Review Article Intracerebral Hemorrhage, Oxidative Stress

Review ArticleIntracerebral Hemorrhage Oxidative Stressand Antioxidant Therapy

Xiaochun Duan12 Zunjia Wen1 Haitao Shen1 Meifen Shen1 and Gang Chen1

1Department of Neurosurgery The First Affiliated Hospital of Soochow University 188 Shizi Street Suzhou 215006 China2Department of Neurosurgery Yangzhou No 1 Peoplersquos Hospital No 45 Taizhou Road Yangzhou 225001 China

Correspondence should be addressed to Meifen Shen 53137452qqcom and Gang Chen nju neurosurgery163com

Received 21 September 2015 Revised 20 November 2015 Accepted 28 March 2016

Academic Editor Norihito Shimamura

Copyright copy 2016 Xiaochun Duan et alThis is an open access article distributed under theCreative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Hemorrhagic stroke is a common and severe neurological disorder and is associated with high rates of mortality and morbidityespecially for intracerebral hemorrhage (ICH) Increasing evidence demonstrates that oxidative stress responses participate inthe pathophysiological processes of secondary brain injury (SBI) following ICH The mechanisms involved in interoperablesystems include endoplasmic reticulum (ER) stress neuronal apoptosis and necrosis inflammation and autophagy In this reviewwe summarized some promising advances in the field of oxidative stress and ICH including contained animal and humaninvestigations We also discussed the role of oxidative stress systemic oxidative stress responses and some research of potentialtherapeutic options aimed at reducing oxidative stress to protect the neuronal function after ICH focusing on the challenges oftranslation between preclinical and clinical studies and potential post-ICH antioxidative therapeutic approaches

1 Introduction

Intracerebral hemorrhage (ICH) is a serious cerebrovascularcondition leading to high mortality and morbidity in adultsThe global incidence of ICH is increasing year by yearwith a trend towards growing incidence at a younger age[1] Despite significant progress in clinical treatment the 5-year mortality rate remains over 50 (52 for males 56for females) in ICH patients older than 45 years [2] Evenafter surgical treatment 20 of ICH patients experiencevarying degrees of neurological dysfunction requiring long-term hospitalization and rehabilitation [3] Thus ICH notonly causes serious morbidity and mortality in patients butalso incurs a serious burden on families and society Thepathological mechanisms of hematoma after ICH withinbrain parenchyma triggers a series of adverse events causingSBI and severe neurological deficits [4] In recent yearsprogress has been made in ICH research In particular ithas been established that oxidative stress plays an importantrole in SBI after ICH which leads to irreversible disruptionof the components of the neurovascular unit constitutinggray and white matter and is followed by blood brain barrier

disruption and deadly brain edema with massive brain celldeath [5] Antioxidative treatment aimed at preventing orreducing oxidative stress has provided new insights into ICHtherapy In this paper we review the mechanism of oxidativestress after ICH and the detection of biomarkers we alsosummarize in detail the latest developments in antioxidativestress therapy

2 Definition of Oxidative Stress

Oxidative stress describes a state when the body respondsto various harmful stimuli and produces excessive amountsof reactive oxygen free radicals known as reactive oxygenspecies (ROS) and reactive nitrogen radicals known asreactive nitrogen species (RNS) Oxidative stress reflects animbalance between the systemic manifestation of reactiveoxygen species and a biological systemrsquos ability to readilydetoxify the reactive intermediates or to repair the resultingdamage This leads to accumulation of ROS and RNS in thebody or in cells causing cell toxicity and eventually leadingto tissue damage The damage to intracellular proteinslipids and DNA caused by oxidative stress products such as

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 1203285 17 pageshttpdxdoiorg10115520161203285

2 Oxidative Medicine and Cellular Longevity

reactive free radicals and peroxides is an important factor[6] in aging and is also involved in the pathogenesis ofcancer [7] Parkinsonrsquos disease [8] Alzheimerrsquos disease [9]atherosclerosis [10] heart failure [11] sickle cell disease [12]lichen planus [13] vitiligo [14] infection [15] chronic fatiguesyndrome and other diseases Although excessive oxidativestress is considered harmful reactive oxygen is beneficial formaintaining the normal physiological activity of the bodyand plays a role in defense killing pathogens by regulatingthe immune system [16] Short-term activation of oxidativestress may have an important role in preventing aging Forexample hydrogen peroxide the most common form ofactive oxygen promotes apoptosis at high concentrationsinducing antioxidant enzyme expression and increasing theantioxidant capacity of cells at low concentration [17] Theoutcome of oxidative stress depends on the degree of dam-age in the balance between the oxidative and antioxidativeresponses of the body Cells are capable of self-regulation ofmild oxidative stress changes and restoring cell homeostasisHowever severe oxidative stress can lead to cell death andit has been reported that although moderate oxidative stresscan cause cell apoptosis intense oxidative stress may lead tonecrosis [18]

3 Oxidative Stress and ICH

Oxidative stress plays an important role in SBI after ICH[19] Oxidative stress is involved not only in the pathologicalprocess of ICH but also at various important stages of patho-physiological response during ICH [5] A variety of pathwayscan induce the generation of free radicals after ICH of whichthere are twomajor pathways First blood cell decompositionproducts such as iron ions heme and thrombin can inducethe production of free radicals Experimental results showthat divalent iron ions can interact with lipid and generatefree radicals leading to nerve damage [20 21] Secondinflammatory cells such as microglia and neutrophils cangenerate free radicals During the inflammatory responsefollowing ICH neutrophils are stimulated and activatedresulting in outbreak of the respiratory chain releasing largeamounts of reactive oxygen species nitric oxide and soon and the excessive consumption of superoxide dismutase(SOD) and the occurrence of lipid peroxidation [22] Damageto nerve cells caused by free radicals manifests in a numberof ways with free radicals involved in pathological processesranging from cell membrane damage to DNA interruptionor even apoptosis [23] Cell damage caused by oxygen freeradicals is due to the induction of lipid peroxidation Thelipid-rich brain tissue is particularly sensitive to oxygenfree radicals that can enhance lipid peroxidation causemembrane damage and increase cell membrane permeabil-ity and calcium ion influx [23] In the meantime cross-linking and polymerization of membrane lipids will occurdue to lipid peroxidation which will indirectly inhibit theactivities of membrane proteins such as calcium pumpssodium pumps and Na+Ca2+ exchangers [24] This leadsto a further increase in intracellular calcium concentrationwhich subsequently stimulatesmitochondrial calciumpumps

to take in calcium Calcium and phosphate in the mito-chondria combine and form insoluble calcium phosphatewhich causes interference in mitochondrial oxidative phos-phorylation and leads to a decrease in ATP production [25]Meanwhile increased intracellular calcium ion concentrationcan activate phospholipase promoting membrane phospho-lipid decomposition and causing damage to the structureof cell and organelle membranes [26 27] In summary freeradicals are the major killers of hemorrhagic brain tissuewith considerable recent research indicating that free radicalsare closely related to brain injury and disorders caused bybleeding (Figure 1)

31 Oxidative Stress and Inflammation following ICH Inflam-mation and oxidative stress are closely related Oxidativestress induces inflammation while inflammation causesdamage through oxidative stress [28] ROS can induce theexpression of acute proinflammatory cytokines directly suchas Tumor Necrosis Factor (TNF-120572) and Interleukin-10 (IL-10) and also activate nuclear factor-120581B(NF-120581B) which playsthe vital role in inflammation reaction [29 30] On the otherhand proinflammatory cytokines can induce the productionof ROS [29] thus a positive feedback cycle is formed Inrats hemoglobin mediates oxidative and nitration stressafter ICH with the nitration stress induce perihematomaledema which may be involved in neurovascular damage andneurological deficit [31] Oxidative stress may initiate theupregulation of MMP-9 levels in brain damage after ICH[32] MMP-9 levels in animal models have largely showndetrimental correlations with mortality clinical outcomehematoma volume and SBI Animal models and clinicalstudies have established a timeline forMMP-9 expression andcorresponding perihematomal edema after ICH that includean initial peak on days 1ndash3 and a secondary peak on day7 Another study demonstrated that MMP-9 expression wasincreased accompanied by elevated TNF-120572 and IL-1120573 levelsand cerebral edema and SBI were aggravated [33] Clinicalstudies suggest that MMP-9 may be detrimental in the acutephase through destruction of basal lamina activation ofvascular endothelial growth factor and activation of apop-tosis but assist in recovery in the subacute phase throughangiogenesis Therefore MMP-9 activity may have dual roleand temporal profile in post-ICH [34]

Additional studies have shown that prostaglandin-mediated inflammatory mechanisms are involved in sec-ondary brain damage after ICH In a collagenase-inducedICH model in mice prostaglandin E2 receptor 1 (EP1R) wasexpressed in neurons and axons but not in astrocytes andmicroglia EP1R agonists induce brain edema cell deathneurodegeneration neuroinflammation and behavioraldefects while EP1R suppression protects the brain Researchhas confirmed that the inhibition effect of EP1R is mainlythrough the reduction of Scr enzyme phosphorylation levelsand MMP-9 activation thus attenuating oxidative stress andwhite matter damage [35]

Peroxiredoxin I (PrxI) and heme oxygenase-1 (HO-1) areconsidered to be oxidative stress- and heme-related proteinsand heme inhibits PrxI antioxidant activity Studies have

Oxidative Medicine and Cellular Longevity 3

Intracerebral hemorrhage(ICH)

Lipidperoxidation

Proteinoxidation

DNA damage

CytotoxicityROS

Oxidative stressRNS

Inflammation ER stress

AutophagyApoptosis

Secondary brain injury

Brain edema BBB breakdown Vasospasm Endothelial injury

Systemic responseinjury

Neurological dysfunction

necrosis

Ca2+Fe2+

overloaded

Figure 1 Schematic representation of major intracellular pathway in the role of reactive oxygen species radicals in hemorrhagic stroke ROSReactive oxygen species RNS reactive nitrogen species ICH intracerebral hemorrhage ER stress endoplasmic reticulum stress BBB bloodbrain barrier

shown that after ICH the expression of HO-1 and PrxI wasinduced around the hemorrhagic region In the acute bleed-ing phase PrxI and HO-1 are mainly expressed in microgliawhile in subacute and chronic phases expression is mainlyin astrocytes [36] However Prx1 is multifunctional proteinimportant for cell protection against oxidative stress butalso works to facilitate production of prostaglandins E2 andD2 (PGE2 and PGD2) through nuclear factor- (erythroid-derived 2) like 2 (Nrf2) [37] Prx family proteins releasedextracellularly from necrotic brain cells in the ischemicbrain which can induce the production of inflammatorycytokines through Toll-like receptors 2 and 4 prompt therelease of high mobility group box 1 (HMGB1) protein andinhibit the activation of phagocytic cells and promotingcell death even though intracellular Prxs have been shownto be neuroprotective Extracellular Prxs are involved inbrain ischemia-reperfusion injury by activating inflamma-tory pathways [38] Acute inflammation is regulated by thetime- and cell type-dependent production of cytokines andother signaling molecules including reactive oxygen speciesand prostaglandins [37] In SBI after ICH inflammatorydamage oxidative stress calcium overload iron overloadand cytotoxic injury form a complex cascade of reactionsamong which inflammation and oxidative stress may playmajor roles however the relationship between inflammationand oxidative stress is complicated and needs further explo-ration

32 Oxidative Stress and Endoplasmic Reticulum Stress afterICH The pathological conditions may cause an imbalancebetween ER protein folding load and capacity after ICHleading to the accumulation of unfolded proteins in the ERlumen leading to a condition known as ER stress [5] ERprovides a unique oxidation-folding environment favoringdisulfide bond formation thus during the endoplasmicreticulum protein folding process ROS will be produced[39] Moderate activation of unfolded protein response afterexposure to oxidation stress may be an adaption mechanismto protect cell function and survival but ROS accumulationcaused by excessive ER stress will further aggravate oxidativestress [39] After ICH both oxidative and ER stress levels areupregulated [5 40] and alleviating either ER or oxidativestress will help improve secondary neuronal damage [41]NADPH oxidase is thought to play an important contactrole during the oxidative and ER stress process [42] NMDAreceptor is activated after ICH a large amount of Ca2+fluxes into the cells leading to an NADPH oxidase andmitochondrial electron transport chain to produce super-oxide [43 44] Therefore NADPH oxidase generated byNMDA activation is considered a major superoxide source[45] In addition NADPH oxidase plays an important rolein vascular brain disease Using NADPH oxidase inhibitorsand nonspecific ROS scavengers can reduce oxidative stressimprove cerebral vascular function and reduce cerebral amy-loid angiopathy-related microhemorrhages [46] Neurons


mainly express NOX2 in NADPH oxidase which comprisesgp91phox catalytic subunit and p47phox assembly subunit [43]In a gp91phox knockout mouse ICHmodel brain damage andoxidative stress levels were significantly reduced [47] Studieshave shown that NOX-mediated oxidative stress is inducedby unfolded protein responseER stress whereas ER stress-induced apoptosis can be blocked by knockout of NOX2 geneor antioxidant N- acetylcysteine [48 49]

