receptor 1 (NTR1)agonist ABS-201 reduces infarct volume and suppresses celldeath by apoptosis and autophagy in mice subjected to focalischemia [128] A recent meta-analysis of human clinicaltrials on the other hand found no benefit of hypothermiain stroke patients [129] These trials had a limited number ofsubjects however and larger trials are currently in progressfor example EuroHYP-1 and ICTuS23 [130]

75 Flavonoids In some cases whole classes of moleculesare known for having multiple neuroprotective effects Onesuch group of compounds that are currently the subjectof intensive research are the flavonoids These moleculesare naturally occurring compounds that readily cross theblood-brain barrier and are well known for their protectiveeffectsTheflavonoids in cocoa for example have antioxidantproperties and also promote perfusion angiogenesis andneurogenesis in the brain [141] Xanthohumol has beenfound to have anti-inflammatory anti-apoptotic antioxi-dant and antithrombotic properties Following MCAO inrats xanthohumol decreases the levels of TNF120572 hypoxia-inducible factor 1 alpha (HIF-1120572) and inducible nitric oxidesynthase (iNOS) [142] It also reduces expression of activatedcaspase 3 scavenges hydroxyl radicals and inhibits plateletaggregation Treatment with naringenin results in neuropro-tection in tMCAO rats through both antioxidant and anti-inflammatorymechanisms [143] Galangin improves cerebralblood blow inhibits apoptosis and protects mitochondrialfunction after MCAO in rats [144] In tMCAO mice fisetinprotects the brain against ischemic injury by suppressingactivation of cerebral inflammatory cells and inhibiting themigration of macrophages and dendritic cells into the brain[145] In models of intracerebral hemorrhage baicalin hasbeen found to attenuate edema of the brain and inhibitapoptosis [146]

76 Cannabinoids Another major class of molecules withmultiple beneficial effects in stroke are the cannabinoids

10 ISRN Neurology

These compounds are primarily known for their anti-inflammatory effects in many diseases including stroke [147]Recently however evidence suggests that cannabinoids mayalso have antioxidant and antiapoptotic effects [148] Thecannabinoid receptor agonists WIN55212-2 and JWH-133reduce activation of microglia and macrophages after induc-tion of ischemia in mice and rats resulting in reduced infarctsize and neurological impairment as well as protection ofoligodendrocyte precursor cells [149ndash151] Another receptoragonist TAK-937 provides neuroprotection in tMCAO ratsand the neuroprotective effect is increased when given incombinationwith hypothermia [152] Furthermore TAK-937not only is effective in rodent models of stroke but also hasbeen shown to reduce infarct volume in nonhuman primates[153] This specific compound is therefore of considerableinterest for future use in human trials

8 Neuroprotective Agents in HumanClinical Stroke Trials

Perhaps the greatest challenge in the study of neuroprotectionin stroke is the translation of animal studies to humansNumerous treatments that produce robust protection inrodents have failed to provide significant benefit in clinicaltrials The various theories on the reason for this failure havealready been discussed elsewhere and will not be coveredhere [5 154 155] Amid the abundance of discouragingresults however a small number of neuroprotective strategieshave shown promise in human stroke patients A briefsummary of recently completed clinical trials for the studyof neuroprotection in ischemic stroke and subarachnoidhemorrhage is provided below A discussion of recent clinicaltrials for neuroprotection in intracerebral hemorrhage isalready available [8]

81 International Citicoline Trial on Acute Stroke (ICTUS)Citicoline is a nutritional supplement that not only is com-monly used to improve memory retention but also has beenshown to prevent neuronal degeneration and improve visualfunction It has already been approved in some countriesfor the treatment of acute ischemic stroke A randomizedplacebo controlled trial was conducted to evaluate the effi-cacy of citicoline in patients with moderate to severe acuteischemic stroke [156] A total of 2298 patients were admin-istered either citicoline (1000mg every 12 hours) or placebofor up to 6 weeks Outcome was determined at 90 days basedon the National Institute of Health Stroke Scale (NIHSS)modified Rankin Scale (mRS) and modified Barthel Index(mBI scores) plus the occurrence of intracranial hemorrhageneurologic deterioration or death No significant differencein recovery was observed between the citicoline and placebotreatment groups

82 Minocycline Minocycline is an oral antibiotic withproven safety over years of use In addition to its antibioticproperties minocycline also has anti-inflammatory and anti-apoptotic effects that have been shown to be neuroprotectivein animal models of stroke and in previous human trials

The efficacy of oral minocycline was examined in arecent single-blinded open-label study [108] Fifty patientswith acute ischemic stroke were given either minocycline(200mgday) or placebo for five days and assessed for variousindicators of outcome at 1 7 30 and 90 days Patientsreceiving minocycline showed significant improvement after30 days in NIHSS mBI and mRS scores NIHSS scorescontinued to be significantly improved at 90 days Largerphase II and phase III trials are awaited

83 Cerebrolysin Cerebrolysin is a mixture of peptide frag-ments that mimics the action of neurotrophic factors andhas been shown to be neuroprotective in a number of condi-tions such as hyperthermia-induced neurotoxicity vasculardementia Alzheimerrsquos disease traumatic brain injury andstroke A large double-blind clinical trial was conducted totest the efficacy and safety of Cerebrolysin in patients withacute ischemic stroke [157] A total of 1070 patients wereadministered aspirin and either Cerebrolysin (30mLday) orplacebo over a period of 10 days Although no significantdifference between treatment groups was seen after 90 days apositive trendwas seen in those patients with anNIHSS scoregreater than 12

84 Ginsenoside-Rd Ginsenoside-Rd is a calcium channelantagonist that has been previously shown to be neuropro-tective in human trials An extended trial of ginsenoside-Rdwas performed in 390 patients with acute ischemic stroke[158] Subjects were administered ginsenoside-Rd or placebointravenously over a 14-day period and evaluated usingNIHSS and mRS scores for 90 days Significant improvementwas seen with ginsenoside-Rd in NIHSS scores at 15 days andmRS scores at 90 days

85 Granulocyte-Colony Stimulating Factor (G-CSF) G-CSFis a growth factor that stimulates the production and releaseof hematopoietic stem cells in bone marrow and may bebeneficial in the enhancement of recovery after stroke Thesafety of G-CSFwas examined in a randomized phase IIb trial[159] A total of 60 patients with either ischemic or hemor-rhagic stroke were given G-CSF (10 120583gkg) or placebo over 5days and monitored for the frequency of adverse effects G-CSF significantly increased white cell counts and produced atrend toward reduced infarct volume No difference was seenbetween treatment groups in the frequency of adverse effects

86 Evaluating Neuroprotection in Aneurysm Coiling Ther-apy (ENACT) Trial The compound known as NA-1 (Tat-NR2B9c) is an inhibitor of the postsynaptic density-95 (PSD-95) protein that is neuroprotective in primate models ofstroke PSD-95 associates with theNMDAglutamate receptorsubtype and contributes to the process of excitotoxicitywhich is suppressed by treatment with NA-1 The safety andefficacy of NA-1 after endovascular aneurysm repair wereexamined in patients with iatrogenic stroke [160] A totalof 185 patients were treated for a ruptured or unrupturedintracranial aneurysm by endovascular coiling followedby administration of NA-1 or placebo Evaluative criteria

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

[1] S D Reed S C CramerD K Blough KMeyer and J G JarvikldquoTreatment with tissue plasminogen activator and inpatientmortality rates for patients with ischemic stroke treated incommunity hospitalsrdquo Stroke vol 32 no 8 pp 1832ndash1839 2001

