Review Article ROS and Brain Diseases: The Good, the Bad ...downloads.hindawi.com/journals/omcl/2013/963520.pdf · Janus-faced properties of reactive oxygen species. It will describe

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2013 Article ID 963520 14 pageshttpdxdoiorg1011552013963520

Review ArticleROS and Brain Diseases The Good the Bad and the Ugly

Aurel Popa-Wagner1 Smaranda Mitran2 Senthilkumar Sivanesan3

Edwin Chang4 and Ana-Maria Buga12

1 Department of Psychiatry Rostock University Medical School Gehlsheimer Straszlige 20 18147 Rostock Germany2 Center of Clinical and Experimental Medicine University of Medicine and Pharmacy 200349 Craiova Romania3 Department of Biomedical Sciences College of Veterinary Medicine Ames IA 50011 USA4 Stanford University School of Medicine MIPS Canary Center at Stanford for Cancer Early Detection CA 94304 USA

Correspondence should be addressed to Aurel Popa-Wagner aurelpopa-wagnermeduni-rostockde

Received 12 August 2013 Revised 4 November 2013 Accepted 5 November 2013

Academic Editor Cinzia Signorini

Copyright copy 2013 Aurel Popa-Wagner et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms This paper reviews theJanus-faced properties of reactive oxygen species It will describe the positive aspects of moderately induced ROS but it will alsooutline recent research findings concerning the impact of oxidative and nitrooxidative stress on neuronal structure and functionin neuropsychiatric diseases including major depression A common denominator of all neuropsychiatric diseases includingschizophrenia and ADHD is an increased inflammatory response of the brain caused either by an exposure to proinflammatoryagents during development or an accumulation of degenerated neurons oxidized proteins glycated products or lipid peroxidationin the adult brain Therefore modulation of the prooxidant-antioxidant balance provides a therapeutic option which can be usedto improve neuroprotection in response to oxidative stress We also discuss the neuroprotective role of the nuclear factor erythroid2-related factor (Nrf2) in the aged brain in response to oxidative stressors and nanoparticle-mediated delivery of ROS-scavengingdrugs The antioxidant therapy is a novel therapeutic strategy However the available drugs have pleiotropic actions and are notfully characterized in the clinic Additional clinical trials are needed to assess the risks and benefits of antioxidant therapies forneuropsychiatric disorders

1 Introduction

The earth began its life without free oxygen in its atmosphere[1] Oxygen accumulation is a consequence of the estab-lishment and propagation of photosynthesizing archea andbacteria on this planet [2] With the arrival of the worldrsquos firstde facto pollutant (ie oxygen) approximately 3 billion yearsago there evolved organisms that reductively metabolizedoxygen to produce ATP in mitochondria [3] (ie aerobicrespiration)Mitochondrial energymetabolism yields severalreactive oxygen species (ROS) including oxygen ions (O

2

minusthe primary ROS) free radicals and peroxides (inorganic andorganic) The presence of ROS produced profound conse-quences for life on earth both beneficial and deleterious Forexample a wealth of evidence suggests that high levels of ROSare intimately linked to the appearance of neuronal deathin various neurological disorders These include chronic

diseases (Parkinsonrsquos disease or Alzheimerrsquos disease) [4]acute injury of the brain (brain trauma and cerebral ischemia)[5 6] or psychiatric disorders (autism attention deficithyperactivity disorder depression and schizophrenia) [7]

An increase in oxidative and nitrooxidative stress anda decrease in the antioxidant capacity of the brain are keyfactors involved in the etiology of neuropsychiatric diseases(Figure 1) In the following we will detail both the beneficialand deleterious impacts of these Janus-faced processes

2 ROS Are Required forPhysiological Processes

Even though ROS are involved in a number of diseasesthey are also very pertinent mediators of several normalphysiological processes All of the good ROS are products

2 Oxidative Medicine and Cellular Longevity

Free radicalsOxidized proteinsGlycated productsLipid peroxidation

Altered neuronal signaling

NeuroinflammationActivation of cell death mechanisms

Exposure toproinflammatory

agentsOxidative stress

Parkinson ADHD Schizophrenia

Proinflammatory status

Oxidative stress

Stroke

Oxidative stress Mitochondrial

ROS

Alpha-synucleinaggregation

Lewis bodies

Alzheimer Depression

Abeta aggregationNeurofibrillary

tangles

Oxidative andnitrooxidative

BradykinesiaRigidity Tremor

NeurodegenerationMemory loss

Major depressionPsychosis

HyperactivityImpulsivityInattention

stress

Figure 1 Schematic representation of oxidative stress-related mechanisms underlying disease development in Alzheimerrsquos disease (AD)Parkinson disease (PD) stroke attention deficit and hyperactivity disorders (ADHD) schizophrenia and depression

of turnover in the mitochondrial respiratory chain Thehighly reactive nature of singlet oxygen can even be exploitedto make reactive peroxides that can serve as antimicrobialagents [8] Most of the physiological effects are in factmediated by reactive oxygen species (ROS) derivatives ofsuperoxide Similarly the superoxide anion (O