The PERK pathway is considered a molecule pathwaywhich links oxidative and ER stress Nrf2 induces con-siderable antioxidant gene expression [21] After ICH dueto cytotoxicity mediated by heme hemoglobin and ironoverload Nrf2 is phosphorylated by PERK and then dis-sociates from the Nrf2KEAP1 complex and enters into thenucleus to promote antioxidant gene expression leading toa resistance to oxidative stress and playing a cell-protectiverole [21 50] Additionally inNrf2 knockout (Nrf2(minusminus))miceICH model injury volume was significantly larger in 24 hafter induction of ICH which correlated with neurologicaldeficits This exacerbation of brain injury was also associatedwith an increase in leukocyte infiltration production ofreactive oxygen species DNA damage and cytochrome crelease during the critical early phase of the post-ICH period[51] After subarachnoid hemorrhage (SAH) KEAP1-Nrf2-ARE pathway is activated and after sulforaphane or tert-butylhydroquinone activates the Nrf2 pathway NQO1 andGST-1205721 levels are increased thus playing a protective rolein the brain [52ndash54] In addition Nrf2 and TranscriptionalFactor 4 (ATF4) activate antioxidant response factor (ARE)by upregulating its expression [55 56] indicating that theER and oxidative stress signaling pathways have synergisticeffects [57]

Endoplasmic reticulum oxidoreductase (ERO1120572) formsa disulfide bond promoting protein refolding and helpingreduce ER stress However ERO1120572 activation transfers theelectron to the oxygen molecule and produces ROS [58] Theendoplasmic reticulum stress marker CHOP a downstreammolecule of PERK induces ERO1120572 expression and aggravatesER oxidation on the contrary in cells lacking CHOP the ERstress level induced by ERO1120572 is reduced [59]

Other studies have shown that after ER stress inositol145-trisphosphate receptors (IP3Rs) are activated and cal-cium release from the endoplasmic reticulum calcium storageis increased leading to intracellular calcium overload andROS production [60] In addition the elevated ROS levelcauses the activation of ryanodine receptor (RyRs) anotherendoplasmic reticulum Ca2+ release channel and the releaseof Ca2+ from the ER [61 62] Thus Ca2+ activates IP3Rs orRyRs as an input signal aggravating intracellular calciumoverload After ICH ER and oxidative stress activate ER Ca2+release via RyRs and IP3Rs pathways leading to neuronaltoxicity and aggravating SBI [63]

33 Oxidative and Neural Cell Apoptosis or Necrosis afterICH Apoptosis is a regulated cell death which is also calledprogrammed cell death (PCD) The main causes of nervecell apoptosis are the release of thrombin during bloodcoagulation the toxic effects of hematoma components and

its degradation products and the oxidative stress reaction inperihematoma [5] ROS induce neuronal apoptosis througha variety of pathways Excessive free radicals can cause theperoxidation of lipid protein and nucleic acid through directand indirect pathways leading to apoptosis [64] Hypoxianitric oxide (NO) and ROS inducers can all cause theexposure of neuronal membrane phosphatidylserine [65]Hydrogen peroxide andNO can lead to nuclear condensationand DNA fragmentation and have a synergistic effect oninducing neuronal apoptosis [66] Additionally NO caninduce apoptosis of hippocampal and dopamine neurons [6768] and hydrogen peroxide can induce apoptosis throughdisrupting mitochondrial function and promoting proapop-tosis gene expression [69 70] Oxidative stress inducesapoptosis through pathways such as the mitochondrialdeath receptor and endoplasmic reticulum stress pathways Itcan also induce apoptosis by activating themitogen-activatedprotein kinase pathway activating NF-120581B and upregulatingits expression or activating caspases [71] The intrinsic andextrinsic pathways of apoptosis are not necessarily indepen-dent of each other some of the factors in both types ofpathway may have a synergistic effect in the regulation of theapoptosis process initiated by a single stimulator [72]

Hemorrhagic stroke proteins were shown to be involvedin necrosis via proteomics approach [73] Necrosis wasformerly considered to be an accidental unregulated formof cell death resulting from excessive stress although it hasbeen suggested that this is an oversimplistic view as necrosismay under certain circumstances involve the mobilizationof specific transduction mechanisms [74] Research sug-gests that superoxide generated by NADPH oxidase besidesthat generated by the mitochondria may contribute to theremarkable increase in the intracellular level of superoxidein the cells treated with menadione for 6 h resulting inthe switch from apoptosis to necrosis [75] Additionallynecrosis is characterized by plasma membrane rupture aswell as nuclear and cellular swelling other than regulatedcell death However these findings suggest that DNA damagecytosolic reactive oxygen species (cROS) generation andmitochondrial hyperactivation induced necrosis through aPARP1-dependent pathway while generation of nitric oxide(NO) and mitochondrial ROS (mROS) remained unaffected[76] Nevertheless the relationship between necrosis andoxidative stress after ICH is still not fully clear

Necroptosis was recently discovered as one form ofprogrammed cell death (PCD) that shares characteristicswithboth necrosis and apoptosis Necroptosis involves FasTNF-120572death domain receptor activation and inhibition of receptor-interacting protein I kinase [77] Recent study identifieda novel role for the necroptosis inhibitor necrostatin-1in limiting neurovascular injury in tissue culture modelsof hemorrhagic injury [78] Another study demonstratedthat the specific inhibitor necrostatin-1 suppressed apoptosisand autophagy to exert these neuroprotective effects afterICH and that there existed a cross talk among necrop-tosis apoptosis and autophagy after ICH [79] Moreovernecrostatin-1 reduced RIP1-RIP3 interaction and further


inhibited microglia activation and TNF-120572 and IL-1120573 expres-sion after ICH These findings indicate that RIP1RIP3-mediated necroptosis is an important mechanism of celldeath after ICH [80] In another study hemin concentra-tion dependently induced necroptotic cell death in corticalastrocytes within 5 h of treatment Superoxide productionparalleled the increase in iNOS expression and inhibition ofeither iNOS (aminoguanidine or iminopiperdine) or super-oxide (apocynin) significantly reduced cell death Hemin-induced peroxidative injury was associated with a rapiddepletion of intracellular glutathione (GSH) culminating inlipid peroxidation and cell death [81] Together these studiessuggest a novel role for oxidative stress in necroptotic braininjury after ICH

34 Oxidative Stress and Autophagy after ICH Autophagyis a lysosomal degradation pathway that is essential forsurvival development and homeostasis which plays a keyrole in diverse pathologies [82] Recent studies indicate thatautophagy is also involved in the pathological process ofcerebral hemorrhage as a degradation process of proteinsand organelles within the cells [83ndash87] During this processoxidative stress may contribute to autophagy formationIn addition autophagy may reduce oxidative damage byengulfing or degrading stress products [88] The intracellularmechanism which regulates autophagy via ROS levels canbe summarized as transcriptional and posttranscriptionalregulation including various intracellular signaling pathwayssuch as ROS-FOXO3-LC3BNIP3 autophagy ROS-Nrf2-P62autophagy [82] ROS-HIF1-BNIP3NIX autophagy andROS-TIGAR autophagy Autophagy can also regulate ROS levelsthrough a chaperone-mediated autophagy pathway themito-chondrial autophagy pathway and P62-mediated signalingpathways [89] Autophagy plays a dual role in ischemicstroke pathological processes [90] Our study also foundthat autophagy may play different roles in pathogenesis atdifferent stages of cerebral hemorrhage and further studyof the relationship between oxidative stress and autophagyafter ICH may provide a theoretical basis for elucidating thepathogenesis of cerebral hemorrhage [91]

4 Detection of the Level of Oxidative Stress

Biomolecules modified by ROS or any biological processesaffected by ROS can be biomarkers of oxidative stressProteomics has provided a new approach for further studyof biomarkers and mechanisms of the pathological processfollowing cerebral hemorrhage [73] A proteomic analysis ofa collagenase-induced rat ICH model 3 hours after bleedingshowed that compared with a control group there were86 proteins expressed differently that were mainly pro-teins involved in autophagy ischemia necrosis apoptosiscalcium-activation oxidative stress cytokine secretion andso on Following ICH superoxide dismutase-2 (SOD2) gua-nine nucleotide-binding protein peroxiredoxin-1 (PRDX-1) and lactate dehydrogenase are downregulated whereasperoxide catalase expression is upregulated [73] additionallyPRDX-1 protein levels around the hematoma began to rise

one day after ICH [36] Even so PRDX family proteinsinteract with intracellular antioxidant enzymes and play animportant role in the cellular mechanism of SBI Thus it issuggested that expression of the oxidative stress biomarkerfollowing cerebral hemorrhage is a dynamic process relatedto the volume of the cerebral hemorrhage hematoma bleed-ing type and different stages of bleeding A considerablenumber of animal experiments have confirmed that aftercerebral hemorrhage many biomarkers are expressed specif-ically in brain tissue and this has played an important rolein deeper study of the disease [92 93] Ideally a biomarkerfor a disease is detected in the target tissue and organsHowever the direct detection of various biological markersin the human brain is not realistic therefore for an oxidativestress biomarker to have clinical value it must not only beconvenient for specimen collection but also accurately reflectthe main source of ROS

41 Detection of Lipid Peroxidation Markers Lipid perox-ide is an important product of brain damage and mainlyderives from the secondary products of unsaturated fatty acidperoxidation of membrane phospholipid causing structuraland functional damage to the cell membrane Currently thepresence of lipid peroxide in the peripheral blood is the mostcommonly used marker reflecting oxidative stress The lipidperoxides malondialdehyde (MDA) and thiobarbituric acidreactive substance (TBARS) have been studied inmost depthClinical studies and animal experiments have all shown thatserum MDA levels increase rapidly at the early stage ofICH and the level is closely related to clinical symptomseverity [92 94] However estimating lipid peroxide bymeasuring TBARS and MDA levels is not very accurateThe spectrophotometricmethod calculates the concentrationbased on the strength of chromogen produced from TBAreaction but there are a number of substances in body fluidsthat can react with TBA andMDA cannot specifically reflectoxidative stress levels after ICH [95] Moreover MDA andTBARS are derived from endogenous epoxide degradationrather than from the products of peroxidation thus themeasured level of MDA and TBARS can easily lead to anoverestimate of the free radical level

Oxidized low-density lipoprotein (oxLDL) and lectin-like oxidized LDL receptor-1 (LOX-1) can damage endothe-lial function enhancing platelet aggregation and promotingthrombosis thus playing an important role in the patho-genesis of cerebral vasospasm after SAH [96 97] Althoughplasma oxLDL level is considered reflective of the oxidationstate of the body [98] it is uncertain whether it can beused following ICH as a peripheral marker directly related tooxidative stress injury

F2-isoprostane (F2IP) a lipid peroxidationmarker whichcan be detected in both the blood and urine [99] is more sta-ble and has higher sensitivity and specificity when comparedwithMDAandTBARS F2IP is usuallymeasured by gas chro-matographymass spectrometry or high-performance liquidchromatographymass spectrometry Studies have shown thatin SAH patients high levels of F2IP in cerebrospinal fluid aresignificantly correlated with poor prognosis


Measuring F4-neuroprostanes (F4-NPs) can better assessthe oxidative stress level of brain tissue after SAH andpredict the prognosis of patients with SAH [100] 8-iso-Prostaglandin F2120572 (8-iso-PGF2120572) is an isomer derivative ofF2-isoprostanes and is a reliable biomarker currently used toevaluate oxidative stress and lipid peroxidation It is present inblood urine and the fluid secretions of various tissues it canalso exist in tissue cells either in its free form or esterified inphospholipids or other lipids and itmaintains a stable level inthe body Detecting 8-iso-PGF2120572 concentration in the bloodof ICH patients has shown that 8-iso-PGF2120572 levels increasedafter ICH and are positively correlated with NIHSS (NationalInstitute ofHealth Stroke Scale) score and hematoma volumeAnalysis indicates that plasma level of 8-iso-PGF2120572 is anindependent prognostic factor for ICH [101] However eventhough detection of plasma lipid hydroperoxides (ROOH) inpatients with ICH was positively correlated with mortalitywithin one week after ICH regression analysis has shownthat it cannot be used as a prognostic predictor for clinicaloutcome [102] Plasma lipid peroxides are mostly induced byfree radicals and current detection techniques are subject tothe limitations of serum or specimen handling and storageconditions with a risk of self-oxidation of the specimensleading to an abnormal increase in the detection levels ofrelated biological markers Thus their value in clinical use isstill to be determined

42 Detection of DNA Oxidative Damage Markers Mecha-nisms of DNA oxidative damage include oxidative modifica-tion and DNA cleavage more specifically these include DNAdamage especially 8-hydroxy-2-deoxyguanosine (8-OHdG)DNA breakage and DNA-protein cross-linking