[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

10 ISRN Neurology

These compounds are primarily known for their anti-inflammatory effects in many diseases including stroke [147]Recently however evidence suggests that cannabinoids mayalso have antioxidant and antiapoptotic effects [148] Thecannabinoid receptor agonists WIN55212-2 and JWH-133reduce activation of microglia and macrophages after induc-tion of ischemia in mice and rats resulting in reduced infarctsize and neurological impairment as well as protection ofoligodendrocyte precursor cells [149ndash151] Another receptoragonist TAK-937 provides neuroprotection in tMCAO ratsand the neuroprotective effect is increased when given incombinationwith hypothermia [152] Furthermore TAK-937not only is effective in rodent models of stroke but also hasbeen shown to reduce infarct volume in nonhuman primates[153] This specific compound is therefore of considerableinterest for future use in human trials

8 Neuroprotective Agents in HumanClinical Stroke Trials

Perhaps the greatest challenge in the study of neuroprotectionin stroke is the translation of animal studies to humansNumerous treatments that produce robust protection inrodents have failed to provide significant benefit in clinicaltrials The various theories on the reason for this failure havealready been discussed elsewhere and will not be coveredhere [5 154 155] Amid the abundance of discouragingresults however a small number of neuroprotective strategieshave shown promise in human stroke patients A briefsummary of recently completed clinical trials for the studyof neuroprotection in ischemic stroke and subarachnoidhemorrhage is provided below A discussion of recent clinicaltrials for neuroprotection in intracerebral hemorrhage isalready available [8]

81 International Citicoline Trial on Acute Stroke (ICTUS)Citicoline is a nutritional supplement that not only is com-monly used to improve memory retention but also has beenshown to prevent neuronal degeneration and improve visualfunction It has already been approved in some countriesfor the treatment of acute ischemic stroke A randomizedplacebo controlled trial was conducted to evaluate the effi-cacy of citicoline in patients with moderate to severe acuteischemic stroke [156] A total of 2298 patients were admin-istered either citicoline (1000mg every 12 hours) or placebofor up to 6 weeks Outcome was determined at 90 days basedon the National Institute of Health Stroke Scale (NIHSS)modified Rankin Scale (mRS) and modified Barthel Index(mBI scores) plus the occurrence of intracranial hemorrhageneurologic deterioration or death No significant differencein recovery was observed between the citicoline and placebotreatment groups

82 Minocycline Minocycline is an oral antibiotic withproven safety over years of use In addition to its antibioticproperties minocycline also has anti-inflammatory and anti-apoptotic effects that have been shown to be neuroprotectivein animal models of stroke and in previous human trials

The efficacy of oral minocycline was examined in arecent single-blinded open-label study [108] Fifty patientswith acute ischemic stroke were given either minocycline(200mgday) or placebo for five days and assessed for variousindicators of outcome at 1 7 30 and 90 days Patientsreceiving minocycline showed significant improvement after30 days in NIHSS mBI and mRS scores NIHSS scorescontinued to be significantly improved at 90 days Largerphase II and phase III trials are awaited

83 Cerebrolysin Cerebrolysin is a mixture of peptide frag-ments that mimics the action of neurotrophic factors andhas been shown to be neuroprotective in a number of condi-tions such as hyperthermia-induced neurotoxicity vasculardementia Alzheimerrsquos disease traumatic brain injury andstroke A large double-blind clinical trial was conducted totest the efficacy and safety of Cerebrolysin in patients withacute ischemic stroke [157] A total of 1070 patients wereadministered aspirin and either Cerebrolysin (30mLday) orplacebo over a period of 10 days Although no significantdifference between treatment groups was seen after 90 days apositive trendwas seen in those patients with anNIHSS scoregreater than 12

84 Ginsenoside-Rd Ginsenoside-Rd is a calcium channelantagonist that has been previously shown to be neuropro-tective in human trials An extended trial of ginsenoside-Rdwas performed in 390 patients with acute ischemic stroke[158] Subjects were administered ginsenoside-Rd or placebointravenously over a 14-day period and evaluated usingNIHSS and mRS scores for 90 days Significant improvementwas seen with ginsenoside-Rd in NIHSS scores at 15 days andmRS scores at 90 days

85 Granulocyte-Colony Stimulating Factor (G-CSF) G-CSFis a growth factor that stimulates the production and releaseof hematopoietic stem cells in bone marrow and may bebeneficial in the enhancement of recovery after stroke Thesafety of G-CSFwas examined in a randomized phase IIb trial[159] A total of 60 patients with either ischemic or hemor-rhagic stroke were given G-CSF (10 120583gkg) or placebo over 5days and monitored for the frequency of adverse effects G-CSF significantly increased white cell counts and produced atrend toward reduced infarct volume No difference was seenbetween treatment groups in the frequency of adverse effects

86 Evaluating Neuroprotection in Aneurysm Coiling Ther-apy (ENACT) Trial The compound known as NA-1 (Tat-NR2B9c) is an inhibitor of the postsynaptic density-95 (PSD-95) protein that is neuroprotective in primate models ofstroke PSD-95 associates with theNMDAglutamate receptorsubtype and contributes to the process of excitotoxicitywhich is suppressed by treatment with NA-1 The safety andefficacy of NA-1 after endovascular aneurysm repair wereexamined in patients with iatrogenic stroke [160] A totalof 185 patients were treated for a ruptured or unrupturedintracranial aneurysm by endovascular coiling followedby administration of NA-1 or placebo Evaluative criteria

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

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[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

ISRN Neurology 11

included the number and size of ischemic strokes occurringafter the endovascular procedure as well as adverse effectsassociated with NA-1 treatment NA-1 was found to decreasethe number but not the size of strokes occurring aftersurgery No serious adverse effects of NA-1 treatment wereobserved

87 Magnesium for Aneurysmal Subarachnoid Haemorrhage(MASH-2) Trial Magnesium is a glutamate receptor antag-onist that has been shown to be neuroprotective due toreduction of excitotoxicity following stroke A multicenterphase III trial was conducted to determine the effect ofmagnesium therapy on outcome in aneurysmal subarachnoidhemorrhage [161] A total of 1204 patients were administeredintravenous magnesium sulfate (64mmolday) or placeboand evaluated for outcome on the modified Rankin Scalefor up to 90 days No improvement in outcome was seenwith magnesium treatment versus controls In addition aretrospective analysis of 2047 patients from previous trialswas also performed and similarly concluded that magnesiumhas no benefit in the treatment of aneurysmal subarachnoidhemorrhage

88 Albumin in Subarachnoid Hemorrhage (ALISAH) TrialAlbumin is an endogenous protein that has been shownto have multiple neuroprotective effects including antiox-idant activity inhibition of apoptosis improved cellularmetabolism and reduced edemaAmulticenter pilot trial wasconducted to evaluate the safety and tolerability of humanalbumin in patients with subarachnoid hemorrhage [162] Atotal of 47 patients were tested with three different dosagelevels of human albumin administered daily for 7 days Albu-min treatment was found to be well tolerated with minimaladverse effects at doses of 625mgkg and 1250mgkg butnot at higher levels In addition 1250mgkg albumin trendedtoward better outcome than the lower dosage level A phaseIII trial to determine the efficacy of albumin in subarachnoidhemorrhage is currently in progress