2

minus∙) throughits derivative the hydroxyl radical (∙OH) plays an essentialrole in cell physiology by stimulating the activation of guany-late cyclase and formation of the ldquosecond messengerrdquo cGMPin cells and activation of the transcription factor nuclearfactor kB (NF-kB) by hydrogen peroxide in mammaliancells [9] Under normal physiological conditions the NOradical (NO∙) regulates the vascular tone by smooth musclerelaxation

In the inflammatory response macrophages and neu-trophils are attracted by activated T lymphocytes and IL-2and produce high levels of O

2

minus which along with other ROSdestroy the engulfed bacteria (oxidative burst) [10] In braintissue ROS are generated by microglia and astrocytes andmodulate synaptic and nonsynaptic communication betweenneurons and glia ROS also interfere with increased neuronalactivity [11] by modifying the myelin basic protein and caninduce synaptic long-term potentiation a form of activity-dependent synaptic plasticity and memory consolidationFurthermore results from animal models suggest that therole of O

2

minus inmodulating synaptic plasticity memory forma-tion and learning is altered by age [12]

3 Deleterious Effects Associated with ROS

Activated oxygen species especially those that share elec-tronic orbital features with singlet oxygen are highly reactiveand therefore the evolutionary adaptation by organisms tomake oxygen wholly beneficial has never been completeConsequently there are many deleterious effects associatedwith excessive activated ROS ROS are thereby capable ofproducing membrane damage changes in the inner proteinsaffecting their structure and function lipids denaturationand structural damage to DNA In the brain those effectsappear when ROS are in excessive concentrations and thusthe ability of antioxidant mechanisms of neurons to counter-balance the damaging reactions is diminished [13]

The brain is especially susceptible to the assaults per-petrated by ROS This is because the brain as an organis a major metabolizer of oxygen (20 of the body con-sumption) and yet has relatively feeble protective antioxidantmechanisms Thus it is especially vulnerable to oxidativestress The brain contains a large amount of polyunsaturatedperoxidizable fatty acids along with high levels of iron thatact as a prooxidant and sometimes induce autophagic celldeath in hemorrhagic stroke Synaptic transmission involvingdopamine and glutamate oxidation may also occur in thebrain [13ndash15] In addition lipid peroxidation leads to theproduction of toxic compounds such aldehydes or dienals(eg 4-hydroxynonenal) which may cause in turn neuronalapoptosis [16]

Oxidative Medicine and Cellular Longevity 3

At the DNA level oxidative modifications may causerapid depletion of intracellular energy by activating DNArepair enzymes Energy scarcity after stroke will cause inturn endonuclease-mediated DNA fragmentation the keymechanism that leads to DNA-damage [17]

4 Brain Mitochondrion and Oxidative Stress

The mitochondria is the cellular powerhouse that generatesATP and therefore is a key participant in all physiologicaland pathological events Following ischemia-associated exci-totoxicity and other neurodegenerative insults mitochondriawill take up calcium which leads to an increased productionof reactive oxygen species (ROS) As a result neuronalcells face excessive amounts of ROS [18] The mechanismslinking mitochondrial calcium uptake and ROS productionare incompletely understood but may involve an increase inthe permeability of the mitochondrial membranes to smallmolecules and thereby initiate cell death through releaseof apoptosis-inducing factors via the opening of an as yetunidentified megapore protein [18ndash21]

Once opened the pore can cause the collapse of theproton gradientThis promotes collapse of respiratory controlas well as release of Ca2+ stored in the mitochondrial matrixFurthermore since the mitochondrial matrix is negativelycharged K+ can enter through the pore and cause osmoticswelling [22] A bioenergetics failure ensues due to theinhibition of oxidative phosphorylation and ATP synthesisThe few ATPmolecules generated by glycolysis or by residualfunctionalmitochondria are hydrolyzed byATP synthase thatwork in reverse under such extreme conditions [22] If thepore remains open for a long period major consequences forenergy metabolism and even cellular death may occur