8-OHdG is considered a reliable indicator for detectingthe degree of oxidative stress due to its relatively high contentin DNA oxidation products and its high specificity [103104] Research showed 8-OHdG turned positive 3 days afterICH but the apurinicapyrimidinic site began to increase24 hours after hemorrhage peaking in the first 3 daysand beginning recovery from the seventh day [105] Ku-70and ku-86 proteins are DNA repair proteins that begin todecline 24 hours after ICH reducing significantly 3 days afterhemorrhage and returning to normal by the seventh dayKu-70 and ku-86 proteins may participate in DNA damageafter brain hemorrhage along with oxidative damage Otherstudies focusing on the relationship between oxidative stresslevel detection and ICH prognosis have indicated that 8-OHdG level is closely related to prognosis 30 days after ICH[106]

43 Detection of Antioxidant Levels Antioxidants are a groupof compounds that can effectively resist or repair cellularoxidative damage to neuron lipids DNA and proteins Manystudies have used in vivo antioxidant levels as indirect mark-ers for the evaluation of oxidative stress in stroke patientsStudies have shown that in ICH patients the activity of serumSOD myeloperoxidase and glutathione peroxidase (GSH-Px) glutathione S-transferase 1205721 (GST-1205721) and quinoneoxidoreductase 1 (NQO1) increases significantly after ICH or

SAH and this has associated with early brain damage andmultiple organ damage [52 95 107] In MRI-confirmed cere-bral small vessel disease the detection of blood inflammationand oxidative stress markers has shown that tumor necro-sis factor receptor-120572 (TNFR120572) and peroxidase are highlyexpressed in microbleeding lesions while the expression ofperoxidase is decreased in asymptomatic cerebral ischemiapatients [108] Antioxidant enzymes can help scavenge freeradicals and reduce or eliminate oxidative damage thusdetermining the amount and activity of antioxidant enzymesin serum may reflect antioxidant activity in the body

Nonenzymatic antioxidants are an important class ofantioxidants that play important roles in the pathogenesisof cerebral hemorrhage These include glutathione [53 109]antioxidant vitamins [106 110] uric acid [111] ubiquinone-reducing substances [54 112] metallothionein [113] andthioredoxin system [114 115] However methods for thedetection of oxidative stress related nonenzymatic antiox-idants in the peripheral blood are few one study on thelevel of glutathione (GSH) in umbilical cord blood afterneonatal periventricular hemorrhage found that cord bloodGSH level was not related to intraventricular hemorrhage inlow-birthweight neonates [116] Uric acid is an antioxidantmolecule of the body but studies have found that althoughserum uric acid levels are related to ischemic stroke theyhave no significant correlation with ICH [111] Although bothantioxidant enzymes and nonenzymatic antioxidant levelsshow changes in the cerebral hemorrhage patient it still notpossible to determine whether these changes are the cause orthe result of oxidative stress after ICH due to a lack of dataon the antioxidant levels of patients before onset

44 Detection of Other Oxidative Stress Markers Free-iron-mediated oxidative stress reaction after ICH plays an impor-tant role in SBI [93 117 118] and measurement of free ironis an effective method for detecting oxidative stress A novelmultichannel spectral analysis method has been recentlydeveloped to determine the concentration of iron andiron-containing protein polymer in and around hematomaResults have shown a significant increase in total iron inhematoma whereas in perihematoma increases are insignif-icant Iron protein polymers in and around the hematomawere also significantly increased compared with a controlgroup [119] Iron plays an important role in generating freeradicals following cerebral hemorrhage [118] aggravatingbrain damage by producing OHminus through the Fenton reac-tion Transferrin is an iron binding protein which can bindto harmful free iron ions produced after ICH and transportthem back to the cells High-serum ferritin levels increase 3-4days after ICHwhich are independently associatedwith pooroutcome in patients with ICH [120] The study may suggesta neurotoxic effect of increased body iron stores in patientswith hemorrhagic stroke [121] while the cerebrospinal fluidferritin level continues to rise 5 days after ICH or SAHCurrently cerebrospinal fluid ferritin level is considered amore reliable evaluatingmarker for hemorrhagic stroke [122]Unfortunately those results only proved in the experimentresearch that this is difficult to prove with biochemical assays


that fail to differentiate between alterations that occur withinthe hematoma and perihematoma zone in human

Bilirubin is a metabolic product of heme and the levelof bilirubin in the body may reflect oxidative stress intensityafter ICH [123 124] Determination of cerebrospinal fluidbilirubin and oxyhaemoglobin is important for the identifi-cation of spontaneous subarachnoid hemorrhage inCT-scan-negative patients [125]

3-Nitrotyrosine (3-NT) is a maker of ONOOminus forma-tion Under pathological conditions the formation of 3-NTincreases alongwith increase of reactive oxygen and nitrogenOverexpressed NOSwas concomitant with large quantities of3-NT formation in the perihematomal after ICH as evaluatedby Western blot and immunofluorescence Moreover levelsof 3-NT in serum which had a similar upregulation to that ofin brain tissues had a marked correlation with brain edemacontent and neurological deficits Thus 3-NT reflects theseverity of SBI and predicting prognosis [126]

Oxidative stress is the result of imbalance between in vivoROS generation and antioxidant defense and measurementof a single oxidative stress product of antioxidant cannotfully reflect the oxidative stress level of the body thusmeasurement of plasma total antioxidant capacity (TAC) andtotal oxidant status (TOS) is more effective than other singlemeasurement methods Studies have found that TOS andNO serum levels in patients are significantly increased aftercerebral hemorrhage while TAC levels and catalase activityare significantly reducedTherefore the oxidative stress index(OSI) is increased [115 127]

In summary the most commonly used oxidative stressmarkers are lipid peroxides peroxidation products of DNAand protein and antioxidant substances in animal modelIn the past few decades many studies have been dedicatedto finding biomarkers that can effectively reflect the levelof oxidative stress after ICH in human (Table 1) How-ever results remain unsatisfactory due to the complexity ofoxidative stress and the repeatability of antioxidants in avariety of reactionsThis makes it difficult to find a biologicalmarker with high sensitivity and specificity In addition dueto limitations in sample collection storage and pretreat-ment method the reproducibility of the measurement ofICH-related oxidative stress markers is poor Consequentlyimprovement in methodology has become the prerequisitefor a simple accurate and reliable biologicalmarker For nowa comprehensive analysis of various oxidative stress biologicalmarkers after ICH may better reflect the level of oxidativestress of the body

5 Antioxidant Therapy after ICH

Maintaining redox equilibrium of the body is importantfor health maintenance and disease intervention and theincrease in oxidative stress levels and free radicals is relatedto antioxidation ability Lowering the body level of ROS andRNS and increasing antioxidant capacity are two antioxidanttreatment strategies after cerebral hemorrhage Oxidativestress therapy after ICHmainly involves the use of natural andsynthetic antioxidants (Table 2) Natural antioxidants include

enzymes and nonenzyme antioxidants Antioxidant enzymesinclude SOD catalase (CAT) peroxidase glutathione peroxi-dase (GSH-Px) and NADPH and enhancing the activities ofthese can result in antioxidant effects Nonenzymatic antioxi-dants are mostly derived from natural plants or their extractsand include vitamin C vitamin E glutathione melatonincarotenoids resveratrol ursolic acid andmicrominerals suchas copper zinc and selenium

51 Recent Updates in the Treatment of ICH Using NaturalCompounds Nutrition and oxidative stress have a closetwo-way relationship On one hand nutrients can producereactive oxygen intermediates and free radicals during themetabolic process of the body and transition metal traceelements such as iron and copper ions can promote ROSgeneration On the other hand a balanced diet and propernutrition can enhance the antioxidant defense capability ofthe body as some nutrients and food components havedirect or indirect antioxidant effects [128] Pyrroloquinolinequinone (PQQ) is a newly discovered water-soluble vitaminpresent as an antioxidant in food Studies have shown thatpretreatment of ICH rats with 10mgkg PQQ can effectivelyreduce neurological deficit hematoma volume and cerebraledema expansion PQQ treatment reduces ROS productionincreases the Bcl-2Bax protein levels and decreases theexpression of apoptotic-factor-activated caspase-3Thereforein the treatment of cerebral hemorrhage PQQ exerts itsneuroprotective effect via antioxidative stress [129] Mela-tonin is a hormone secreted by the pineal body By scavengingfree radicals promoting antioxidation and inhibiting lipidperoxidation melatonin protects cell structure preventsDNA damage and reduces the level of peroxides in thebody We found that treating SAH rats with intraperitonealinjection of melatonin can regulate oxidative stress levelsthrough the Nrf2-ARE signaling pathway and reduce earlybrain injury after SAH [112] Plasma 120572-lipoic acid levelsreflect the bodyrsquos antioxidant levels and treating SAH ratswith 120572-lipoic acid raised the antioxidation level of the bodyproducing a neuroprotective effect [130] Sulforaphane exertsa brain protection effect by inhibiting oxidative stress [131]the mechanism of which activation of Nrf2 pathway hasbeen confirmed in ICH research [21] Ursolic acid is presentin triterpenoids in natural plants and can effectively reduceoxidative stress levels increase antioxidative stress levels andreduce early brain injury after SAH [132] Sesamin a lignanof sesame seed oil is a promising natural product as a noveltherapeutic strategy based on the regulation of microglialactivities via inhibition of inducible NO synthase (iNOS)protein expression and accompanied by the activated p4442MAPK pathway in ICH [133] Other natural plant extractscan be used as natural antioxidants including resveratrol[134] astaxanthin [135] baicalein [136] astragaloside [137]proanthocyanidin [138] (minus)-epigallocatechin-3-gallate [139]and apple polyphenol [97] Studies in ICH animal modelshave shown that treatment using these extracts can exhibitneuroprotective effects by inhibiting oxidative stress upreg-ulating antioxidant levels and reducing SBI after ICH


Table 1 Human biomarkers and oxidative stress after ICH

Biomarkers Sample Methods Value References

8-iso-Prostaglandin F2120572 Urinary Liquid chromatography tandemmass spectrometry

Independent biomarker of prediction of the riskfor incident stroke [140]

8-iso-Prostaglandin F2120572 Plasma Enzyme-linked immunosorbentassay

Disease severity and clinical outcome after acuteICH associated with concentration [101]

8-OHdG Plasma HPLC-electrochemical detector Level associated with 30-day outcome after ICH [106]

Bilirubin Plasma Reflectance spectrophotometry Serum bilirubin levels were significantly elevatedin the early phases in hemorrhagic stroke [141]

Vitamin C uric acid (UA)vitamin E ubiquinol-10 Plasma HPLC-electrochemical detector

Lower plasma levels of UA and higher plasmalevels of others correlated with the severity of the

neurological impairment after ICH[142]

ROOH Plasma HPLC-electrochemical detector Predictor of poor clinical outcome in sICHsurvivors [102]

TAC TOS Plasma Spectrophotometrically TOS levels increased and TAC levels decreased inacute hemorrhagic stroke [127]

MDA myeloperoxidase erythrocyte glutathione peroxidase 8-OHdG leukocyte 8-hydroxy-21015840-deoxyguanosine HPLC high-performance liquid chromatog-raphy TAC total antioxidant capacity TOS total oxidant status

Table 2 The development for antioxidative treatment of ICH

Drug name Administration Probable mechanism of action or drug targeting Preclinical orclinical References

PQQ Pretreated with10mgkg

Exhibited increased ratio of Bcl-2Bax alleviative toactivated caspase-3 Rat model of ICH [129]

Melatonin150mgkgd ip

5mgkg12 h ip 15 or150mgkg ip

Attenuated inflammatory response (IL-1120573 IL-6 andTNF-120572 NF-120581B MMP-9 and vEGF) decreased theexpression of TLR4 pathway (MyD88 TLR4 NF-120581Band HMGB1) attenuated lipid peroxidation and

activated the Nrf2-ARE pathway

Rat model of SAHor ICH

[112 143ndash146]

Sulforaphane 5mgkg ipActivated Nrf2 in modulating microglia function andhematoma clearance via inducing antioxidative defense

components

Rat and micemodel of ICH [50]

Sesamin 30 nmol icvSesamin prevented ICH-induced increase of microglialcells in the perihematomal area accompanied by the

activated p4442 MAPK pathwayRat model of ICH [133]

FeTPPS 30mgkg ip ONOOminus decomposition catalyst prevented activationof MMP-9 and Hb-induced neurovascular injuries Rat model of ICH [31]

Deferoxamine 100mgkg ip Reduces neuronal death and neurological deficits afterICH in aged rats Rat model of ICH [147]

Edaravone 6mgkg SCAttenuated ICH-induced brain edema neurologicdeficits and oxidative injury (apurinicapyrimidinicabasic sites and 8-hydroxyl-21015840-deoxyguanosine)

Rat model of ICH [103]

Edaravone 10mgkg SC Improved cerebral metabolism around the hematomaby attenuating apoptotic cell death after ICH Rat model of ICH [148]