9 Summary

The pathology of stroke is incredibly complex and treatmentof its devastating effects is a continuing medical challengeThe topic of neuroprotection in stroke is equally complexas can be seen by the wide variety of approaches currentlybeing studied by the scientific community On the onehand no treatment or combination of treatments can beexpected to encompass the entirety of damaging processesthat occur during stroke In this respect the search for bettertherapies is never ending On other hand the availabilityof a large number of neuroprotective strategies increasesthe probability that one or more will ultimately prove to beeffective This fact is particularly relevant considering thatthe largemajority of neuroprotective treatments developed inanimal models have failed to produce significant benefits inhuman trials As a result treatment options for stroke are stilllimited A few neuroprotective agents have shown promise

however and it is hopeful that they may be approved forgeneral use in the future

The failure of preclinical studies to translate into clinicaltrials highlights the importance that these studies be properlydesigned To this end the StrokeTherapy Academic IndustryRoundtable (STAIR) has developed a set of recommendationsfor the preclinical assessment of neuroprotective treatments[163] These include consideration of the proper animalmodel dosage level and time points to be used as well as theuse of physiological monitoring and more than one measureof outcome Recommendations for phase III clinical trialsof potential stroke therapies have also been developed tofacilitate the transition to phase III trials [164] It is criticalthat both preclinical studies and clinical trials be designedto complement one another in order to ensure that theresults are comparable and to allow subsequent investigationof the reasons behind the success or failure of neuroprotectivetreatments in humans It has also been proposed that ratherthan proceeding directly from animal studies to clinicaltrials international multicenter preclinical studies should beperformed on promising neuroprotective agents to identifypotential problems in translating from animals to humans[165 166]

One complicating factor in the development of neuropro-tective strategies is the dual nature of many of the processesthat occur in the brain during stroke The activity of MMPsmicroglia and other inflammatory cells for example can beeither damaging or protective depending on the magnitudelocation and timing of their effects Even mechanisms ofcell death such as apoptosis and autophagy can be beneficialin the right circumstances The development of potentialneuroprotective treatments therefore must take both thepositive and negative aspects of the stroke response intoconsideration to ensure that they are administered under theconditions that are most appropriate and that will producethe greatest benefit

Conflict of Interests

The author has received research funding support from theNational Institute of Health (NIH) and the American StrokeAssociation (ASA)

References

[1] S D Reed S C CramerD K Blough KMeyer and J G JarvikldquoTreatment with tissue plasminogen activator and inpatientmortality rates for patients with ischemic stroke treated incommunity hospitalsrdquo Stroke vol 32 no 8 pp 1832ndash1839 2001

[2] M A Moskowitz E H Lo and C Iadecola ldquoThe science ofstrokemechanisms in search of treatmentsrdquoNeuron vol 67 no2 pp 181ndash198 2010

[3] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke vol 42no 6 pp 1781ndash1786 2011

[4] D Zemke M U Farooq A M Yahia and A Majid ldquoDelayedischemia after subarachnoid hemorrhage result of vasospasmalone or a broader vasculopathyrdquo Vascular Medicine vol 12no 3 pp 243ndash249 2007

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

12 ISRN Neurology

[5] J N Stankowski and R Gupta ldquoTherapeutic targets for neu-roprotection in acute ischemic stroke lost in translationrdquoAntioxidants amp Redox Signaling vol 14 no 10 pp 1841ndash18512011

[6] A R Noorian R G Nogueira and R Gupta ldquoNeuroprotectionin acute ischemic strokerdquo Journal of Neurosurgical Sciences vol55 no 2 pp 127ndash138 2011

[7] D T Laskowitz and B J Kolls ldquoNeuroprotection in subarach-noid hemorrhagerdquo Stroke vol 41 supplement 10 pp S79ndashS842010

[8] C P Kellner and E S Connolly ldquoNeuroprotective strategies forintracerebral hemorrhage trials and translationrdquo Stroke vol 41supplement 10 pp S99ndashS102 2010

[9] R Liu H Yuan F Yuan and S-H Yang ldquoNeuroprotectiontargeting ischemic penumbra and beyond for the treatment ofischemic strokerdquo Neurological Research vol 34 no 4 pp 331ndash337 2012

[10] R J Traystman ldquoAnimal models of focal and global cerebralischemiardquo ILAR Journal vol 44 no 2 pp 85ndash95 2003

[11] A Manaenko H Chen J H Zhang and J Tang ldquoComparisonof different preclinical models of intracerebral hemorrhagerdquoActa Neurochirurgica no 111 pp 9ndash14 2011

[12] E Titova R P Ostrowski J H Zhang and J Tang ldquoExperimen-tal models of subarachnoid hemorrhage for studies of cerebralvasospasmrdquo Neurological Research vol 31 no 6 pp 568ndash5812009

[13] P R Krafft E L Bailey T Lekic et al ldquoEtiology of stroke andchoice of modelsrdquo International Journal of Stroke vol 7 no 5pp 398ndash406 2012

[14] R Jin G Yang and G Li ldquoInflammatory mechanisms inischemic stroke role of inflammatory cellsrdquo Journal of Leuko-cyte Biology vol 87 no 5 pp 779ndash789 2010

[15] S E Lakhan A Kirchgessner and M Hofer ldquoInflammatorymechanisms in ischemic stroke therapeutic approachesrdquo Jour-nal of Translational Medicine vol 7 article 97 2009

[16] G J del Zoppo K J Becker and J M Hallenbeck ldquoInflamma-tion after stroke is it harmfulrdquo Archives of Neurology vol 58no 4 pp 669ndash672 2001

[17] A Jablonska and B Lukomska ldquoStroke induced brain changesimplications for stem cell transplantationrdquo Acta NeurobiologiaeExperimentalis vol 71 no 1 pp 74ndash85 2011

[18] J M Pradillo A Denes A D Greenhalgh et al ldquoDelayedadministration of interleukin-1 receptor antagonist reducesischemic brain damage and inflammation in comorbid ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 32 no 9pp 1810ndash1819 2012

[19] J S Yoon J-H Lee and D Tweedie ldquo3 61015840-dithiothalidomideimproves experimental stroke outcome by suppressing neuroin-flammationrdquo Journal of Neuroscience Research vol 91 no 5 pp671ndash680 2013

[20] S Wang H Guo L Hu et al ldquoCaffeic acid ester fraction fromErigeron breviscapus inhibits microglial activation and pro-vides neuroprotectionrdquo Chinese Journal of Integrative Medicinevol 18 no 6 pp 437ndash444 2012

[21] T Ewen L Qiuting T Chaogang et al ldquoNeuroprotective effectof atorvastatin involves suppression of TNF-120572 and upregulationof IL-10 in a rat model of intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 66 no 2 pp 337ndash346 2013

[22] R K Sumbria R J Boado and W M Pardridge ldquoBrain pro-tection from stroke with intravenous TNF120572 decoy receptor-Trojan horse fusion proteinrdquo Journal of Cerebral Blood Flow andMetabolism vol 32 no 10 pp 1933ndash1938 2012

[23] P Zhang X Liu Y Zhu S Chen D Zhou and Y WangldquoHonokiol inhibits the inflammatory reaction during cerebralischemia reperfusion by suppressing NF-120581B activation andcytokine production of glial cellsrdquoNeuroscience Letters vol 534pp 123ndash127 2013

[24] H Luan Z Kan Y Xu C Lv and W Jiang ldquoRosmarinic acidprotects against experimental diabetes with cerebral ischemiarelation to inflammation responserdquo Journal of Neuroinflamma-tion vol 10 article 28 2013