An increasing number of studies report the preva-lence of oxidative stress and mitochondrial abnormalities innumerous neuropsychiatric disorders [23ndash30] A spectrumof oxidative stress markers involved in schizophrenia andanxiety related disorders were thoroughly categorized basedon several biochemical assays [31 32] as well as geneticassessment studies [32] Recent genetic studies pinpointat mutations in several genes encoding proteins requiredfor synaptic plasticity suggesting a plausible link betweenneuropsychiatric diseases and neurodevelopmental abnor-malities [33 34] Notablymutations in PTEN-induced kinase1 (PINK1) gene function have been attributed to oxidativestress and mitochondrial fragmentation [35] However alter-ations in GMP-PKG signaling leading to increased brainphosphodiesterase-2 (PDE2) levels [26 36 37] and NOX2-dependent mechanisms [38] are believed to drive oxidativestress-related events in the pathogenesis of psychiatric disor-ders

Defects in the electron transport chain (ETC) system andespecially themitochondrial complex dysfunctions have beenreported to be involved in autism [39 40] and schizophrenia[40] Additionally defects in pyruvate dehydrogenase activityand copy number variations in mtDNA were also seen inautistic subjects [40] In a more recent work involving a

transgenic mouse model that expresses the gene ldquoputa-tive dominant-negative disrupted in schizophrenia 1rdquo (DN-DISC1) a plausible mechanistic link between prefrontaloxidative stress and neuropsychiatric problems was explored[41] Likewisemore recent genetic studies point to alterationsin a set of genes associated with epigenetic mechanismsand oxidative stress pathology thereby suggesting histonemodifications andDNAmethylation in schizophrenia relatedpsychopathology [42]

5 Oxidative Stress Mediated Inflammationand Neuropsychiatric Diseases

Recent findings suggest that neuroinflammation is an impor-tant player in the pathophysiology of neuropsychiatric dis-eases such as stroke depression Alzheimerrsquos diseases orschizophrenia [43 44]

51 Cerebral Ischemia (CI) After the onset of cerebralischemia oxidative stress plays a major role in neuroinflam-matory reactions [45 46] In postischemic brains oxidativestress triggers activation of microglia and astrocytes [47]leading to striking elevations in the levels of inflammatorymediators such as cytokines chemokines and matrix met-alloproteases [48] and causing the loss of endothelial cellintegrity in the brain as manifested by upregulation of celladhesion molecules and neutrophil infiltration [49] Thisprobably provokes subsequently secondary inflammationand glial immune response resulting in permanent brain celldamage [48]

Redox-mediated increase in free radicals in the postis-chemic brains notably leads to augmented expression ofseveral proinflammatory genes whose expression is mediatedthrough the transcription factor nuclear factor-kappa-B orNF-120581B [48] Importantly NF-120581B mediated proinflamma-tory reactions and innate immune responses are prominentfeatures in cerebral ischemic conditions [50ndash52] Althoughactivation of innate immunity by Toll-like receptors seemsto promote regenerative mechanisms [53] neuronal losscritically involves ROS induced TLR-mediated inflammatoryresponses during cerebral ischemia [54ndash57]

52 Parkinsonrsquos Disease In Parkinsonrsquos disease (PD) a con-siderable body of evidence suggests that both dopaminergicand nondopaminergic cells undergo degeneration [58ndash60]The innate immune response seen in the CNS of PD subjectsinvolves a spectrum of oxidative stress and inflammatoryresponses that cause neurodegeneration However the keyloss of dopaminergic neurons involves oxidative stress andneuroinflammatory mechanisms through increased levels ofinducible nitric oxide synthase (iNOS) followed by activatedmicroglia T-cell infiltration and astrogliosis leading to accu-mulation of O

2

minus and NO free radicals [59] Dopaminergicneuronal loss via oxidative stress-mediated inflammationalso involves cyclooxygenase-2 (COX2) overexpression [59]Additionally higher levels of myeloperoxidase generated byreactive astrocytes could even elevate the levels of reactive(∙OH) and NO

2

minus radicals that could in turn lead to neuronal


loss in Parkinsonrsquos disease [59] Similarly the upregulationof NADPH-oxidase which is known to be associated withinflammation and ROS generation in PD has been tied tomicroglial activation local ROS elevation and subsequentdopaminergic neuronal loss [61]

The involvement of microglial activation most likelyattracts lymphocytes to the site of injury Subsequent patho-physiological sequelae involve damage to the integrity of theblood brain barrier (BBB) and then increased shedding ofseveral inflammatory cytokines into the cerebral spinal fluid(CSF) of PD patients [62 63] As reactive microgliosis seemsto be amajor event in PD pathogenesis altered cytokines andROS levels in microglia [64] as well as augmented microglialNADPH-derived ROS accumulation [65] all contribute to theneurotoxicity seen in PD