Hydrogen gas Inhaled 29 Reduces damage to the blood brain barrier followingICH and improves SBI Mice model of ICH [149 150]

Rosiglitazone 05mg infused intothe hematoma regions

A remarkable decrease in perihematomal levels ofPPAR120574 MMP-9 BBB permeability and BWC following

minimally invasive surgery for ICH treatment

Rabbits model ofICH [151]

Minocycline 45mgkg ipReduces iron accumulation and inhibits microglia

activation contributing to brain damage after ICH viasuppressing MMP-9

Rat model of ICH [152 153]

Atorvastatin 2 5 and 10mgkgorally

Decreasing the brain injury and protecting neurons inICH involving suppression of TNF-120572MMP-9 and

upregulation of IL-10Rat model of ICH [154 155]

PQQ pyrroloquinoline quinine MMP-9 matrix metallopeptidase 9 TLR4 Toll-like receptor 4 iNOS inducible nitric oxide synthase MyD88 myeloiddifferentiation factor 88 ip intraperitoneal injection icv intracerebroventricular injection SC subcutaneous injection


52 Treatment of ICH Using Hydrogen and Active HydrogenCompounds Hydrogen sulfide exhibits a protective role inthe brain reducing oxidative stress after SAH [156] Studieshave found that hydrogen sulfide reduces ROS and MDAlevels after SAH reverses the decrease of SOD and GSH-Pxincreases the expression level of hydrogen sulfide productsCBS and 3MST in the brain tissues and inhibits neuronalcell apoptosis by inhibiting the caspase-dependent apoptosispathway Hydrogen sulfide can also inhibit the secretion ofinflammatory cytokines IL-1120573 IL-10 and TNF-120572 after SAHRecent antioxidation research on hydrogen shows that in ananimal model of cerebral hemorrhage hydrogen inhalationor injecting hydrogen-rich saline can significantly reduceearly brain damage and cerebral vasospasm following SAH[157 158] and hydrogen inhalation preserved blood brainbarrier disruption by prevention of mast cell activation afterICH [149] Research has confirmed that hydrogen decreasesthe release of inflammatory cytokines by reducing lipid per-oxides increasing antioxidant enzyme activity and reducingoxidative stress levels after SAH meanwhile inhalation ofhydrogen reduces damage to the blood brain barrier follow-ing ICH and improves SBI [149 150] Recent clinical trialsusing hydrogen to treat acute cerebral anemia have provedthat hydrogen treatment is safe [159] Moreover a randomdouble-blind trial using hydrogen to treat SAH patients isunderway although not yet completed [160]

53 Targeted Therapy against Oxidative Stress Signaling Path-ways Rosiglitazone is a highly selective and potent agonistto peroxisome proliferator-activated receptor 120574 Continuoustreatmentwith 6mgkg rosiglitazone for 6 days reduces gluta-mate level upregulates GLT-1 expression reduces MDA andcatalase levels and ameliorates vasospasm following SAHexhibiting a protective role in the brain [161] Treatment withrosiglitazone in cerebral hemorrhage regulates antioxidationand anti-inflammatory effects possibly through the interac-tion of Nrf-2 retinoid X receptor (RXR) and NF-120581B andreduces SBI [162] Recently study showsRSG infusion therapyfollowing minimally invasive surgery for ICH evacuationon perihematomal secondary brain damage which mightbe more efficacious for reducing the levels of MMP-9 andsecondary brain damage than minimally invasive surgerytherapy alone [151]

Recent studies show that nitrate peroxide decompositioncatalyst 5101520-tetrakis(4-sulfonatophenyl)porphyrinatoiron (FeTPPS) reduced neurovascular damage and improvedneurological deficits in a rat ICH model induced by caudatenucleus injection of hemoglobin experimental data indicatedthat the activation ofMMP-9may be involved [31]Moreovereffects of minocycline a nonspecific MMP inhibitor andpyrrolidine dithiocarbamate an upstream regulator ofMMPs on MMP-9 activity and thereby the degree of ICHwere also tested in another study the result suggests thatsuppression of MMP-9 by minocycline [152] or pyrrolidinedithiocarbamate attenuated ICH suggesting the therapeuticpotential of MMP inhibitors in ICH [153] However attemptsat MMP inhibition in spontaneous ICH have solely beenmade under experimental conditions and were associated

with a wide range of possible side effects Therefore furthercomprehensive elucidating investigations in this field arevital before any conclusions could be translated to humans[163]

Antioxidant research on statin drugs confirmed thatstatin treatment reduced plasma OxLDL levels in acuteischemic stroke patients [164] In ICH rat model atorvastatinshowed significant effects in reducing the brainwater contentblocking neuron apoptosis and decreasing plasma MMP-9 levels [154] Other studies have shown that atorvastatininduced a dose-dependent reduction of TNF-120572 and increaseof IL-10 levels [155] Thus that can decrease the brain injuryand protect neurons in rats with ICH However recentliterature suggests that statin treatment may not be effectivein ICH [165]

As an iron-chelating agent deferoxamine (DFX) bindsto iron ions competitively thereby preventing oxidation-reduction reaction of iron ions reducing the generation offree radicals following hemorrhagic stroke and exhibitinga neuroprotective effect [166 167] Studies show that afterICH in animal models DFX was most efficacious whenadministered 2ndash4 h after ICH at a dose of 10ndash50mgkgdepending on species and this beneficial effect remainedfor up to 24 h after injury [168] However in contrast tostudies using the whole-blood model DFX treatment didnot improve outcome in the collagenase model [169] There-fore those studies suggest that there are critical differencesbetween these ICHmodels Additionally bipyridine an iron-chelator does not lessen intracerebral iron-induced damageor improve outcome after ICH in rats [170] Perhaps thecurrent clinical work with iron-chelator will help identify themore clinically predictive model for future neuroprotectionstudies [171] Other studies have shown that DFX amelioratesthe long-term sequelae of fetal rat matrix hemorrhage [172]and may also reduce hydrocephalus after ICH [173] Defer-oxamine mesylate (DFO) another iron-chelator improvesneurological recovery in animal models of ICH Moreover Ithas been shown that 3 days of 62mgkgday DFO (maximumdose not to exceed 6000mgday) is safe and tolerated byintracerebral hemorrhage (ICH) patients [174] Currentlythe trial to determine therapeutic benefits of systemic DFOadministration in ICH patients is required to form definitiveconclusions in further investigation [175]

54 Synthetic Antioxidant Drugs Edaravone Edaravone isa scavenger for oxygen free radicals which has been con-firmed to have protective effects in brain injuries in animalexperiments After a rat intraventricular hemorrhage modelhad been established immediate treatment with edaravonereduced lipid peroxidation and cerebral edema followingintraventricular hemorrhage continuous treatment for 2days significantly improved memory impairment and learn-ing [183] Another set of experiments examined cerebralmetabolism around hematoma after cerebral hemorrhageby studying the PETCT images and found that edaravonetreatment significantly improved brain metabolism allevi-ated movement disorders and reduced cerebral edema andapoptosis [148] Clinical trials with edaravone have alsomade


Table 3 Potential medications that target oxidative stress in patients after hemorrhagic stroke

Drug name Clinical trialsDifferent types ofintracerebralhemorrhage

Action mechanism Outcome References

NXY-059 NCT00075959(CHANT) ICH Free radical-trapping agent No benefit [176]

Deferoxaminemesylate

NCT01662895(Hi-Def) ICH Iron-chelator Phase II clinical

trial [177]

Hydrogen-rich fluid UMIN000014696 SAH Delayed cerebral ischemia andcerebral vasospasm Ongoing [160]

Edaravone mdash SAH Free radical scavenger Preliminary [178]

Simvastatin NCT01077206ISRCTN75948817 SAH Lipid-lowering therapy No benefit [179 180]

Lipid-loweringmedication

NCT00226096 andNCT00716079(INTERACT)

ICH Lipid-lowering therapy No benefit [181]

Statin NCT00221104 SAH Lipid-lowering therapy No benefit [182]ICH intracranial hemorrhage SAH subarachnoid hemorrhage

important progress Edaravone treatment in patients withaneurysmal SAH reduced late-onset neurological disordersand vascular spasm and improved patient outcomes [178]In another study of ICH patients following removal ofhematoma with minimally invasive surgery edaravone treat-ment significantly improved the NIHSS score and reducedserum MMP-9 levels [184] However the results of onelarge-scale clinical trial suggest that although edaravonetreatment improved neurological deficits in some patientsit did not reduce mortality and long-term clinical benefitswere uncertain [185] Thus high quality large-scale clinicaltrials are still needed to evaluate the benefit of edaravoneadministration in the treatment of brain bleeding disorders[186] (Table 3)

55 TargetedGeneTherapy Gene therapy is a proven effectivetreatment however conventional gene therapy has draw-backs and is limited in practical application Cheng andcolleagues designed a damage-induced vector system whichincluded a hypoxia response element and an antioxidantresponse element which could be activated under oxygendeprivation conditions or upon hydrogen peroxide treat-ment The advantage of overexpressing Nrf-2 using thisvector system to exert neuroprotective effects is that itactivates the expression of neuroprotective genes in thenervous system under hypoxia and oxidative stress [187]Research into a HO-2 (heme oxygenase 2) knockout mousemodel with ICH induced by autologous blood injectionfound that 4ndash8 days after ICH neuron survival in the micewas significantly increased with a reduction in neuromotordeficits Therefore HO-2 is considered a target for oxidativestress treatment for cerebral hemorrhage [188] However ina collagenase-induced cerebral hemorrhage model in HO-2 knockout mice the lesion volume around the hematomanerve inflammation and brain edema were aggravated withsignificantly worse neurological defects [189] This may havebeen due to the different injury mechanism of the different

animal models [190] In addition to toxicity mediated byiron release hemin can directly injure cells by oxidative andmembrane destabilizing effects [191] Cultured HO-2 knock-out neurons are more vulnerable to inorganic iron perhapsdue to the protective effect of the other products of hemebreakdown [192] The net effect of HO-2 therefore appearsto be dependent on the iron binding capacity of the cellularmicroenvironment In cerebral hemorrhage the expressiontime points and location of HO-1 and HO-2 are different[193] and they play different roles for regulating antioxidantgene expression [194] Heme treatment induces perivascularHO-1 expression and reduces blood brain barrier damageand neurological defects thus heme is believed to play aneuroprotective effect throughHO-1 [195] In conclusionHOplays an important role in SBI after cerebral hemorrhage andregulating HO-1 and HO-2 expression may be a promisingtherapeutic strategy Other studies have used neural stem celltransplantation to treat SBI following cerebral hemorrhagebut the host reaction after transplantation led to graft failureand death whichmay be related to elevated levels of oxidativestress after transplantThereforeWakai and colleagues trans-planted neural stem cells overexpressing SOD1 (copperzinc-superoxide dismutase) to treat cerebral hemorrhage whichsignificantly reduced mortality and oxidative stress speedingup recovery from neurological disorders after ICH [196]

6 Conclusions

Multitudinous results have provided information aboutoxidative stress biomarkers preclinical and clinical researchevidence in ICH further revealed the progress of pathophys-iology in cerebral hemorrhage and provided the basis fortargeted therapy [5 93] However truly clinically effectivetreatment strategies are few mainly because the conflicts oftranslating preclinical studies into clinical studies have yet tobe resolved The pathological process of survival and reha-bilitation in patients after ICH involves complexmechanisms


[197] Secondary brain injuries after ICH include nerve celltoxicity microglial cell activation cerebral vascular injuryblood brain barrier damage arterial venous recanalizationand reconstruction and even other organ damage caused bythe interaction of oxidative stress and inflammation [198]These harmful factors must be effectively addressed to makeclinically effective treatment strategies possible

Competing Interests

The authors declare that there are no competing interestsregarding the publication of this paper

Authorsrsquo Contributions

Xiaochun Duan and Zunjia Wen contributed equally to thiswork

Acknowledgments

This work was supported by grants from the National NaturalScience Foundation of China (nos 81371279 81422013 and81471196) Jiangsu Provincersquos OutstandingMedical AcademicLeader Program (no LJ201139) Scientific Department ofJiangsu Province (no BL2014045) and Suzhou Government(nos LCZX201301 SZS201413 and SYS201332) and a projectfunded by the Priority Academic Program Development ofJiangsu Higher Education Institutions

References

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[2] J F Meschia C Bushnell B Boden-Albala et al ldquoGuidelinesfor the primary prevention of stroke a statement for healthcareprofessionals from the American Heart AssociationAmericanStroke Associationrdquo Stroke vol 45 no 12 pp 3754ndash3832 2014

[3] A GustavssonM Svensson F Jacobi et al ldquoCost of disorders ofthe brain in Europe 2010rdquo European Neuropsychopharmacologyvol 21 no 10 pp 718ndash779 2011

[4] P K Belur J J Chang S He B A Emanuel and WJ Mack ldquoEmerging experimental therapies for intracerebralhemorrhage targeting mechanisms of secondary brain injuryrdquoNeurosurgical Focus vol 34 no 5 article E9 2013