[25] T Jiang L Gao J Guo J Lu Y Wang and Y ZhangldquoSuppressing inflammation by inhibiting the NF-120581B pathwaycontributes to the neuroprotective effect of angiotensin-(1-7)in rats with permanent cerebral ischaemiardquo British Journal ofPharmacology vol 167 no 7 pp 1520ndash1532 2012

[26] L Yu C Chen L-F Wang et al ldquoNeuroprotective effect ofkaempferol glycosides against brain injury and neuroinflam-mation by inhibiting the activation of NF-120581B and STAT3 intransient focal strokerdquo PLoS ONE vol 8 no 2 Article IDe55839 2013

[27] A Lanzillotta G Pignataro C Branca et al ldquoTargeted acety-lation of NF-120581BRelA and histones by epigenetic drugs reducespost-ischemic brain injury in mice with an extended therapeu-tic windowrdquo Neurobiology of Disease vol 49 pp 177ndash189 2012

[28] D Michalski M Heindl J Kacza et al ldquoSpatio-temporalcourse ofmacrophage-like cell accumulation after experimentalembolic stroke depending on treatment with tissue plasmino-gen activator and its combination with hyperbaric oxygena-tionrdquo European Journal of Histochemistry vol 56 no 2 artivlee14 2012

[29] J-S Park J A Shin J-S Jung et al ldquoAnti-inflammatorymechanism of compound K in activated microglia and itsneuroprotective effect on experimental stroke in micerdquo Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 59ndash67 2012

[30] M Ohnishi A Monda R Takemoto et al ldquoSesamin suppressesactivation of microglia and p4442 MAPK pathway whichconfers neuroprotection in rat intracerebral hemorrhagerdquoNeu-roscience vol 232 pp 45ndash52 2012

[31] H Matsushita M Hijioka A Hisatsune Y Isohama K Shudoand H Katsuki ldquoNatural and synthetic retinoids afford thera-peutic effects on intracerebral hemorrhage in micerdquo EuropeanJournal of Pharmacology vol 683 no 1ndash3 pp 125ndash131 2012

[32] F JOrtega J JolkkonenNMahy andM J Rodrıguez ldquoGliben-clamide enhances neurogenesis and improves long-term func-tional recovery after transient focal cerebral ischemiardquo Journalof Cerebral Blood Flow and Metabolism vol 33 no 3 pp 356ndash364 2013

[33] F J Ortega J Gimeno-Bayon J F Espinosa-Parrilla et al ldquoATP-dependent potassium channel blockade strengthens microglialneuroprotection after hypoxia-ischemia in ratsrdquo ExperimentalNeurology vol 235 no 1 pp 282ndash296 2012

[34] B Wali T Ishrat F Atif F Hua D G Stein and I Say-eed ldquoGlibenclamide administration attenuates infarct volumehemispheric swelling and functional impairments followingpermanent focal cerebral ischemia in ratsrdquo Stroke Research andTreatment vol 2012 Article ID 460909 6 pages 2012

[35] E Parada J Egea I Buendia et al ldquoThe microglial 1205727-acetylcholine nicotinic receptor is a key element in promotingneuroprotection by inducing heme oxygenase-1 via nuclearfactor erythroid-2-related factor 2rdquo Antioxidants amp Redox Sig-naling vol 19 no 11 pp 1135ndash1148 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

ISRN Neurology 13

[36] H Pradeep J B Diya S Shashikumar and G K RajanikantldquoOxidative stressmdashassassin behind the ischemic strokerdquo FoliaNeuropathologica vol 50 no 3 pp 219ndash230 2012

[37] G H Heeba and A A El-Hanafy ldquoNebivolol regulates eNOSand iNOS expressions and alleviates oxidative stress in cerebralischemiareperfusion injury in ratsrdquo Life Sciences vol 90 no11-12 pp 388ndash395 2012

[38] K A Radermacher KWingler F Langhauser et al ldquoNeuropro-tection after stroke by targeting NOX4 as a source of oxidativestressrdquo Antioxidants amp Redox Signaling vol 18 no 12 pp 1418ndash1427 2013

[39] G Li H-K Luo L-F Li et al ldquoDual effects of hydrogensulphide on focal cerebral ischaemic injury via modulation ofoxidative stress-induced apoptosisrdquo Clinical and ExperimentalPharmacology amp Physiology vol 39 no 9 pp 765ndash771 2012

[40] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 pp 103ndash111 2012

[41] P Y Lam N Chen P Y Chiu H Y Leung and K M KoldquoNeuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mito-chondrial antioxidant status and functional capacityrdquo Journal ofMedicinal Food vol 15 no 7 pp 629ndash638 2012

[42] H-F Huang F Guo Y-Z Cao W Shi and Q Xia ldquoNeu-roprotection by manganese superoxide dismutase (MnSOD)mimics antioxidant effect and oxidative stress regulation inacute experimental strokerdquo CNS Neuroscience amp Therapeuticsvol 18 no 10 pp 811ndash818 2012

[43] A Ahmad M M Khan S S Raza et al ldquoOcimum sanctumattenuates oxidative damage and neurological deficits followingfocal cerebral ischemiareperfusion injury in ratsrdquo NeurologicalSciences vol 33 no 6 pp 1239ndash1247 2012

[44] Y Zhan C Chen H Suzuki Q Hu X Zhi and J H ZhangldquoHydrogen gas ameliorates oxidative stress in early brain injuryafter subarachnoid hemorrhage in ratsrdquo Critical Care Medicinevol 40 no 4 pp 1291ndash1296 2012

[45] B J Connell and T M Saleh ldquoCo-administration of apocyninwith lipoic acid enhances neuroprotection in a rat model ofischemiareperfusionrdquo Neuroscience Letters vol 507 no 1 pp43ndash46 2012

[46] J Yang H-N Ahn M Chang P Narasimhan P H Chanand Y S Song ldquoComplement component 3 inhibition byan antioxidant is neuroprotective after cerebral ischemia andreperfusion in micerdquo Journal of Neurochemistry vol 124 no 4pp 523ndash535 2013

[47] X Zeng K Asmaro C Ren et al ldquoAcute ethanol treat-ment reduces blood-brain barrier dysfunction followingischemiareperfusion injuryrdquo Brain Research vol 1437 pp127ndash133 2012

[48] J Xiang R Lan Y-P Tang Y-P Chen and D-F Cai ldquoApoc-ynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9-2 in a rat model of cerebral ischemia-reperfusion injuryrdquoNeurochemical Research vol 37 no 8 pp 1820ndash1828 2012

[49] D Michalski C Hobohm C Weise et al ldquoInterrelations bet-ween blood-brain barrier permeability and matrix metallopro-teinases are differently affected by tissue plasminogen activatorand hyperoxia in a rat model of embolic strokerdquo Medical GasResearch vol 2 no 1 article 2 2012

[50] Z Wang Y Xue H Jiao Y Liu and P Wang ldquoDoxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctionsand PKC120575 signaling in ratsrdquo Journal of Molecular Neurosciencevol 47 no 1 pp 89ndash100 2012

[51] H Shi B Sheng F Zhang et al ldquoKruppel-like factor 2 protectsagainst ischemic stroke by regulating endothelial blood brainbarrier functionrdquo American Journal of Physiology Heart andCirculatory Physiology vol 304 no 6 pp H796ndashH805 2013

[52] D Chen X Wei J Guan et al ldquoInhibition of c-Jun N-terminalkinase prevents blood-brain barrier disruption and normalizesthe expression of tight junction proteins clautin-5 and ZO-1 in arat model of subarachnoid hemorrhagerdquo Acta Neurochirurgicavol 154 no 8 pp 1469ndash1476 2012