The research findings from Reynolds and colleaguesimplicate the role of adaptive immunity functions duringmicroglial inflammation in Parkinsonrsquos disease [66] On theother hand the effector T-cell (E) responses are believedto be the mediators of microglial activation and subsequentneurodegeneration Taken together both innate and adaptiveimmunity play consistent prominent roles in causing neu-ronal death in PD

53 Alzheimerrsquos Disease (AD) Major events associatedwith oxidative stress could exacerbate inflammation-relatedpathologies in Alzheimerrsquos disease (AD) [67ndash69] Recentreports suggest that oxidative stress-mediated binding ofadvanced glycation endproduct (AGE) to its receptor (RAGE)can adversely increase the microglial inflammation andcytokine release Such events contribute to neuronal lossin AD [70] In AD patients both reactive astrocytes andmicroglial activation are involved in amyloid beta protein-mediated oxidative stress and inflammation [71ndash73] as wellas compromised immune responses [71] within the cerebralparenchyma Recent genomic studies [74] in AD patientsconfirmed previous observations that showed upregulationof several pathways associated with the innate immunesystem following microglia activation and inflammation inaging The researchers concluded that such findings wouldultimately account for neurodegeneration and memory lossin AD

The important role conferred to Toll-like receptors (TLR2and TLR4) in AD as peripheral biomarkers [75] of ADpathophysiology [75ndash77] is well studied Notably the partplayed by TLR receptors in AD progression addresses theimportance of innate immune responses [78] However thestriking elevation of TLR4 expression in neurons by the toxicaction of Abeta 1ndash42 or by increased elevation of the lipidperoxidation product 4-hydroxynonenal (HNE) obviouslysuggests that oxidative stress does drive neuronal loss in AD[77]

54Multiple Sclerosis Thedemyelination and axonal damagetriggered by oxidative stress and inflammatory reactionsare widely reported in multiple sclerosis (MS) [79] Thesubsequent appearance of peroxynitratemolecules is believedto inflict severe damage to brain cells and especially neurons

[80] Recently both ROS and RNS (reactive nitrogen species)compounds are considered to be the early causative factorsfor the inflammatory reactions associated with MS Thissubsequently leads to considerable loss of oligodendrocytesand axons [81] Moreover the early mitochondrial damagecaused by oxidative stress seems to be critical for subsequentinflammatory processes and neuronal loss in multiple sclero-sis [82]

55 Neurodevelopmental Disorders Epidemiological studieson prenatal exposure to infection during the developmentalperiod suggests that the immune system plays an impor-tant role in a number of disorders such as schizophre-nia depression or cognitive impairment [83] The innateimmune system triggers a cascade of events that results inan increased synthesis of cytokines interferons and otherimmunologicalmediators thereby altering the balance of pro-and anti-inflammatory cytokines Since cytokine receptorsare expressed as early as the fetal period it is thought thatinflammatory cytokines may represent a key mechanisminvolved in neurodevelopmental disorders [84 85] Indeedrecent studies have shown that prenatal exposure to proin-flammatory agents like Ilndash6 Ilndash8 and TNF alpha can increasethe risk for diseases like autism or schizophrenia by inducingboth neuromorphological and neurochemical changes in theimmature brain [86ndash88]

The vulnerability to develop psychiatric diseases laterin life (fetal programming) involves not only the immuneresponse of the brain but also the changes in glial cell func-tion [89 90] Thus assessment of microglia in postmortemautism cases revealed a strong microglial cortical activationsuggesting that activated microglia may play a central role inthe pathogenesis of autism [91]

56 Depressive Disorders Major depressive disorders areoften associated with an increased inflammatory responseof the brain A study employing the serotonin transporter(SERT) mutant rats has shown that deletion of the SERTgene is associated with an increased level of proinflammatorycytokines and an increased number of activated microgliasuggesting that the serotonin transporter dysfunction playsan important role in the pathogenesis of depressive disordersvia an increased glial response to inflammatory agents [9293] More specific Macchi and colleagues [93] showed thatthe SERT mutant rats displayed an activated microglialphenotype under basal conditions The mechanisms formicroglial activation and its consequences are still not com-pletely understoodHowever several studies investigating therole of proinflammatory cytokines like tumor necrosis factor(TNF) alpha or interleukins (IL1 beta IL6 and IL8) haveinvolved microglial activation in schizophrenia pathogenesis[94 95]

The progression of bipolar disorders is multifactorialand include the interaction between the neurotransmittersneuropeptides oxidative and nitrosative stress and cytokinesand neurotrophins including BDNF [96 97] Most impor-tantly emerging evidence in animal models and also in


humans suggests that anti-inflammatory therapy may delaythe progression of the diseases [98]