[5] J Aronowski and X Zhao ldquoMolecular pathophysiology ofcerebral hemorrhage secondary brain injuryrdquo Stroke A journalof cerebral circulation vol 42 no 6 pp 1781ndash1786 2011

[6] B M Hybertson B Gao S K Bose and J M McCordldquoOxidative stress in health and disease the therapeutic potentialof Nrf2 activationrdquoMolecular Aspects ofMedicine vol 32 no 4ndash6 pp 234ndash246 2011

[7] B Halliwell ldquoOxidative stress and cancer have we movedforwardrdquoThe Biochemical Journal vol 401 no 1 pp 1ndash11 2007

[8] O Hwang ldquoRole of oxidative stress in Parkinsonrsquos diseaserdquoExperimental Neurobiology vol 22 no 1 pp 11ndash17 2013

[9] E E Dubinina L V Schedrina N G Neznanov N MZalutskaya and D V Zakharchenko ldquoOxidative stress andits effect on cells functional activity of alzheimerrsquos diseaserdquoBiomeditsinskaia Khimiia vol 61 no 1 pp 57ndash69 2015

[10] R Rezzani F Bonomini S Tengattini A Fabiano and RBianchi ldquoAtherosclerosis and oxidative stressrdquo Histology andHistopathology vol 23 no 3 pp 381ndash390 2008

[11] T Munzel T Gori J F Keaney C Maack and A DaiberldquoPathophysiological role of oxidative stress in systolic and dias-tolic heart failure and its therapeutic implicationsrdquo EuropeanHeart Journal vol 36 no 38 pp 2555ndash2564 2015

[12] E Nur B J Biemond H-M Otten D P Brandjes and J-J BSchnog ldquoOxidative stress in sickle cell disease pathophysiologyand potential implications for disease managementrdquo AmericanJournal of Hematology vol 86 no 6 pp 484ndash489 2011

[13] N Mortazavi ldquoRole of oxidative stress in malignant transfor-mation of oral lichen planusrdquo Oral Oncology vol 49 no 12 ppe41ndashe42 2013

[14] S S Deo A R Bhagat and R N Shah ldquoStudy of oxidativestress in peripheral blood of Indian vitiligo patientsrdquo IndianDermatology Online Journal vol 4 no 4 pp 279ndash282 2013

[15] M Pohanka ldquoRole of oxidative stress in infectious diseases Areviewrdquo Folia Microbiologica vol 58 no 6 pp 503ndash513 2013

[16] W M Nauseef ldquoHow human neutrophils kill and degrademicrobes an integrated viewrdquo Immunological Reviews vol 219no 1 pp 88ndash102 2007

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[18] S V Lennon S J Martin and T G Cotter ldquoDose-dependentinduction of apoptosis in human tumour cell lines by widelydiverging stimulirdquo Cell Proliferation vol 24 no 2 pp 203ndash2141991

[19] N M Robbins and R A Swanson ldquoOpposing effects of glucoseon stroke and reperfusion injury acidosis oxidative stress andenergy metabolismrdquo Stroke vol 45 no 6 pp 1881ndash1886 2014

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[21] X Zhao and J Aronowski ldquoNrf2 to pre-condition the brainagainst injury caused by products of hemolysis after ICHrdquoTranslational Stroke Research vol 4 no 1 pp 71ndash75 2013

[22] Y-P Yu X-L Chi and L-J Liu ldquoA hypothesis hydrogen sulfidemight be neuroprotective against subarachnoid hemorrhageinduced brain injuryrdquo The Scientific World Journal vol 2014Article ID 432318 9 pages 2014

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[25] Q Li S M Pogwizd S D Prabhu and L Zhou ldquoInhibit-ing Na+K+ ATPase can impair mitochondrial energetics andinduce abnormal Ca2+ cycling and automaticity in guinea pigcardiomyocytesrdquo PLoS ONE vol 9 no 4 Article ID e939282014

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barrier permeabilityrdquo Frontiers in Bioscience vol 3 no 4 pp1216ndash1231 2011

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[29] N Khaper S Bryan S Dhingra et al ldquoTargeting the viciousinflammation-oxidative stress cycle for the management ofheart failurerdquo Antioxidants amp Redox Signaling vol 13 no 7 pp1033ndash1049 2010

[30] W Hu P H Zhou T Rao X Zhang W Wang and LJ Zhang ldquoAdrenomedullin attenuates interleukin-1120573-inducedinflammation and apoptosis in rat Leydig cells via inhibition ofNF-120581B signaling pathwayrdquo Experimental Cell Research vol 339no 2 pp 220ndash230 2015

[31] R Ding L Feng L He et al ldquoPeroxynitrite decompositioncatalyst prevents matrix metalloproteinase-9 activation andneurovascular injury after hemoglobin injection into the cau-date nucleus of ratsrdquo Neuroscience vol 297 pp 182ndash193 2015

[32] M Katsu K Niizuma H Yoshioka N Okami H Sakata andP H Chan ldquoHemoglobin-induced oxidative stress contributesto matrix metalloproteinase activation and blood-brain barrierdysfunction in vivordquo Journal of Cerebral Blood Flow andMetabolism vol 30 no 12 pp 1939ndash1950 2010

[33] D Han S Li Q Xiong L Zhou and A Luo ldquoEffect of propofolon the expression of MMP-9 and its relevant inflammatoryfactors in brain of rat with intracerebral hemorrhagerdquo CellBiochemistry and Biophysics vol 72 no 3 pp 675ndash679 2015

[34] J J Chang B A Emanuel W J Mack G Tsivgoulis andA V Alexandrov ldquoMatrix metalloproteinase-9 dual role andtemporal profile in intracerebral hemorrhagerdquo Journal of Strokeand Cerebrovascular Diseases vol 23 no 10 pp 2498ndash25052014

[35] X Zhao T Wu C-F Chang et al ldquoToxic role of prostaglandinE2receptor EP1 after intracerebral hemorrhage in micerdquo Brain

Behavior and Immunity vol 46 pp 293ndash310 2015[36] K Nakaso M Kitayama E Mizuta et al ldquoCo-induction

of heme oxygenase-1 and peroxiredoxin I in astrocytes andmicroglia around hemorrhagic region in the rat brainrdquo Neuro-science Letters vol 293 no 1 pp 49ndash52 2000

[37] T Ishii ldquoClose teamwork between Nrf2 and peroxiredoxins 1and 6 for the regulation of prostaglandin D

2and E

2production

in macrophages in acute inflammationrdquo Free Radical Biologyand Medicine B vol 88 pp 189ndash198 2015

[38] T Shichita EHasegawaAKimura et al ldquoPeroxiredoxin familyproteins are key initiators of post-ischemic inflammation in thebrainrdquo Nature Medicine vol 18 no 6 pp 911ndash917 2012

[39] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007

[40] M Jeanne C Labelle-Dumais J Jorgensen et al ldquoCOL4A2mutations impair COL4A1 and COL4A2 secretion and causehemorrhagic strokerdquoThe American Journal of Human Geneticsvol 90 no 1 pp 91ndash101 2012

[41] H Wei S-J Kim Z Zhang P-C Tsai K R Wisniewskiand A B Mukherjee ldquoER and oxidative stresses are commonmediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are allevi-ated by chemical chaperonesrdquo Human Molecular Genetics vol17 no 4 pp 469ndash477 2008

[42] G Li C Scull L Ozcan and I Tabas ldquoNADPH oxidaselinks endoplasmic reticulum stress oxidative stress and PKR

activation to induce apoptosisrdquoThe Journal of Cell Biology vol191 no 6 pp 1113ndash1125 2010

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[44] V Cavallucci E Bisicchia M T Cencioni et al ldquoAcute focalbrain damage alters mitochondrial dynamics and autophagy inaxotomized neuronsrdquo Cell Death amp Disease vol 5 Article IDe1545 2014

[45] AM Brennan SW Suh S JWon et al ldquoRA NADPH oxidaseis the primary source of superoxide induced byNMDA receptoractivationrdquoNatureNeuroscience vol 12 no 7 pp 857ndash863 2009

[46] B H Han M-L Zhou A W Johnson et al ldquoContributionof reactive oxygen species to cerebral amyloid angiopathyvasomotor dysfunction and microhemorrhage in aged Tg2576micerdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 112 no 8 pp E881ndashE890 2015

[47] J Tang J Liu C Zhou et al ldquoRole of NADPH oxidasein the brain injury of intracerebral hemorrhagerdquo Journal ofNeurochemistry vol 94 no 5 pp 1342ndash1350 2005

[48] F R M Laurindo T L S Araujo and T B Abrahao ldquoNoxNADPH oxidases and the endoplasmic reticulumrdquo Antioxi-dants amp Redox Signaling vol 20 no 17 pp 2755ndash2775 2014

[49] C X Santos A A Nabeebaccus A M Shah L L CamargoS V Filho and L R Lopes ldquoEndoplasmic reticulum stress andnox-mediated reactive oxygen species signaling in the periph-eral vasculature potential role in hypertensionrdquo Antioxidantsand Redox Signaling vol 20 no 1 pp 121ndash134 2014

[50] X Zhao G Sun S-M Ting et al ldquoCleaning up after ICH therole of Nrf2 in modulating microglia function and hematomaclearancerdquo Journal of Neurochemistry vol 133 no 1 pp 144ndash152 2015

[51] J Wang J Fields C Zhao et al ldquoRole of Nrf2 in protectionagainst intracerebral hemorrhage injury in micerdquo Free RadicalBiology amp Medicine vol 43 no 3 pp 408ndash414 2007

[52] G Chen Q Fang J Zhang D Zhou and Z Wang ldquoRole ofthe Nrf2-ARE pathway in early brain injury after experimentalsubarachnoid hemorrhagerdquo Journal of Neuroscience Researchvol 89 no 4 pp 515ndash523 2011

[53] Y Liu J Qiu Z Wang et al ldquoDimethylfumarate alleviates earlybrain injury and secondary cognitive deficits after experimentalsubarachnoid hemorrhage via activation of Keap1-Nrf2-AREsystemrdquo Journal of Neurosurgery vol 123 no 4 pp 915ndash9232015

[54] Z Wang C Ji L Wu et al ldquoTert-butylhydroquinone alleviatesearly brain injury and cognitive dysfunction after experimentalsubarachnoid hemorrhage role of Keap1Nrf2ARE pathwayrdquoPLoS ONE vol 9 no 5 Article ID e97685 2014

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[56] D M Miller I N Singh J A Wang and E D Hall ldquoNrf2-AREactivator carnosic acid decreases mitochondrial dysfunctionoxidative damage and neuronal cytoskeletal degradation fol-lowing traumatic brain injury inmicerdquoExperimental Neurologyvol 264 pp 103ndash110 2015

[57] N Chaudhari P Talwar A Parimisetty C L drsquoHellencourtand P Ravanan ldquoA molecular web endoplasmic reticulum


stress inflammation and oxidative stressrdquo Frontiers in CellularNeuroscience vol 8 article 213 2014

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[60] N Pathak S Mitra and S Khandelwal ldquoCadmium inducesthymocyte apoptosis via caspase-dependent and caspase-independent pathwaysrdquo Journal of Biochemical and MolecularToxicology vol 27 no 3 pp 193ndash203 2013

[61] B Bhandary A Marahatta H-R Kim and H-J Chae ldquoAninvolvement of oxidative stress in endoplasmic reticulum stressand its associated diseasesrdquo International Journal of MolecularSciences vol 14 no 1 pp 434ndash456 2013

[62] L L Cooper W Li Y Lu et al ldquoRedox modification ofryanodine receptors by mitochondria-derived reactive oxygenspecies contributes to aberrant Ca2+ handling in ageing rabbitheartsrdquoThe Journal of Physiology vol 591 no 23 pp 5895ndash59112013

[63] A Ruiz C Matute and E Alberdi ldquoEndoplasmic reticulumCa2+ release through ryanodine and IP3 receptors contributesto neuronal excitotoxicityrdquo Cell Calcium vol 46 no 4 pp 273ndash281 2009

[64] P J Crack and J M Taylor ldquoReactive oxygen species and themodulation of strokerdquo Free Radical Biology ampMedicine vol 38no 11 pp 1433ndash1444 2005

[65] Z Z Chong S-H Lin J-Q Kang and KMaiese ldquoThe tyrosinephosphatase SHP2 modulates MAP kinase p38 and caspase1 and 3 to foster neuronal survivalrdquo Cellular and MolecularNeurobiology vol 23 no 4-5 pp 561ndash578 2003

[66] J-Y Wang A Y C Shum Y-J Ho and J-Y Wang ldquoOxidativeneurotoxicity in rat cerebral cortex neurons synergistic effectsof H2O2and NO on apoptosis involving activation of p38

mitogen-activated protein kinase and caspase-3rdquo Journal ofNeuroscience Research vol 72 no 4 pp 508ndash519 2003

[67] S K Sharma and M Ebadi ldquoMetallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress indopaminergic neuronsrdquo Antioxidants and Redox Signaling vol5 no 3 pp 251ndash264 2003