[53] B Huang P R Krafft Q Ma et al ldquoFibroblast growth factorspreserve blood-brain barrier integrity through RhoA inhibitionafter intracerebral hemorrhage in micerdquo Neurobiology of Dis-ease vol 46 no 1 pp 204ndash214 2012

[54] B Lapergue B Q Dang J-P Desilles et al ldquoHigh-densitylipoprotein-based therapy reduces the hemorrhagic complica-tions associated with tissue plasminogen activator treatment inexperimental strokerdquo Stroke vol 44 no 3 pp 699ndash707 2013

[55] D R Pillai N C Shanbhag M S Dittmar U Bogdahn andF Schlachetzki ldquoNeurovascular protection by targeting earlyblood-brain barrier disruption with neurotrophic factors afterischemia-reperfusion in ratslowastrdquo Journal of Cerebral Blood Flowand Metabolism vol 33 no 4 pp 557ndash566 2013

[56] A Mdzinarishvili R Sumbria D Langc and J Klein ldquoGinkgoextract EGb761 confers neuroprotection by reduction of glu-tamate release in ischemic brainrdquo Journal of Pharmacy ampPharmaceutical Sciences vol 15 no 1 pp 94ndash102 2012

[57] S E Nada and Z A Shah ldquoPreconditioning with Ginkgobiloba (EGb 761) provides neuroprotection through HO1 andCRMP2rdquo Neurobiology of Disease vol 46 no 1 pp 180ndash1892012

[58] M M Harraz S M Eacker X Wang T M Dawson andV L Dawson ldquoMicroRNA-223 is neuroprotective by targetingglutamate receptorsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 109 no 46 pp 2ndash52012

[59] L Li W Qu L Zhou et al ldquoActivation of transient receptorpotential vanilloid 4 increases NMDA-activated current inhippocampal pyramidal neuronsrdquo Frontiers in Cellular Neuro-science vol 7 article 17 2013

[60] D Afshari N Moradian and M Rezaei ldquoEvaluation of theintravenous magnesium sulfate effect in clinical improvementof patients with acute ischemic strokerdquo Clinical Neurology andNeurosurgery vol 115 no 4 pp 400ndash404 2013

[61] K R Lees K W Muir I Ford et al ldquoMagnesium for acutestroke (Intravenous Magnesium Efficacy in Stroke Trial) ran-domised controlled trialrdquo The Lancet vol 363 no 9407 pp439ndash445 2004

[62] J L Saver C Kidwell M Eckstein and S Starkman ldquoPrehospi-tal neuroprotective therapy for acute stroke results of the FieldAdministration of Stroke Therapy-Magnesium (FAST-MAG)pilot trialrdquo Stroke vol 35 no 5 pp e106ndashe108 2004

[63] H Li J Huang W Du C Jia H Yao and Y Wang ldquoTRPC6inhibited NMDA receptor activities and protected neuronsfrom ischemic excitotoxicityrdquo Journal of Neurochemistry vol123 no 6 pp 1010ndash1018 2012

[64] Y Lin J-C Zhang J Fu et al ldquoHyperforin attenuates braindamage induced by transient middle cerebral artery occlusion

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

14 ISRN Neurology

(MCAO) in rats via inhibition of TRPC6 channels degradationrdquoJournal of Cerebral Blood Flow andMetabolism vol 33 no 2 pp253ndash262 2013

[65] Y Zhang L Zhou X Zhang J Bai M Shi and G ZhaoldquoGinsenoside-Rd attenuates TRPM7 and ASIC1a but promotesASIC2a expression in rats after focal cerebral ischemiardquo Neuro-logical Sciences vol 33 no 5 pp 1125ndash1131 2012

[66] A Majid D Zemke and M Kassab ldquoPathophysiology ofischemic strokerdquo in UpToDate D Basow Ed UpToDateWaltham Mass USA 2013

[67] T Zgavc D de Geyter A-G Ceulemans et al ldquoMild hypother-mia reduces activated caspase-3 up to 1 week after a focal cere-bral ischemia induced by endothelin-1 in ratsrdquo Brain Researchvol 1501 pp 81ndash88 2013

[68] T Kinouchi K T Kitazato K Shimada et al ldquoActivation of sig-nal transducer and activator of transcription-3 by a peroxisomeproliferator-activated receptor gamma agonist contributes toneuroprotection in the peri-infarct region after ischemia inoophorectomized ratsrdquo Stroke vol 43 no 2 pp 478ndash483 2012

[69] W-Y Lin Y-C Chang C-J Ho and C-C Huang ldquoIschemicpreconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatalbrainrdquo Stroke vol 44 no 1 pp 162ndash169 2013

[70] P Fu C Peng J Y Ding et al ldquoAcute administration ofethanol reduces apoptosis following ischemic stroke in ratsrdquoNeuroscience Research vol 76 no 1-2 pp 93ndash97 2013

[71] Q Zhao C Zhang X Wang L Chen H Ji and YZhang ldquo(S)-ZJM-289 a nitric oxide-releasing derivative of 3-n-butylphthalide protects against ischemic neuronal injuryby attenuating mitochondrial dysfunction and associated celldeathrdquoNeurochemistry International vol 60 no 2 pp 134ndash1442012

[72] Z Xie B Lei Q Huang et al ldquoNeuroprotective effect ofCyclosporin A on the development of early brain injury in asubarachnoid hemorrhagemodel a pilot studyrdquo Brain Researchvol 1472 pp 113ndash123 2012

[73] G Hu Z Wu F Yang et al ldquoGinsenoside Rdblocks AIFmitochondrio-nuclear translocation and NF-120581B nuclear accu-mulation by inhibiting poly(ADP-ribose) polymerase-1 afterfocal cerebral ischemia in ratsrdquo Neurological Sciences vol 34no 12 pp 2101ndash2106 2013

[74] G Wei D-F Chen X-P Lai et al ldquoMuscone exerts neuropro-tection in an experimental model of stroke via inhibition of thefas pathwayrdquo Natural Product Communications vol 7 no 8 pp1069ndash1074 2012

[75] Y Jiang D-W Liu X-Y Han et al ldquoNeuroprotective effectsof anti-tumor necrosis factor-alpha antibody on apoptosisfollowing subarachnoid hemorrhage in a rat modelrdquo Journal ofClinical Neuroscience vol 19 no 6 pp 866ndash872 2012

[76] B Gabryel A Kost and D Kasprowska ldquoNeuronal autophagyin cerebral ischemiamdasha potential target for neuroprotectivestrategiesrdquo Pharmacological Reports vol 64 no 1 pp 1ndash152012

[77] D Zemke S Azhar and A Majid ldquoThe mTOR pathway asa potential target for the development of therapies againstneurological diseaserdquo Drug News and Perspectives vol 20 no8 pp 495ndash499 2007

[78] C-H Jing L Wang P-P Liu C Wu D Ruan and GChen ldquoAutophagy activation is associatedwith neuroprotectionagainst apoptosis via a mitochondrial pathway in a rat model ofsubarachnoid hemorrhagerdquo Neuroscience vol 213 pp 144ndash1532012

[79] M Papadakis G Hadley M Xilouri et al ldquoTsc1 (hamartin)confers neuroprotection against ischemia by inducing auto-phagyrdquo Nature Medicine vol 19 no 3 pp 351ndash357 2013