6 Biomarkers of Oxidative Stress inNeuropsychiatric Diseases

The levels of several growth factors and metabolites arealtered in cerebral tissue cerebrospinal fluid (CSF) andserum of patients exposed to oxidative stress and can be usedto assess risk factors or as potential biomarkers Similarlylongitudinal in vivo 1H-MRS that was used to evaluate thepostinjury evolution of 20 individual neurochemicals aftertraumatic brain injury (TBI) revealed a dramatic depletionof glutathione (GSH) and ascorbate (Asc) two endogenousantioxidants with the highest concentration in the centralnervous system [99] The following sections give an accountof current biomarkers of oxidative stress in neuropsychiatricdiseases

61 Developmental Disorders Although many of the cog-nitive and behavioral features of autism spectrum dis-orders (ASD) are associated with dysfunctions of thecentral nervous system ASD also appears to be associ-ated with systemic metabolic abnormalities such as oxida-tive stress and mitochondrial dysfunction [100ndash102] Glu-tathione deficiency also contributes to abnormalities seenin autistic behavior [40 103] as well as schizophrenia andbipolar disorders [104] Likewise examination of urinarysamples from schizophrenia subjects revealed considerablealterations in 8-oxo-78-dihydro-20-deoxyguanosine and 8-oxo-78-dihydroguanosine levels indicating oxidative stressinduced nucleic acids damage [105] Similarly in plasma F2-dihomo-isoprostanes a specific component of myelin in thebrain of primates plasma represents an early marker of Rettsyndrome a developmental disorder that almost exclusivelyaffects females but has been found inmale patients too [106]

A recent meta-analysis of oxidative stress in schizophre-nia suggests that red blood cells (RBC) SOD levels andto a lesser extent RBC catalase and plasma nitrites weresignificantly decreased in acutely relapsed inpatients first-episode psychosis and stable medicated outpatients [107]

Several markers of lipid peroxidation including the ubiq-uitous lipid peroxidation product malondialdehyde (MDA)have been found to be significantly increased in ADHDpatients The study comprised 20 adult-ADHD patients and21 healthy volunteers to whom malondialdehyde levels weremeasured in plasma The study evaluated indirectly the levelof ROS and found that the mean plasma MDA levels ofpatients having adult-ADHD were significantly higher thanthose of the control group The results suggest a relationbetween oxidative metabolism and adult ADHD [108]

62 Depressive Disorders Studies conducted on postmortemtissue from depressed patients have shown reduced levels ofhippocampal an anatomical structure involved in anxietyand depressive behaviors as well as cortical BDNF [109]In addition a polymorphism in the BDNF gene has beenassociated with depression [110ndash113]

In the periphery a meta-analysis provided strong evi-dence that BDNF levels in serum of depressed subjects arelower as compared to those of the healthy controls Furtherthe antidepressant treatment restored BDNF to normal levels[114]

After adipose tissue the organ with the highest lipidcontent is the brain and elevated serum levels of lipidperoxidation products have been often reported in bipolardisorders Because the axonalmembranes andmyelin sheathsof the brain are rich in lipids it has been proposed thatlipid peroxidation products may be promising peripheralbiomarkers of underlying white matter abnormalities inbipolar disorders (BP) A recent study combined diffusiontensor imaging and biochemical analysis of serum to examinerelationships between measures of white matter integrityas measured by fractional anisotropy radial diffusivity andperipheralmeasures of lipid peroxidation the lipid hydroper-oxides LPH and 4-hydroxy-2-nonenal 4-HNE The studysuggests that serum LPH may be useful in the developmentof a clinically relevant assay for peripheral biomarkers of BD[115]

Similarly lipofuscin granule accumulation has beendescribed in biopsies from patients suffering from majordepressive disorder (MDD) indicating the impact of oxidativestress on neurovascular abnormalities in these patients [116]

63 Alzheimer Disease Mitochondrial dysfunction can alsobe detected in peripheral tissues Although erythrocytes areconsidered as passive ldquoreporter cellsrdquo for the oxidative statusof the whole organism decreased glutathione peroxidaseactivity (GPx) in RBCmay be considered as a new peripheralmarker forAD [117] Several other studies showed a decreasedcytochrome c activity and increased levels of ROS in humanplatelets from AD patients [118ndash120] Similarly lymphocytesofADpatients are characterised by increased basal ROS levels[121]

Other classical markers of oxidative stress in plasma ofearly stage AD patients include thiobarbituric acid reactivesubstances (TBARS) as an index of lipid peroxidation proteincarbonyl content as an index of protein oxidation theenzymatic activities of GPx catalase (CAT) and superox-ide dismutase (SOD) as well as the plasma levels of totalglutathione (reduced GSH plus oxidized glutathione (GSSG)[122]