[68] P Calcerrada G Peluffo and R Radi ldquoNitric oxide-derivedoxidants with a focus on peroxynitrite molecular targetscellular responses and therapeutic implicationsrdquo Current Phar-maceutical Design vol 17 no 35 pp 3905ndash3932 2011

[69] G C Higgins P M Beart and P Nagley ldquoOxidative stresstriggers neuronal caspase-independent death endonuclease Ginvolvement in programmed cell death-type IIIrdquo Cellular andMolecular Life Sciences vol 66 no 16 pp 2773ndash2787 2009

[70] G C Higgins R J Devenish P M Beart and P Nagley ldquoTran-sitory phases of autophagic death and programmed necrosisduring superoxide-induced neuronal cell deathrdquo Free RadicalBiology and Medicine vol 53 no 10 pp 1960ndash1967 2012

[71] K Maiese Z Z Chong J Hou and Y C Shang ldquoOxidativestress biomarkers and novel therapeutic pathwaysrdquo Experimen-tal Gerontology vol 45 no 3 pp 217ndash234 2010

[72] DG Fujikawa ldquoThe role of excitotoxic programmednecrosis inacute brain injuryrdquoComputational and Structural BiotechnologyJournal vol 13 pp 212ndash221 2015

[73] C Ren J Guingab-Cagmat F Kobeissy et al ldquoA neuropro-teomic and systems biology analysis of rat brain post intracere-bral hemorrhagic strokerdquo Brain Research Bulletin vol 102 pp46ndash56 2014

[74] C C T Smith and D M Yellon ldquoNecroptosis necrostatins andtissue injuryrdquo Journal of Cellular and Molecular Medicine vol15 no 9 pp 1797ndash1806 2011

[75] E Niemczyk AMajczak AHallmann J KedziorMWozniakand T Wakabayashi ldquoA possible involvement of plasma mem-brane NAD(P)H oxidase in the switch mechanism of the celldeath mode from apoptosis to necrosis in menadione-inducedcell injuryrdquo Acta Biochimica Polonica vol 51 no 4 pp 1015ndash1022 2004

[76] H-J Shin H K Kwon J H Lee et al ldquoDoxorubicin-induced necrosis is mediated by poly-(ADP-ribose) polymerase1 (PARP1) but is independent of p53rdquo Scientific Reports vol 5Article ID 15798 2015

[77] WWu P Liu and J Li ldquoNecroptosis an emerging form of pro-grammed cell deathrdquo Critical Reviews in OncologyHematologyvol 82 no 3 pp 249ndash258 2012

[78] M D King W A Whitaker-Lea J M Campbell C H AlleyneJr and K M Dhandapani ldquoNecrostatin-1 reduces neurovascu-lar injury after intracerebral hemorrhagerdquo International Journalof Cell Biology vol 2014 Article ID 495817 10 pages 2014

[79] P Chang W Dong M Zhang et al ldquoAnti-necroptosis chem-ical necrostatin-1 can also suppress apoptotic and autophagicpathway to exert neuroprotective effect in mice intracerebralhemorrhage modelrdquo Journal of Molecular Neuroscience vol 52no 2 pp 242ndash249 2014

[80] X Su H Wang D Kang et al ldquoNecrostatin-1 amelioratesintracerebral hemorrhage-induced brain injury in micethrough inhibiting RIP1RIP3 pathwayrdquo NeurochemicalResearch vol 40 no 4 pp 643ndash650 2015

[81] M D Laird C Wakade C H Alleyne Jr and K MDhandapani ldquoHemin-induced necroptosis involves glutathionedepletion inmouse astrocytesrdquoFree Radical BiologyampMedicinevol 45 no 8 pp 1103ndash1114 2008

[82] T Jiang B HarderM Rojo de la Vega P KWong E ChapmanandDD Zhang ldquoP62 links autophagy andNrf2 signalingrdquo FreeRadical Biology and Medicine B vol 88 pp 199ndash204 2015

[83] J-Y Lee Y He O Sagher R Keep Y Hua and G XildquoActivated autophagy pathway in experimental subarachnoidhemorrhagerdquo Brain Research vol 1287 pp 126ndash135 2009

[84] S Hu G Xi H Jin Y He R F Keep and Y Hua ldquoThrombin-induced autophagy a potential role in intracerebral hemor-rhagerdquo Brain Research vol 1424 pp 60ndash66 2011

[85] Z Wang X-Y Shi J Yin G Zuo J Zhang and G ChenldquoRole of autophagy in early brain injury after experimentalsubarachnoid hemorrhagerdquo Journal of Molecular Neurosciencevol 46 no 1 pp 192ndash202 2012

[86] Y Liu J Li Z Wang Z Yu and G Chen ldquoAttenuation ofearly brain injury and learning deficits following experimentalsubarachnoid hemorrhage secondary to cystatin C possibleinvolvement of the autophagy pathwayrdquo Molecular Neurobiol-ogy vol 49 no 2 pp 1043ndash1054 2014

[87] Y He S Wan Y Hua R F Keep and G Xi ldquoAutophagy afterexperimental intracerebral hemorrhagerdquo Journal of CerebralBlood Flow and Metabolism vol 28 no 5 pp 897ndash905 2008

[88] G Filomeni D De Zio and F Cecconi ldquoOxidative stress andautophagy the clash between damage and metabolic needsrdquoCell Death and Differentiation vol 22 no 3 pp 377ndash388 2015


[89] N Rubio J Verrax M Dewaele et al ldquoP38MAPK-regulatedinduction of p62 and NBR1 after photodynamic therapy pro-motes autophagic clearance of ubiquitin aggregates and reducesreactive oxygen species levels by supporting Nrf2-antioxidantsignalingrdquo Free Radical Biology and Medicine vol 67 pp 292ndash303 2014

[90] A-W Shao H-J Wu S Chen A-B Ammar J-M Zhang andY Hong ldquoResveratrol attenuates early brain injury after sub-arachnoid hemorrhage through inhibition ofNF-120581B-dependentinflammatoryMMP-9 pathwayrdquo CNS Neuroscience amp Thera-peutics vol 20 no 2 pp 182ndash185 2014

[91] L Li J Tan YMiao P Lei andQ Zhang ldquoROS and autophagyinteractions and molecular regulatory mechanismsrdquo Cellularand Molecular Neurobiology vol 35 no 5 pp 615ndash621 2015

[92] N Han S-J Ding T Wu and Y-L Zhu ldquoCorrelation of freeradical level and apoptosis after intracerebral hemorrhage inratsrdquo Neuroscience Bulletin vol 24 no 6 pp 351ndash358 2008

[93] R F Keep Y Hua and G Xi ldquoIntracerebral haemorrhagemechanisms of injury and therapeutic targetsrdquo The LancetNeurology vol 11 no 8 pp 720ndash731 2012

[94] GWang Q Yang G Li et al ldquoTime course of heme oxygenase-1 and oxidative stress after experimental intracerebral hemor-rhagerdquo Acta Neurochirurgica vol 153 no 2 pp 319ndash325 2011

[95] R Aygul B Demircan F Erdem H Ulvi A Yildirim and FDemirbas ldquoPlasma values of oxidants and antioxidants in acutebrain hemorrhage role of free radicals in the development ofbrain injuryrdquo Biological Trace Element Research vol 108 no 1ndash3 pp 43ndash52 2005

[96] M Uno K T Kitazato K Nishi H Itabe and S NagahiroldquoRaised plasma oxidised LDL in acute cerebral infarctionrdquoJournal of Neurology Neurosurgery and Psychiatry vol 74 no3 pp 312ndash316 2003

[97] N Matsuda H Ohkuma M Naraoka A Munakata N Shi-mamura and K Asano ldquoRole of oxidized LDL and lectin-likeoxidized LDL receptor-1 in cerebral vasospasm after subarach-noid hemorrhagerdquo Journal of Neurosurgery vol 121 no 3 pp621ndash630 2014

[98] Y Ishigaki Y Oka and H Katagiri ldquoCirculating oxidizedLDL a biomarker and a pathogenic factorrdquo Current Opinion inLipidology vol 20 no 5 pp 363ndash369 2009

[99] P Pignatelli D Pastori R Carnevale et al ldquoSerum NOX2 andurinary isoprostanes predict vascular events in patients withatrial fibrillationrdquo Thrombosis and Haemostasis vol 113 no 3pp 617ndash624 2015

[100] Y-P Hsieh C-L Lin A-L Shiue et al ldquoCorrelation of F4-neuroprostanes levels in cerebrospinal fluid with outcome ofaneurysmal subarachnoid hemorrhage in humansrdquo Free RadicalBiology amp Medicine vol 47 no 6 pp 814ndash824 2009

[101] QDuW-H Yu X-QDong et al ldquoPlasma 8-iso-ProstaglandinF2120572 concentrations and outcomes after acute intracerebralhemorrhagerdquo Clinica Chimica Acta vol 437 pp 141ndash146 2014

[102] M L Alexandrova and M P Danovska ldquoSerum C-reactiveprotein and lipid hydroperoxides in predicting short-termclinical outcome after spontaneous intracerebral hemorrhagerdquoJournal of Clinical Neuroscience vol 18 no 2 pp 247ndash252 2011

[103] T Nakamura Y Kuroda S Yamashita et al ldquoEdaravoneattenuates brain edema and neurologic deficits in a rat model ofacute intracerebral hemorrhagerdquo Stroke vol 39 no 2 pp 463ndash469 2008

[104] I Wiswedel ldquoF(2)-isoprostanes sensitive biomarkers of oxida-tive stress in vitro and in vivo a gas chromatography-mass

spectrometric approachrdquo Methods in Molecular Biology vol580 pp 3ndash16 2009

[105] T Nakamura R F Keep Y Hua J T Hoff and G Xi ldquoOxida-tive DNA injury after experimental intracerebral hemorrhagerdquoBrain Research vol 1039 no 1-2 pp 30ndash36 2005

[106] Y-C Chen C-M Chen J-L Liu S-T ChenM-L Cheng andD T-Y Chiu ldquoOxidative markers in spontaneous intracerebralhemorrhage leukocyte 8-hydroxy-21015840-deoxyguanosine as anindependent predictor of the 30-day outcome clinical articlerdquoJournal of Neurosurgery vol 115 no 6 pp 1184ndash1190 2011

[107] W Zheng L-Z Huang L Zhao et al ldquoSuperoxide dismutaseactivity and malondialdehyde level in plasma and morpho-logical evaluation of acute severe hemorrhagic shock in ratsrdquoAmerican Journal of Emergency Medicine vol 26 no 1 pp 54ndash58 2008

[108] A Shoamanesh S R Preis A S Beiser et al ldquoInflammatorybiomarkers cerebral microbleeds and small vessel diseaseframinghamHeart StudyrdquoNeurology vol 84 no 8 pp 825ndash8322015

[109] Y-Q Yang H Li X-S Zhang et al ldquoInhibition of SENP3by lentivirus induces suppression of apoptosis in experimentalsubarachnoid hemorrhage in ratsrdquo Brain Research vol 1622 pp270ndash278 2015

[110] D Pastori R Carnevale R Cangemi et al ldquoVitamin E serumlevels and bleeding risk in patients receiving oral anticoagulanttherapy a retrospective cohort studyrdquo Journal of the AmericanHeart Association vol 2 no 6 Article ID e000364 2013

[111] Y Wang H Wu Q Jia et al ldquoDecreased uric acid levelscorrelate with poor outcomes in acute ischemic stroke patientsbut not in cerebral hemorrhage patientsrdquo Journal of Stroke andCerebrovascular Diseases vol 23 no 3 pp 469ndash475 2014

[112] ZWang CMa C-JMeng et al ldquoMelatonin activates theNrf2-ARE pathway when it protects against early brain injury in asubarachnoid hemorrhage modelrdquo Journal of Pineal Researchvol 53 no 2 pp 129ndash137 2012

[113] S Yamashita M Okauchi Y Hua W Liu R F Keep andG Xi ldquoMetallothionein and brain injury after intracerebralhemorrhagerdquo Acta Neurochirurgica Supplement vol 105 pp37ndash40 2008

[114] H Shang D Yang W Zhang et al ldquoTime course of Keap1-Nrf2pathway expression after experimental intracerebral haemor-rhage correlation with brain oedema and neurological deficitrdquoFree Radical Research vol 47 no 5 pp 368ndash375 2013

[115] B Kaya F Erdi I Kılınc et al ldquoAlterations of the thioredoxinsystem during subarachnoid hemorrhage-induced cerebralvasospasmrdquo Acta Neurochirurgica vol 157 no 5 pp 793ndash8002015

[116] J P S Caldas C A Braghini T N Mazzola M M S Vilelaand S T M Marba ldquoPeri-intraventricular hemorrhage andoxidative and inflammatory stress markers in very-low birthweight newbornsrdquo Jornal de Pediatria vol 91 no 4 pp 373ndash379 2015