[80] L Gao T Jiang J Guo et al ldquoInhibition of autophagy con-tributes to ischemic postconditioning-induced neuroprotectionagainst focal cerebral ischemia in ratsrdquo PLoS ONE vol 7 no 92012

[81] D Zemke J L SmithM J Reeves andAMajid ldquoIschemia andischemic tolerance in the brain an overviewrdquo NeuroToxicologyvol 25 no 6 pp 895ndash904 2004

[82] J Lehotsky J Burda V Danielisova M Gottlieb P Kaplan andB Saniova ldquoIschemic tolerance the mechanisms of neuropro-tective strategyrdquo Anatomical Record vol 292 no 12 pp 2002ndash2012 2009

[83] U Dirnagl R P Simon and J M Hallenbeck ldquoIschemictolerance and endogenous neuroprotectionrdquo Trends in Neuro-sciences vol 26 no 5 pp 248ndash254 2003

[84] T Kirino ldquoIschemic tolerancerdquo Journal of Cerebral Blood Flowand Metabolism vol 22 no 11 pp 1283ndash1296 2002

[85] T P Obrenovitch ldquoMolecular physiology of preconditioning-induced brain tolerance to ischemiardquo Physiological Reviews vol88 no 1 pp 211ndash247 2008

[86] J M Gidday ldquoCerebral preconditioning and ischaemic toler-ancerdquo Nature Reviews Neuroscience vol 7 no 6 pp 437ndash4482006

[87] C Sommer ldquoIschemic preconditioning postischemic struc-tural changes in the brainrdquo Journal of Neuropathology andExperimental Neurology vol 67 no 2 pp 85ndash92 2008

[88] V R Venna J Li S E Benashski S Tarabishy and L DMcCullough ldquoPreconditioning induces sustained neuropro-tection by downregulation of adenosine 51015840-monophosphate-activated protein kinaserdquo Neuroscience vol 201 pp 280ndash2872012

[89] N Bedirli E U Bagriacik H Emmez G Yilmaz Y Unaland Z Ozkose ldquoSevoflurane and isoflurane preconditioningprovides neuroprotection by inhibition of apoptosis-relatedmRNA expression in a rat model of focal cerebral ischemiardquoJournal of Neurosurgical Anesthesiology vol 24 no 4 pp 336ndash344 2012

[90] O-N Bae K Rajanikant J Min et al ldquoLymphocyte cellkinase activation mediates neuroprotection during ischemicpreconditioningrdquoThe Journal of Neuroscience vol 32 no 21 pp7278ndash7286 2012

[91] G Pignataro O Cuomo A Vinciguerra et al ldquoNCX as a keyplayer in the neuroprotection exerted by ischemic precondi-tioning and postconditioningrdquo in Sodium Calcium Exchange AGrowing Spectrum of Pathophysiological Implications L Annun-ziato Ed vol 961 of Advances in Experimental Medicine andBiology pp 223ndash240 2013

[92] G Pignataro F Boscia E Esposito et al ldquoNCX1 and NCX3twonew effectors of delayed preconditioning in brain ischemiardquoNeurobiology of Disease vol 45 no 1 pp 616ndash623 2012

[93] X-R Liu M Luo F Yan et al ldquoIschemic postconditioningdiminishes matrix metalloproteinase 9 expression and attenu-ates loss of the extracellular matrix proteins in rats followingmiddle cerebral artery occlusion and reperfusionrdquo CNS Neuro-science ampTherapeutics vol 18 no 10 pp 855ndash863 2012

[94] M N Hoda S Siddiqui S Herberg et al ldquoRemote ischemicperconditioning is effective alone and in combination withintravenous tissue-type plasminogen activator inmurinemodelof embolic strokerdquo Stroke vol 43 no 10 pp 2794ndash2799 2012

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

ISRN Neurology 15

[95] B Peng Q-L Guo Z-J He et al ldquoRemote ischemicpostconditioning protects the brain from global cerebralischemiareperfusion injury by up-regulating endothelial nitricoxide synthase through the PI3KAkt pathwayrdquo Brain Researchvol 1445 pp 92ndash102 2012

[96] N R Gonzalez R Hamilton A Bilgin-Freiert et al ldquoCerebralhemodynamic and metabolic effects of remote ischemic pre-conditioning in patients with subarachnoid hemorrhagerdquo ActaNeurochirurgica vol 115 pp 193ndash198 2013

[97] K J Kwon J N Kim M K Kim et al ldquoNeuroprotective effectsof valproic acid against hemin toxicity possible involvementof the down-regulation of heme oxygenase-1 by regulatingubiquitin-proteasomal pathwayrdquo Neurochemistry Internationalvol 62 no 3 pp 240ndash250 2013

[98] H-J Chun D W Kim H-J Yi et al ldquoEffects of statin anddeferoxamine administration on neurological outcomes in a ratmodel of intracerebral hemorrhagerdquo Neurological Sciences vol33 no 2 pp 289ndash296 2012

[99] Y Hong S Guo S Chen C Sun J Zhang and X SunldquoBeneficial effect of hydrogen-rich saline on cerebral vasospasmafter experimental subarachnoid hemorrhage in ratsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1670ndash1680 2012

[100] S Gatti C Lonati F Acerbi et al ldquoProtective action of NDP-MSH in experimental subarachnoid hemorrhagerdquo Experimen-tal Neurology vol 234 no 1 pp 230ndash238 2012

[101] F Atif S Yousuf I Sayeed T Ishrat F Hua and D G SteinldquoCombination treatment with progesterone and vitamin D hor-mone is more effective than monotherapy in ischemic strokethe role of BDNFTrkBErk12 signaling in neuroprotectionrdquoNeuropharmacology vol 67 pp 78ndash87 2013

[102] Y Du X Zhang H Ji H Liu S Li and L Li ldquoProbucol andatorvastatin in combination protect rat brains inMCAOmodelupregulating Peroxiredoxin2 Foxo3a and Nrf2 expressionrdquoNeuroscience Letters vol 509 no 2 pp 110ndash115 2012

[103] X Guo X Bu J Jiang P Cheng and Z Yan ldquoEnhancedneuroprotective effects of co-administration of G-CSF withsimvastatin on intracerebral hemorrhage in ratsrdquo Turkish Neu-rosurgery vol 22 no 6 pp 732ndash739 2012

[104] B Kallmunzer S Schwab and R Kollmar ldquoMild hypothermiaof 34∘C reduces side effects of rt-PA treatment after throm-boembolic stroke in ratsrdquo Experimental amp Translational StrokeMedicine vol 4 no 1 article 3 2012

[105] YWang Z Zhang N Chow et al ldquoAn activated protein C ana-log with reduced anticoagulant activity extends the therapeuticwindow of tissue plasminogen activator for ischemic stroke inrodentsrdquo Stroke vol 43 no 9 pp 2444ndash2449 2012

[106] F Campos T Qin J Castillo et al ldquoFingolimod reduceshemorrhagic transformation associated with delayed tissueplasminogen activator treatment in a mouse thromboembolicmodelrdquo Stroke vol 44 no 2 pp 505ndash511 2013

[107] D Zemke and A Majid ldquoThe potential of minocycline forneuroprotection in human neurologic diseaserdquo Clinical Neu-ropharmacology vol 27 no 6 pp 293ndash298 2004

[108] M V P Srivastava A Bhasin R Bhatia et al ldquoEfficacy ofminocycline in acute ischemic stroke a single-blinded placebo-controlled trialrdquo Neurology India vol 60 no 1 pp 23ndash28 2012