64 Parkinsonrsquos Disease Similarly 4-hydroxynonenal (4-HNE) an alpha beta-unsaturated hydroxyalkenal producedby peroxidation of polyunsaturated fatty acids is widelyrecognized as a specific marker of oxidative stress bothcentrally and in the CSF and serum of PD patients [123ndash127]

Likewise several markers of lipid peroxidation includingthe ubiquitous lipid peroxidation product malondialdehyde(MDA) have been found to be significantly increased inPD brains [128ndash131] There is also strong evidence for lipidperoxidation products like hydroxyeicosatetraenoic acid inplasma leukocytes and erythrocytes from PD patients [132ndash134] Finally higher nitric oxide and peroxynitrite serum


levels have been recently reported in Parkinsonrsquos diseaseversus controls [135]

7 Targets of Therapy inNeuropsychiatric Disorders

Oxidative stress and neuroinflammation are key factorscontributing to aging of the brain Many studies highlightedthe importance of antioxidative defenses in the aging process[22 136 137] but it is still unclear whether these responsesare beneficial or detrimental A diminished endogenousantioxidative capacity of the brain can promote aged-relateddiseases such as cerebral ischemia or neurodegenerativedisorders In order to protect the brain from both aged-associated pathological diseases and the aging process itself itbecomes imperative to understand themolecular and cellularmechanisms of antioxidative andor inflammatory response

71 Activators of the Nrf2ARE Pathway The nuclear factorerythroid 2 related factor (Nrf2) is a dimer of the p45 proteinand a member of the small Maf family proteins involved inthe modulation of both antioxidant and anti-inflammatorysignaling [138]

As cells are permanently exposed to a variety of oxidativestressors they must be able to trigger antioxidative signalingpathways in order to maintain redox homeostasis To thisend Nrf2 is activated via phosphorylation while underoxidative stress (such as in hypoxiaischemia reperfusion orin neurodegenerative diseases) it is shuttled to the nucleuswhere it builds up a dimer with the small Maf The activatedcomplex in turn promotes the transcription of genes involvedin neuroprotection An in vitro study on primary corticalcultures has recently shown that prolonged expression of thetranscription factor NF-E2-related factor 2 (Nrf2) induced byhypoxia and oxidative stress acts neuroprotectively againstoxygen glucose deprivation By inserting the Nrf2 gene inan inducible gene construct a controlled neuroprotectiveeffect can be achieved by overexpressingNrf2 not only duringhypoxia but also after reperfusion [139]

The key trigger to this neuroprotective cascade is thebinding of Nrf2 to the antioxidant response elements (AREs)[140ndash142] Therefore exogenous Nrf2ARE activators mayrepresent powerful drugs to activate the antioxidant anddefensive acting genes The Nrf2ARE pathway can bepharmacologically activated both by natural products suchas sulforaphane [143 144] polyphenols epigallocatechin 3-gallate (EGCG) and curcumin [145] and synthetic drugsincluding triterpenoids and N-(4-(2-pyridyl)(13-thiazol-2-yl))-2-(246-trimethylphenoxy) acetamide known as CPN-9[146]

Interestingly recent studies have also shown that Nrf2Hmox activation may enhance cell proliferation and survivalin the subventricular zone (SVZ) of aged brains by revertingmicroglial phenotype into the proneurogenic phenotype [147148]We also have observed that during conditions of cerebralischemia the aged brain upregulates the Hmox1 gene onlypartially and later (day 14 after-ischemia) as compared to

young animals which activate this gene strongly and early(day 3 after-infarct) after stroke [149]

72 Biochemicals Omega-3 Polyunsaturated Fatty Acids andVitamins Of these omega-3 polyunsaturated fatty acid(PUFA) is one of the few compounds that are able tomodulate the expression of genes involved in cell signalingdivision apoptosis and oxidative stress [150] Mountingevidence indicates that fatty acid deficiencies or imbalancesmay also contribute to a range of adult psychiatric andneurologic disorders includingADHDDCD (developmentalcoordination disorder) and autism

A recent study investigated the antioxidant effect ofalpha linolenic acid in adults and children with ADHDDCD and autism Omega-3 polyunsaturated fatty acids weregiven as supplements to patients diet and the changes inhyperactivity attention and other disruptive behaviors wereanalyzed The patients who received flax oil (an oil rich in18 carbon omega-3 fatty alpha-linolenic acid) did show asignificant improvement in the symptoms of ADHD reflectedby a reduction in total hyperactivity scores [151] Howeverthe diet with mixed omega-3 and omega-6 supplementationhad only a modest effect on attention and hyperactivitysymptoms in 117 children with DCD The treatment did notshow a significant effect on motor skills but did show asignificant improvement in reading spelling and behaviorversus placebo during the 3 months of treatment [152]