[117] C Gao H Du Y Hua R F Keep J Strahle and G XildquoRole of red blood cell lysis and iron in hydrocephalus afterintraventricular hemorrhagerdquo Journal of Cerebral Blood Flowand Metabolism vol 34 no 6 pp 1070ndash1075 2014

[118] X-Y Xiong J Wang Z-M Qian and Q-W Yang ldquoIronand intracerebral hemorrhage frommechanism to translationrdquoTranslational Stroke Research vol 5 no 4 pp 429ndash441 2014

[119] M J Hackett M DeSouza S Caine et al ldquoA new method toimage heme-Fe total Fe and aggregated protein levels after


intracerebral hemorrhagerdquo ACS Chemical Neuroscience vol 6no 5 pp 761ndash770 2015

[120] MMehdiratta S KumarDHackneyG Schlaug andM SelimldquoAssociation between serum ferritin level and perihematomaedema volume in patients with spontaneous intracerebral hem-orrhagerdquo Stroke vol 39 no 4 pp 1165ndash1170 2008

[121] N Perez de la Ossa T Sobrino Y Silva et al ldquoIron-related braindamage in patients with intracerebral hemorrhagerdquo Stroke vol41 no 4 pp 810ndash813 2010

[122] S Wan Y Hua R F Keep J T Hoff and G Xi ldquoDeferoxaminereduces CSF free iron levels following intracerebral hemor-rhagerdquo Acta Neurochirurgica Supplement vol 96 pp 199ndash2022006

[123] J F Clark M Loftspring W L Wurster et al ldquoBilirubin oxida-tion products oxidative stress and intracerebral hemorrhagerdquoActa Neurochirurgica Supplementum no 105 pp 7ndash12 2008

[124] K Lakovic J Ai J DrsquoAbbondanza et al ldquoBilirubin and itsoxidation products damage brain white matterrdquo Journal ofCerebral Blood Flow and Metabolism vol 34 no 11 pp 1837ndash1847 2014

[125] M O McCarron and M J OrsquoKane ldquoAccurate diagnosis ofsubarachnoid haemorrhagerdquo Annals of Clinical Biochemistryvol 51 no 6 pp 629ndash630 2014

[126] R Ding Y Chen S Yang et al ldquoBlood-brain barrier disruptioninduced by hemoglobin in vivo involvement of up-regulationof nitric oxide synthase and peroxynitrite formationrdquo BrainResearch vol 1571 pp 25ndash38 2014

[127] H Gonullu M Aslan S Karadas et al ldquoSerum prolidaseenzyme activity and oxidative stress levels in patients withacute hemorrhagic strokerdquo Scandinavian Journal of Clinical andLaboratory Investigation vol 74 no 3 pp 199ndash205 2014

[128] J M Gostner K Becker F Ueberall and D Fuchs ldquoThe goodand bad of antioxidant foods an immunological perspectiverdquoFood and Chemical Toxicology vol 80 pp 72ndash79 2015

[129] H Lu J Shen X Song et al ldquoProtective Effect of Pyrroloquino-line Quinone (PQQ) in rat model of intracerebral hemorrhagerdquoCellular and Molecular Neurobiology vol 35 no 7 pp 921ndash9302015

[130] Y Wang A Gao X Xu et al ldquoThe neuroprotection of lyso-somotropic agents in experimental subarachnoid hemorrhageprobably involving the apoptosis pathway triggering by cathep-sins via chelating intralysosomal ironrdquo Molecular Neurobiologvol 52 no 1 pp 64ndash77 2015

[131] C E Guerrero-Beltran M Calderon-Oliver J Pedraza-Chaverri and Y I Chirino ldquoProtective effect of sulforaphaneagainst oxidative stress recent advancesrdquo Experimental andToxicologic Pathology vol 64 no 5 pp 503ndash508 2012

[132] T Zhang J Su K Wang T Zhu and X Li ldquoUrsolic acidreduces oxidative stress to alleviate early brain injury followingexperimental subarachnoid hemorrhagerdquo Neuroscience Lettersvol 579 pp 12ndash17 2014

[133] 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 2013

[134] S F Nabavi H Li M Daglia and S M Nabavi ldquoResveratroland stroke from chemistry tomedicinerdquoCurrentNeurovascularResearch vol 11 no 4 pp 390ndash397 2014

[135] X-S Zhang X Zhang M-L Zhou et al ldquoAmeliorationof oxidative stress and protection against early brain injuryby astaxanthin after experimental subarachnoid hemorrhage

laboratory investigationrdquo Journal of Neurosurgery vol 121 no1 pp 42ndash54 2014

[136] C-P Kuo L-L Wen C-M Chen et al ldquoAttenuation ofneurological injury with early baicalein treatment followingsubarachnoid hemorrhage in ratsrdquo Journal of Neurosurgery vol119 no 4 pp 1028ndash1037 2013

[137] A Shao S Guo S Tu et al ldquoAstragaloside IV alleviates earlybrain injury following experimental subarachnoid hemorrhagein ratsrdquo International Journal of Medical Sciences vol 11 no 10pp 1073ndash1081 2014

[138] A Tekiner M B Yilmaz E Polat T Goker M F Sargonand A Arat ldquoThe therapeutic value of proanthocyanidinin experimental cerebral vasospasm following subarachnoidhemorrhagerdquo Turkish Neurosurgery vol 24 no 6 pp 885ndash8902014

[139] Q He L Bao J Zimering et al ldquoThe protective role of (-)-epigallocatechin-3-gallate in thrombin-induced neuronal cellapoptosis and JNK-MAPK activationrdquoNeuroReport vol 26 no7 pp 416ndash423 2015

[140] H-J Lin S-T Chen H-Y Wu et al ldquoUrinary biomarkers ofoxidative and nitrosative stress and the risk for incident strokea nested case-control study from a community-based cohortrdquoInternational Journal of Cardiology vol 183 pp 214ndash220 2015

[141] K Dohi Y Mochizuki K Satoh et al ldquoTransient elevationof serum bilirubin (a heme oxygenase-1 metabolite) level inhemorrhagic stroke bilirubin is amarker of oxidant stressrdquoActaneurochirurgica Supplement vol 86 pp 247ndash249 2003

[142] M C Polidori P Mecocci and B Frei ldquoPlasma vitamin C levelsare decreased and correlated with brain damage in patients withintracranial hemorrhage or head traumardquo Stroke vol 32 no 4pp 898ndash902 2001

[143] Q Fang G Chen W Zhu W Dong and Z Wang ldquoInfluenceof melatonin on cerebrovascular proinflammatory mediatorsexpression and oxidative stress following subarachnoid hemor-rhage in rabbitsrdquo Mediators of Inflammation vol 2009 ArticleID 426346 6 pages 2009

[144] Z-Q Li G-B Liang Y-X Xue and Y-H Liu ldquoEffects ofcombination treatment of dexamethasone and melatonin onbrain injury in intracerebral hemorrhage model in ratsrdquo BrainResearch vol 1264 pp 98ndash103 2009

[145] Z Wang L Wu W You C Ji and G Chen ldquoMelatoninalleviates secondary brain damage and neurobehavioral dys-function after experimental subarachnoid hemorrhage possibleinvolvement of TLR4-mediated inflammatory pathwayrdquo Journalof Pineal Research vol 55 no 4 pp 399ndash408 2013

[146] J ChenGChen J Li et al ldquoMelatonin attenuates inflammatoryresponse-induced brain edema in early brain injury following asubarachnoid hemorrhage a possible role for the regulation ofpro-inflammatory cytokinesrdquo Journal of Pineal Research vol 57no 3 pp 340ndash347 2014

[147] T Hatakeyama M Okauchi Y Hua R F Keep and G XildquoDeferoxamine reduces neuronal death and hematoma lysisafter intracerebral hemorrhage in aged ratsrdquo TranslationalStroke Research vol 4 no 5 pp 546ndash553 2013

[148] H Shang D Cui D Yang S Liang W Zhang and WZhao ldquoThe radical scavenger edaravone improves neurologicfunction and perihematomal glucose metabolism after acuteintracerebral hemorrhagerdquo Journal of Stroke and Cerebrovascu-lar Diseases vol 24 no 1 pp 215ndash222 2015

[149] A Manaenko T Lekic Q Ma J H Zhang and J TangldquoHydrogen inhalation ameliorated mast cell-mediated brain


injury after intracerebral hemorrhage in micerdquo Critical CareMedicine vol 41 no 5 pp 1266ndash1275 2013

[150] A Manaenko T Lekic Q Ma R P Ostrowski J H Zhang andJ Tang ldquoHydrogen inhalation is neuroprotective and improvesfunctional outcomes in mice after intracerebral hemorrhagerdquoActa Neurochirurgica Supplement vol 111 pp 179ndash183 2011

[151] G Wu J Wu Y Jiao L Wang F Wang and Y ZhangldquoRosiglitazone infusion therapy following minimally invasivesurgery for intracerebral hemorrhage evacuation decreasesmatrix metalloproteinase-9 and blood-brain barrier disruptionin rabbitsrdquo BMC Neurology vol 15 article 37 2015

[152] F Zhao Y Hua Y He R F Keep and G Xi ldquoMinocycline-induced attenuation of iron overload and brain injury afterexperimental intracerebral hemorrhagerdquo Stroke vol 42 no 12pp 3587ndash3593 2011

[153] C Z Lee Z Xue Y Zhu G-Y Yang and W L Young ldquoMatrixmetalloproteinase-9 inhibition attenuates vascular endothelialgrowth factor-induced intracerebral hemorrhagerdquo Stroke vol38 no 9 pp 2563ndash2568 2007

[154] J-J Cui D Wang F Gao and Y-R Li ldquoEffects of atorvastatinon pathological changes in brain tissue and plasma MMP-9in rats with intracerebral hemorrhagerdquo Cell Biochemistry andBiophysics vol 62 no 1 pp 87ndash90 2012

[155] 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

[156] Y Cui X Duan H Li et al ldquoHydrogen sulfide amelioratesearly brain injury following subarachnoid hemorrhage in ratsrdquoMolecular Neurobiology 2015

[157] 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

[158] 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

[159] K Nagatani H Nawashiro S Takeuchi et al ldquoSafety of intra-venous administration of hydrogen-enriched fluid in patientswith acute cerebral ischemia initial clinical studiesrdquo MedicalGas Research vol 3 article 13 2013

[160] S Takeuchi K Mori H Arimoto et al ldquoEffects of intravenousinfusion of hydrogen-rich fluid combined with intra-cisternalinfusion of magnesium sulfate in severe aneurysmal subarach-noid hemorrhage study protocol for a randomized controlledtrialrdquo BMC Neurology vol 14 no 1 article 176 2014

[161] B-F Lin C-Y Kuo L-L Wen et al ldquoRosiglitazone attenuatescerebral vasospasm and provides neuroprotection in an exper-imental rat model of subarachnoid hemorrhagerdquo NeurocriticalCare vol 21 no 2 pp 316ndash331 2014

[162] X-R Zhao N Gonzales and J Aronowski ldquoPleiotropic role ofPPAR120574 in intracerebral hemorrhage an intricate system involv-ing Nrf2 RXR and NF-120581Brdquo CNS Neuroscience amp Therapeuticsvol 21 no 4 pp 357ndash366 2015

[163] M Florczak-Rzepka C Grond-Ginsbach J Montaner andT Steiner ldquoMatrix metalloproteinases in human spontaneousintracerebral hemorrhage an updaterdquoCerebrovascularDiseasesvol 34 no 4 pp 249ndash262 2012

[164] N-W Tsai L-H Lee C-RHuang et al ldquoStatin therapy reducesoxidized low density lipoprotein level a risk factor for strokeoutcomerdquo Critical Care vol 18 no 1 article R16 2014

[165] Q Lei W N Peng H You Z P Hu and W Lu ldquoStatinsin nervous system-associated diseases angels or devilsrdquo DiePharmazie vol 69 no 6 pp 448ndash454 2014

[166] J-Y Lee R F Keep Y He O Sagher Y Hua and G XildquoHemoglobin and iron handling in brain after subarachnoidhemorrhage and the effect of deferoxamine on early braininjuryrdquo Journal of Cerebral Blood Flow and Metabolism vol 30no 11 pp 1793ndash1803 2010

[167] M C Loftspring ldquoIron and early brain injury after sub-arachnoid hemorrhagerdquo Journal of Cerebral Blood Flow andMetabolism vol 30 no 11 pp 1791ndash1792 2010

[168] H-J Cui H-Y He A-L Yang et al ldquoEfficacy of deferoxaminein animal models of intracerebral hemorrhage a systematicreview and stratified meta-analysisrdquo PLoS ONE vol 10 no 5Article ID e0127256 2015

[169] AMAuriat G Silasi ZWei et al ldquoFerric iron chelation lowersbrain iron levels after intracerebral hemorrhage in rats but doesnot improve outcomerdquo Experimental Neurology vol 234 no 1pp 136ndash143 2012