[109] X Fan E H Lo and X Wang ldquoEffects of minocycline plustissue plasminogen activator combination therapy after focalembolic stroke in type 1 diabetic ratsrdquo Stroke vol 44 no 3 pp745ndash752 2013

[110] X Jin J Liu K J Liu G A Rosenberg Y Yang and W LiuldquoNormobaric hyperoxia combined with minocycline provides

greater neuroprotection than either alone in transient focalcerebral ischemiardquo Experimental Neurology vol 240 pp 9ndash162013

[111] E C S Franco M M Cardoso A Gouveia A Pereiraand W Gomes-Leal ldquoModulation of microglial activationenhances neuroprotection and functional recovery derivedfrom bone marrow mononuclear cell transplantation aftercortical ischemiardquoNeuroscience Research vol 73 no 2 pp 122ndash132 2012

[112] M M Cardoso E C S Franco C C de Souza M C DaSilva A Gouveia and W Gomes-Leal ldquoMinocycline treat-ment and bone marrow mononuclear cell transplantation afterendothelin-1 induced striatal ischemiardquo Inflammation vol 36no 1 pp 197ndash205 2013

[113] H Sakata K Niizuma H Yoshioka et al ldquoMinocycline-preconditioned neural stem cells enhance neuroprotection afterischemic stroke in ratsrdquo Journal of Neuroscience vol 32 no 10pp 3462ndash3473 2012

[114] F Bellia G Vecchio S Cuzzocrea V Calabrese and ERizzarelli ldquoNeuroprotective features of carnosine in oxidativedriven diseasesrdquoMolecular Aspects of Medicine vol 32 no 4ndash6pp 258ndash266 2011

[115] A A Boldyrev S L Stvolinsky T N Fedorova and Z ASuslina ldquoCarnosine as a natural antioxidant and geroprotectorfrom molecular mechanisms to clinical trialsrdquo RejuvenationResearch vol 13 no 2-3 pp 156ndash158 2010

[116] O-N Bae K Serfozo S-H Baek et al ldquoSafety and efficacyevaluation of carnosine an endogenous neuroprotective agentfor ischemic strokerdquo Stroke vol 44 no 1 pp 205ndash212 2013

[117] Y Shen P He Y-Y Fan et al ldquoCarnosine protects against per-manent cerebral ischemia in histidine decarboxylase knockoutmice by reducing glutamate excitotoxicityrdquo Free Radical Biologyamp Medicine vol 48 no 5 pp 727ndash735 2010

[118] G K Rajanikant D Zemke M-C Senut et al ldquoCarnosine isneuroprotective against permanent focal cerebral ischemia inmicerdquo Stroke vol 38 no 11 pp 3023ndash3031 2007

[119] J Min M-C Senut K Rajanikant et al ldquoDifferential neuro-protective effects of carnosine anserine andN-acetyl carnosineagainst permanent focal ischemiardquo Journal of NeuroscienceResearch vol 86 no 13 pp 2984ndash2991 2008

[120] RGKrishnamurthyM-C SenutD Zemke et al ldquoAsiatic acida pentacyclic triterpene from Centella asiatica is neuroprotec-tive in a mouse model of focal cerebral ischemiardquo Journal ofNeuroscience Research vol 87 no 11 pp 2541ndash2550 2009

[121] K Y Lee O-N Bae K Serfozo et al ldquoAsiatic acid atten-uates infarct volume mitochondrial dysfunction and matrixmetalloproteinase-9 induction after focal cerebral ischemiardquoStroke vol 43 pp 1632ndash1638 2012

[122] MXu Y Xiong J Liu J Qian L Zhu and J Gao ldquoAsiatic acid apentacyclic triterpene inCentella asiatica attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Ycellsrdquo Acta Pharmacologica Sinica vol 33 no 5 pp 578ndash5872012

[123] R Tabassum K Vaibhav P Shrivastava et al ldquoCentella asiaticaattenuates the neurobehavioral neurochemical and histologicalchanges in transient focalmiddle cerebral artery occlusion ratsrdquoNeurological Sciences vol 34 no 6 pp 925ndash933 2013

[124] R Kollmar and S Schwab ldquoHypothermia and ischemic strokerdquoCurrent Treatment Options in Neurology vol 14 no 2 pp 188ndash196 2012

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

16 ISRN Neurology

[125] S S Song and P D Lyden ldquoOverview of therapeutic hypother-miardquo Current Treatment Options in Neurology vol 14 no 6 pp541ndash548 2012

[126] H A Choi N Badjatia and S A Mayer ldquoHypothermia foracute brain injurymdashmechanisms and practical aspectsrdquo NatureReviews Neurology vol 8 no 4 pp 214ndash222 2012

[127] S Nagel M Papadakis K Pfleger C Grond-Ginsbach A MBuchan and S Wagner ldquoMicroarray analysis of the global geneexpression profile following hypothermia and transient focalcerebral ischemiardquo Neuroscience vol 208 pp 109ndash122 2012

[128] K-E Choi C L Hall J-M Sun et al ldquoA novel stroke therapyof pharmacologically induced hypothermia after focal cerebralischemia in micerdquo FASEB Journal vol 26 no 7 pp 2799ndash28102012

[129] S E Lakhan and F Pamplona ldquoApplication of mild therapeutichypothermia on stroke a systematic review and meta-analysisrdquoStroke Research and Treatment vol 2012 Article ID 295906 12pages 2012

[130] R Kollmar B Gebhardt and S Schwab ldquoEuroHYP-1 trial EU-funded therapy study on the effectiveness of mild therapeutichypothermia for acute ischemic strokerdquoDer Nervenarzt vol 83no 10 pp 1252ndash1259 2012

[131] S Lorrio VGomez-Rangel PNegredo et al ldquoNovelmultitargetligand ITH33IQM921 provides neuroprotection in in vitro andin vivo models related to brain ischemiardquo Neuropharmacologyvol 67 pp 403ndash411 2013

[132] F Guo W-L Jin L-Y Li et al ldquoM9 a novel region of Amino-Nogo-A attenuates cerebral ischemic injury by inhibitingNADPH oxidase-derived superoxide production in micerdquo CNSNeuroscience ampTherapeutics vol 19 no 5 pp 319ndash328 2013

[133] S-W Kim Y Jin J-H Shin et al ldquoGlycyrrhizic acid affordsrobust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibitingHMGB1 phosphorylation andsecretionrdquo Neurobiology of Disease vol 46 no 1 pp 147ndash1562012

[134] J Y Kim H Y Jeong H K Lee et al ldquoNeuroprotection of theleaf and stem of Vitis amurensis and their active compoundsagainst ischemic brain damage in rats and excitotoxicity incultured neuronsrdquo Phytomedicine vol 19 no 2 pp 150ndash1592012

[135] C Ju S Hwang G-S Cho et al ldquoDifferential anti-ischemic efficacy and therapeutic time window of trans-and cis-hinokiresinols stereo-specific antioxidant and anti-inflammatory activitiesrdquo Neuropharmacology vol 67 pp465ndash475 2013

[136] X Zhang X Zhang C Wang et al ldquoNeuroprotection of earlyand short-time applying berberine in the acute phase of cere-bral ischemia up-regulated pAkt pGSK and pCREB down-regulated NF-120581B expression ameliorated BBB permeabilityrdquoBrain Research vol 1459 pp 61ndash70 2012