Vitamins have also been used in clinical trials A studywas performed on patients over 70 years old who werediagnosed with dementia and other cognitive dysfunctions[153] An improvement in their cognitive performance wasobserved after vitamin C and E were given as food sup-plements Of note a positive response was seen in vasculardementia but not in Alzheimerrsquos disease [153] In otherstudies long-term high dosing of vitamin E supplementationincreased the risk of hemorrhagic stroke and other causesof mortality raising questions about the benefit or the harmof this treatment [154] The presence of vitamin D seems toregulate autophagy that is used by the cell to degrade cytosolicmacromolecules and organelles in the lysosome Being anadaptive response the autophagy can be useful or deleteriousdepending on the energetic status of the cell [155 156]

8 Peroxisome Proliferator-ActivatedReceptor-Gamma Agonists

In human and animal models the cognitive decline in vas-cular dementia is dependent on the hippocampal functionRecently peroxisome proliferator-activated receptor gamma(PPAR-gamma) agonists were shown to diminish oxidativestress inflammation and apoptosis in the central nervoussystem [157 158] Peroxisome-proliferator activator receptor-gamma is a nuclear receptor with a key role in energyhomeostasis and inflammation that has been implicated inthe oxidative stress response

Telmisartan is a special angiotensin II receptor blocker(ARB) and a partial agonist of the (PPAR-gamma) A recentstudy asked if telmisartan protects against cognitive decline


in a rat model of vascular dementia Indeed it was found thattelmisartan acts neuroprotectively against cognitive declineafter cerebral ischemia by promoting anti-inflammatoryand antioxidant effects [159 160] In particular it hasbeen hypothesized that ARB might act neuroprotectivelyby upregulating the levels of BDNF a known antioxidantin the hippocampus Indeed after 28 days of treatmentwith telmisartan BDNF expression in the hippocampus wassignificantly higher as compared to controls and the animalsshowed an improved cognitive performance It was inferredthat telmisartan may protect the cells via upregulation ofBDNF and its receptor TrkB in the hippocampus possibly viaangiotensin II-induced anti-oxidative stress [161] Recentlyanother PPAR-gamma agonist 15d-PGJ2 has been shown toexert neuroprotection by inhibiting neuronal autophagy instroke model [162]

Thiazolidinediones (TZDs) are still another potent syn-thetic agonists of PPAR-gamma that have been successfullyused to diminish inflammation after cerebral ischemia [163]Similarly pioglitazone and rosiglitazone are two TZDs withproven efficacy in reducing inflammation and upregulat-ing antioxidant enzymes after spinal cord injury [164]Recently the neuroprotective efficacy of a TZD-unrelatedPPARgamma agonist L-796449 has been tested in an animalmodel of stroke The study showed that L-796449 decreasedthe infarct size and improved neurologic outcomes [165]

81 Gases Hyperbaric Oxygen and H2S The first study

that used hyperbaric oxygen therapy to treat autistic chil-dren showed a significant level of improvement of autisticsymptoms in 75 of patients [166] The results have beenconfirmed in a second study that evaluated social devel-opment fine motor and eye-hand coordination languagedevelopment gross motor development and self-help skillsbefore and after the treatment of children with autism Itshould be noted that the beneficial effect of hyperbaricoxygen for brain diseases has been previously shown byD A Rossignol and L W Rossignol in 2006 who showedthat hyperbaric oxygen therapy improved oxygen levels inischemic area by increasing the oxygen concentration inplasma as a compensatory mechanism in hypoxia [167]

Hydrogen sulfide (H2S) is another gas recently used in

several neuroprotective studies H2S is a mild inhibitor of

oxidative phosphorylation and can protect neurons aftera stroke [168] The study was performed on 17-month-oldmale Sprague-Dawley rats and focal cerebral ischemia wasinduced by reversible occlusion of the right middle cerebralartery Exposure of poststroke rats to a mixture of air andhydrogen sulfide for 2 days resulted in deep and sustainedhypothermia (318 plusmn 07∘C) An improvement in the post-stroke recovery of complex sensorimotor skills along witha 50 reduction in infarct size was noted There were noobvious physiological side effects Hypothermia resulted ina reduction in the number of phagocytic cells as well asdecreased transcriptional activity of several genes related toinflammation and apoptosis including caspase 12 NF-kappaB and grp78 in the peri-infarcted region [168]