[170] J Caliaperumal S Wowk S Jones Y Ma and F ColbourneldquoBipyridine an iron chelator does not lessen intracerebraliron-induced damage or improve outcome after intracerebralhemorrhagic stroke in ratsrdquo Translational Stroke Research vol4 no 6 pp 719ndash728 2013

[171] L M Warkentin A M Auriat S Wowk and F ColbourneldquoFailure of deferoxamine an iron chelator to improve outcomeafter collagenase-induced intracerebral hemorrhage in ratsrdquoBrain Research vol 1309 pp 95ndash103 2010

[172] D Klebe P R Krafft C Hoffmann et al ldquoAcute and delayeddeferoxamine treatment attenuates long-term sequelae aftergerminal matrix hemorrhage in neonatal ratsrdquo Stroke vol 45no 8 pp 2475ndash2479 2014

[173] J Strahle H J L Garton C O Maher K M Muraszko R FKeep and G Xi ldquoMechanisms of hydrocephalus after neonataland adult intraventricular hemorrhagerdquo Translational StrokeResearch vol 3 supplement 1 pp 25ndash38 2012

[174] M Selim S Yeatts J N Goldstein et al ldquoSafety and tolerabilityof deferoxamine mesylate in patients with acute intracerebralhemorrhagerdquo Stroke vol 42 no 11 pp 3067ndash3074 2011

[175] Y YuW Zhao C Zhu et al ldquoThe clinical effect of deferoxaminemesylate on edema after intracerebral hemorrhagerdquo PLoS ONEvol 10 no 4 Article ID e0122371 2015

[176] P D Lyden A Shuaib K R Lees et al ldquoSafety and tolerabilityof NXY-059 for acute intracerebral hemorrhage the CHANTtrialrdquo Stroke vol 38 no 8 pp 2262ndash2269 2007

[177] S D Yeatts Y Y Palesch C S Moy and M Selim ldquoHighdose deferoxamine in intracerebral hemorrhage (HI-DEF) trialrationale design and methodsrdquo Neurocritical Care vol 19 no2 pp 257ndash266 2013

[178] AMunakata HOhkuma TNakanoN Shimamura K Asanoand M Naraoka ldquoEffect of a free radical scavenger edaravonein the treatment of patients with aneurysmal subarachnoidhemorrhagerdquo Neurosurgery vol 64 no 3 pp 423ndash429 2009

[179] G K C Wong D Y C Chan D Y W Siu et al ldquoHigh-dosesimvastatin for aneurysmal subarachnoid hemorrhage mul-ticenter randomized controlled double-blinded clinical trialrdquoStroke vol 46 no 2 pp 382ndash388 2015

[180] P J Kirkpatrick C L Turner C Smith P J Hutchinsonand G D Murray ldquoSimvastatin in aneurysmal subarachnoidhaemorrhage (STASH) amulticentre randomised phase 3 trialrdquoThe Lancet Neurology vol 13 no 7 pp 666ndash675 2014


[181] M Priglinger H Arima C Anderson et al ldquoNo relationshipof lipid-lowering agents to hematoma growth pooled analysisof the intensive blood pressure reduction in acute cerebralhemorrhage trials studiesrdquo Stroke vol 46 no 3 pp 857ndash8592015

[182] B D Lizza A Kosteva M B Maas et al ldquoPreadmission statinuse does not improve functional outcomes or prevent delayedischemic events in patients with spontaneous subarachnoidhemorrhagerdquo Pharmacotherapy vol 34 no 8 pp 811ndash817 2014

[183] Z Chen J Zhang Q Chen J Guo G Zhu and H FengldquoNeuroprotective effects of edaravone after intraventricularhemorrhage in ratsrdquo NeuroReport vol 25 no 9 pp 635ndash6402014

[184] F Zhao and Z Liu ldquoBeneficial effects of edaravone on theexpression of serum matrix metalloproteinase-9 after cerebralhemorrhagerdquo Neurosciences vol 19 no 2 pp 106ndash110 2014

[185] J Yang M Liu J Zhou S Zhang S Lin and H ZhaoldquoEdaravone for acute intracerebral haemorrhagerdquoTheCochraneDatabase of Systematic Reviews vol 2 Article ID CD0077552011

[186] J Yang X Cui J Li C Zhang J Zhang andM Liu ldquoEdaravonefor acute stroke meta-analyses of data from randomized con-trolled trialsrdquo Developmental Neurorehabilitation vol 18 no 5pp 330ndash335 2015

[187] M Y Cheng I-P Lee M Jin et al ldquoAn insult-inducible vectorsystem activated by hypoxia and oxidative stress for neuronalgene therapyrdquoTranslational Stroke Research vol 2 no 1 pp 92ndash100 2011

[188] J Chen-Roetling W Liu and R F Regan ldquoIron accumulationand neurotoxicity in cortical cultures treated with holotransfer-rinrdquo Free Radical Biology amp Medicine vol 51 no 11 pp 1966ndash1974 2011

[189] J Wang and S Dore ldquoHeme oxygenase 2 deficiency increasesbrain swelling and inflammation after intracerebral hemor-rhagerdquo Neuroscience vol 155 no 4 pp 1133ndash1141 2008

[190] J Chen-Roetling X Lu and R F Regan ldquoTargeting hemeoxygenase after intracerebral hemorrhagerdquoTherapeutic Targetsfor Neurological Diseases vol 2 no 1 article 474 2015

[191] S R Robinson T N Dang R Dringen and G M BishopldquoHemin toxicity a preventable source of brain damage follow-ing hemorrhagic strokerdquo Redox Report vol 14 no 6 pp 228ndash235 2009

[192] J Wang H Zhuang and S Dore ldquoHeme oxygenase 2 is neu-roprotective against intracerebral hemorrhagerdquoNeurobiology ofDisease vol 22 no 3 pp 473ndash476 2006

[193] JWang and S Dore ldquoHeme oxygenase-1 exacerbates early braininjury after intracerebral haemorrhagerdquo Brain vol 130 no 6pp 1643ndash1652 2007

[194] Q Lin S Weis G Yang et al ldquoHeme oxygenase-1 proteinlocalizes to the nucleus and activates transcription factorsimportant in oxidative stressrdquo Journal of Biological Chemistryvol 282 no 28 pp 20621ndash20633 2007

[195] X Lu J Chen-Roetling and R F Regan ldquoSystemic hemin ther-apy attenuates blood-brain barrier disruption after intracerebralhemorrhagerdquoNeurobiology of Disease vol 70 pp 245ndash251 2014

[196] T Wakai H Sakata P Narasimhan H Yoshioka H Kinouchiand P H Chan ldquoTransplantation of neural stem cells that over-express SOD1 enhances amelioration of intracerebral hemor-rhage in micerdquo Journal of Cerebral Blood Flow and Metabolismvol 34 no 3 pp 441ndash449 2014

[197] A S Pandey and G Xi ldquoIntracerebral hemorrhage a multi-modality approach to improving outcomerdquo Translational StrokeResearch vol 5 no 3 pp 313ndash315 2014

[198] K A Hanafy and M H Selim ldquoAntioxidant strategies inneurocritical carerdquo Neurotherapeutics vol 9 no 1 pp 44ndash552012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


reactive free radicals and peroxides is an important factor[6] in aging and is also involved in the pathogenesis ofcancer [7] Parkinsonrsquos disease [8] Alzheimerrsquos disease [9]atherosclerosis [10] heart failure [11] sickle cell disease [12]lichen planus [13] vitiligo [14] infection [15] chronic fatiguesyndrome and other diseases Although excessive oxidativestress is considered harmful reactive oxygen is beneficial formaintaining the normal physiological activity of the bodyand plays a role in defense killing pathogens by regulatingthe immune system [16] Short-term activation of oxidativestress may have an important role in preventing aging Forexample hydrogen peroxide the most common form ofactive oxygen promotes apoptosis at high concentrationsinducing antioxidant enzyme expression and increasing theantioxidant capacity of cells at low concentration [17] Theoutcome of oxidative stress depends on the degree of dam-age in the balance between the oxidative and antioxidativeresponses of the body Cells are capable of self-regulation ofmild oxidative stress changes and restoring cell homeostasisHowever severe oxidative stress can lead to cell death andit has been reported that although moderate oxidative stresscan cause cell apoptosis intense oxidative stress may lead tonecrosis [18]

3 Oxidative Stress and ICH

Oxidative stress plays an important role in SBI after ICH[19] Oxidative stress is involved not only in the pathologicalprocess of ICH but also at various important stages of patho-physiological response during ICH [5] A variety of pathwayscan induce the generation of free radicals after ICH of whichthere are twomajor pathways First blood cell decompositionproducts such as iron ions heme and thrombin can inducethe production of free radicals Experimental results showthat divalent iron ions can interact with lipid and generatefree radicals leading to nerve damage [20 21] Secondinflammatory cells such as microglia and neutrophils cangenerate free radicals During the inflammatory responsefollowing ICH neutrophils are stimulated and activatedresulting in outbreak of the respiratory chain releasing largeamounts of reactive oxygen species nitric oxide and soon and the excessive consumption of superoxide dismutase(SOD) and the occurrence of lipid peroxidation [22] Damageto nerve cells caused by free radicals manifests in a numberof ways with free radicals involved in pathological processesranging from cell membrane damage to DNA interruptionor even apoptosis [23] Cell damage caused by oxygen freeradicals is due to the induction of lipid peroxidation Thelipid-rich brain tissue is particularly sensitive to oxygenfree radicals that can enhance lipid peroxidation causemembrane damage and increase cell membrane permeabil-ity and calcium ion influx [23] In the meantime cross-linking and polymerization of membrane lipids will occurdue to lipid peroxidation which will indirectly inhibit theactivities of membrane proteins such as calcium pumpssodium pumps and Na+Ca2+ exchangers [24] This leadsto a further increase in intracellular calcium concentrationwhich subsequently stimulatesmitochondrial calciumpumps

to take in calcium Calcium and phosphate in the mito-chondria combine and form insoluble calcium phosphatewhich causes interference in mitochondrial oxidative phos-phorylation and leads to a decrease in ATP production [25]Meanwhile increased intracellular calcium ion concentrationcan activate phospholipase promoting membrane phospho-lipid decomposition and causing damage to the structureof cell and organelle membranes [26 27] In summary freeradicals are the major killers of hemorrhagic brain tissuewith considerable recent research indicating that free radicalsare closely related to brain injury and disorders caused bybleeding (Figure 1)

31 Oxidative Stress and Inflammation following ICH Inflam-mation and oxidative stress are closely related Oxidativestress induces inflammation while inflammation causesdamage through oxidative stress [28] ROS can induce theexpression of acute proinflammatory cytokines directly suchas Tumor Necrosis Factor (TNF-120572) and Interleukin-10 (IL-10) and also activate nuclear factor-120581B(NF-120581B) which playsthe vital role in inflammation reaction [29 30] On the otherhand proinflammatory cytokines can induce the productionof ROS [29] thus a positive feedback cycle is formed Inrats hemoglobin mediates oxidative and nitration stressafter ICH with the nitration stress induce perihematomaledema which may be involved in neurovascular damage andneurological deficit [31] Oxidative stress may initiate theupregulation of MMP-9 levels in brain damage after ICH[32] MMP-9 levels in animal models have largely showndetrimental correlations with mortality clinical outcomehematoma volume and SBI Animal models and clinicalstudies have established a timeline forMMP-9 expression andcorresponding perihematomal edema after ICH that includean initial peak on days 1ndash3 and a secondary peak on day7 Another study demonstrated that MMP-9 expression wasincreased accompanied by elevated TNF-120572 and IL-1120573 levelsand cerebral edema and SBI were aggravated [33] Clinicalstudies suggest that MMP-9 may be detrimental in the acutephase through destruction of basal lamina activation ofvascular endothelial growth factor and activation of apop-tosis but assist in recovery in the subacute phase throughangiogenesis Therefore MMP-9 activity may have dual roleand temporal profile in post-ICH [34]

Additional studies have shown that prostaglandin-mediated inflammatory mechanisms are involved in sec-ondary brain damage after ICH In a collagenase-inducedICH model in mice prostaglandin E2 receptor 1 (EP1R) wasexpressed in neurons and axons but not in astrocytes andmicroglia EP1R agonists induce brain edema cell deathneurodegeneration neuroinflammation and behavioraldefects while EP1R suppression protects the brain Researchhas confirmed that the inhibition effect of EP1R is mainlythrough the reduction of Scr enzyme phosphorylation levelsand MMP-9 activation thus attenuating oxidative stress andwhite matter damage [35]

Peroxiredoxin I (PrxI) and heme oxygenase-1 (HO-1) areconsidered to be oxidative stress- and heme-related proteinsand heme inhibits PrxI antioxidant activity Studies have



Lipidperoxidation

Proteinoxidation

DNA damage

CytotoxicityROS

Oxidative stressRNS


AutophagyApoptosis





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6 Conclusions




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6 Conclusions




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Documents

Review Article Intracerebral Hemorrhage, Oxidative Stress