[137] M Khan T S Dhammu H Sakakima et al ldquoThe inhibitoryeffect of S-nitrosoglutathione on blood-brain barrier disruptionand peroxynitrite formation in a rat model of experimentalstrokerdquo Journal of Neurochemistry vol 123 supplement s2 pp86ndash97 2012

[138] P M Gharibani J Modi C Pan et al ldquoThe mechanism oftaurine protection against endoplasmic reticulum stress in ananimal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culturerdquoAdvances inExperimental Medicine and Biology vol 776 pp 241ndash258 2013

[139] C Cheyuo A Jacob R Wu et al ldquoRecombinant humanMFG-E8 attenuates cerebral ischemic injury its role in anti-inflammation and anti-apoptosisrdquo Neuropharmacology vol 62no 2 pp 890ndash900 2012

[140] Y Sun P Yu G Zhang et al ldquoTherapeutic effects of tetram-ethylpyrazine nitrone in rat ischemic stroke modelsrdquo Journal ofNeuroscience Research vol 90 no 8 pp 1662ndash1669 2012

[141] A Nehlig ldquoThe neuroprotective effects of cocoa flavanol and itsinfluence on cognitive performancerdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 716ndash727 2013

[142] T-L Yen C-K Hsu W-J Lu et al ldquoNeuroprotective effectsof xanthohumol a prenylated flavonoid from hops (humuluslupulus) in ischemic stroke of ratsrdquo Journal of Agricultural andFood Chemistry vol 60 no 8 pp 1937ndash1944 2012

[143] S S Raza M M Khan A Ahmad et al ldquoNeuroprotectiveeffect of naringenin is mediated through suppression of NF-120581B signaling pathway in experimental strokerdquoNeuroscience vol230 pp 157ndash171 2013

[144] S Li CWu L Zhu et al ldquoBy improving regional cortical bloodflow attenuating mitochondrial dysfunction and sequentialapoptosis galangin acts as a potential neuroprotective agentafter acute ischemic strokerdquoMolecules vol 17 no 11 pp 13403ndash13423 2012

[145] M Gelderblom F Leypoldt J Lewerenz et al ldquoThe flavonoidfisetin attenuates postischemic immune cell infiltration activa-tion and infarct size after transient cerebralmiddle artery occlu-sion in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 32 no 5 pp 835ndash843 2012

[146] Q-B Zhou Q Jia Y Zhang L-Y Li Z-F Chi and P LiuldquoEffects of baicalin on protease-activated receptor-1 expressionand brain injury in a rat model of intracerebral hemorrhagerdquoThe Chinese Journal of Physiology vol 55 no 3 pp 202ndash2092012

[147] L S A Capettini S Q Savergnini R F Da Silva et al ldquoUpdateon the role of cannabinoid receptors after ischemic strokerdquoMediators of Inflammation vol 2012 Article ID 824093 8 pages2012

[148] P Pacher and K Mackie ldquoInterplay of cannabinoid 2 (CB2)receptors with nitric oxide synthases oxidative and nitrativestress and cell death during remote neurodegenerationrdquo Jour-nal of Molecular Medicine vol 90 no 4 pp 347ndash351 2012

[149] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[150] J Sun Y Fang H Ren et al ldquoWIN55 212-2 protects oligo-dendrocyte precursor cells in stroke penumbra following per-manent focal cerebral ischemia in ratsrdquo Acta PharmacologicaSinica vol 34 no 1 pp 119ndash128 2013

[151] D Fernandez-Lopez J Faustino N Derugin et al ldquoReducedinfarct size and accumulation of microglia in rats treated withWIN 55212-2 after neonatal strokerdquo Neuroscience vol 207 pp307ndash315 2012

[152] N Suzuki M Suzuki K Hamajo K Murakami T TsukamotoandM Shimojo ldquoContribution of hypothermia and CB1 recep-tor activation to protective effects of TAK-937 a cannabinoidreceptor agonist in rat transientMCAOmodelrdquo PLoSONE vol7 no 7 Article ID e40889 2012

[153] N Suzuki M Suzuki K Murakami K Hamajo T Tsukamotoand M Shimojo ldquoCerebroprotective effects of TAK-937 a

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013

ISRN Neurology 17

cannabinoid receptor agonist on ischemic brain damage inmiddle cerebral artery occluded rats and non-human primatesrdquoBrain Research vol 1430 pp 93ndash100 2012

[154] S-Y Xu and S-Y Pan ldquoThe failure of animal models ofneuroprotection in acute ischemic stroke to translate to clinicalefficacyrdquoMedical ScienceMonitor Basic Research vol 19 pp 37ndash45 2013

[155] B A Sutherland J Minnerup J S Balami F Arba A MBuchan and C Kleinschnitz ldquoNeuroprotection for ischaemicstroke translation from the bench to the bedsiderdquo InternationalJournal of Stroke vol 7 no 5 pp 407ndash418 2012

[156] A Davalos J Alvarez-Sabın J Castillo et al ldquoCiticoline inthe treatment of acute ischaemic stroke an international ran-domised multicentre placebo-controlled study (ICTUS trial)rdquoThe Lancet vol 380 no 9839 pp 349ndash357 2012

[157] W-D Heiss M Brainin N M Bornstein J Tuomilehto and ZHong ldquoCerebrolysin in patients with acute ischemic stroke inAsia results of a double-blind placebo-controlled randomizedtrialrdquo Stroke vol 43 no 3 pp 630ndash636 2012

[158] X Liu L Wang A Wen et al ldquoGinsenoside-Rd improvesoutcome of acute ischaemic strokemdasha randomized double-blind placebo-controlled multicenter trialrdquo European Journalof Neurology vol 19 no 6 pp 855ndash863 2012

[159] T J England M Abaei D P Auer et al ldquoGranulocyte-colonystimulating factor for mobilizing bone marrow stem cells insubacute stroke the stem cell trial of recovery enhancementafter stroke 2 randomized controlled trialrdquo Stroke vol 43 no2 pp 405ndash411 2012

[160] M D Hill R H Martin D Mikulis et al ldquoSafety and efficacyof NA-1 in patients with iatrogenic stroke after endovascularaneurysm repair (ENACT) a phase 2 randomised double-blind placebo-controlled trialrdquo The Lancet Neurology vol 11no 11 pp 942ndash950 2012

[161] S M D Mees A Algra W P Vandertop et al ldquoMagnesiumfor aneurysmal subarachnoid haemorrhage (MASH-2) a ran-domised placebo-controlled trialrdquo The Lancet vol 380 no9836 pp 44ndash49 2012

[162] J I Suarez R H Martin E Calvillo et al ldquoThe albumin insubarachnoid hemorrhage (ALISAH) multicenter pilot clinicaltrial safety and neurologic outcomesrdquo Stroke vol 43 no 3 pp683ndash690 2012

[163] M Fisher ldquoRecommendations for standards regarding preclin-ical neuroprotective and restorative drug developmentrdquo Strokevol 30 no 12 pp 2752ndash2758 1999

[164] G W Albers J Bogousslavsky M A Bozik et al ldquoRecommen-dations for clinical trial evaluation of acute stroke therapiesrdquoStroke vol 32 no 7 pp 1598ndash1606 2001

[165] U Dirnagl and M Fisher ldquoInternational multicenter random-ized preclinical trials in translational stroke research itrsquos time toactrdquo Journal of Cerebral Blood Flow and Metabolism vol 32 no6 pp 933ndash935 2012

[166] UDirnagl AHakimMMacleod et al ldquoA concerted appeal forinternational cooperation in preclinical stroke researchrdquo Strokevol 44 no 6 pp 1754ndash1760 2013