Two further studies showed that indeed hydrogen-richsaline can benefit the brain in a global cerebral ischemiareperfusion model (four-vessel occlusion model) and in a ratmodel with permanent focal cerebral ischemia (permanentmiddle cerebral artery occlusion) respectively [169 170]The results demonstrated that intraperitoneal injection ofhydrogen-rich saline offers strong neuroprotective effects byreducing oxidative stress and inflammation Thus the levelof endogenous antioxidant enzymes (superoxide dismutase-SOD and catalase-CAT) was increased whereas the concen-tration of oxidative products (8-iso-PGF2120572 andmalondialde-hyde) and inflammatory cytokines (TNF-120572 and IL-6) wasdecreased [169 170]

82 Metals Lithium Healthy volunteers treated with lithiumfor a period of 2ndash4 weeks showed decreased superoxidedismutase levels and superoxide dismutasecatalase ratioas well as diminished hydrogen peroxide concentrationsTherefore lithium has a potential role for neuroprotectionin bipolar disorders and even in neurodegenerative diseasesLithium seems to be the gold standard due to its ability topreventor reverse DNA damage lipid peroxidation and freeradical formation [171] In addition lithium induces BDNF inneuronal cultures [172]

83 ROS Scavengers Amechanism that implicates the oxida-tive stress in the appearance of depressive symptoms is themetabolism of the nitric oxide (NO) NO is generated bynitric oxide synthase (NOS) that catalyzes the metabolismof L-arginine to L-citrulline and nitric oxide (∙NO) in thepresence of molecular oxygen and NADPH NO is a gas thatacts as second messenger in a number of organs includingthe brain and is also a free radical involved in the etiologyand progression of many diseases

Neuronal NOS (nNOS) is a Ca2+-calmodulin-dependentisoform of NOS that is constitutively expressed in neuronalcells A persistent expression of nNOS may result in anincreased production of reactive nitrogen species (RNS) suchas ∙NO and peroxynitrite (ONOOminus) and thus may result inneuronal death due to increased nitrativenitrosative stressNOS can also generate superoxide when levels of the naturalsubstrates L-arginine and tetrahydrobiopterin decrease [173]

The ldquoNO hypothesisrdquo was tested in a small clinical studydone on 78 patients diagnosed with recurrent depressivedisorder and healthy controls High levels of plasmaNOweretested alongwith the efficiency of visual-spatial and auditory-verbal working memory and short-term declarative memoryThe concentration of plasma NO was found to be directlyproportional with the severity of depressive symptoms [174]

In a recent study Yoshitomi and colleagues [175] havereported the synthesis of pH-responsive nitroxide radical-containing nanoparticles which act as highly efficient scav-engers of ROS thus bringing new hopes for antioxidanttherapies

Recently it is has been suggested that not only antiox-idants but also the prooxidant system plays an importantrole in neuropsychiatric disorders Xanthine oxidase (XO) isan enzyme of special interest in this context since it acts as


Table 1 Drugs with anti-inflammatory and antioxidant effects currently under investigation for the treatment of several neuropsychiatricdiseases

Drug Brain disease Mechanism Reference120596-3 PUFA ADHD Nonspecific antioxidant effect [151 152]Vitamin C Vascular dementia Free radical scavenger [153]Hyperbaric O2 Autism Anti-inflammatory and reduces oxidative stress [157]

H2SFocal cerebralischemiareperfusion

Inhibits oxidative phosphorylationinflammation and apoptosis [159]

H2-rich saline Focal or global cerebralischemiareperfusion Reduces oxidative stress and inflammation [160 161]

Lithium Healthy volunteers Preventsor reverses DNA damage lipidperoxidation and free radical formation [164]

Pifithrin-120583 Perinatal hypoxic-ischemicbrain damage

Inhibition of the apoptotic pathways andreduction of the oxidative stress [166]

Telmisartan Vascular dementia Anti-inflammatory and antioxidant effects [174ndash176]Nanodrugs ROS scavengers [177]Triterpenoids Parkinson Antioxidants via Nrf2ARE pathway [146]PPARgammaagonists Neurodegenerative diseases Anti-inflammatory [162ndash164]

a prooxidant but its main product uric acid is a powerfulantioxidant By examining the activity of XO in the occipitalcortex and thalamus of patients with psychosis the authorsfound a decreased activity of XO suggesting a downregulationof cellular defence mechanisms in schizophrenia [176]

The available drugs currently in use either for research ortherapeutic purposes for several brain diseases are shown inTable 1

9 Conclusions

Here we reviewed many aspects of therapeutic strategiesaimed to improve the neuroprotection and the function ofthe brain Many preclinical models showed an increasedneuroprotection to stressors like hypoxia Although manypromising drugs in particular antioxidants have been devel-oped and shown to be beneficial to experimental animalmodels the results of recent clinical trials investigating thesepromising drugs have been largely negative As alludedto previously the oxidative stress is a key contributor toneurodegeneration Therefore the antioxidant therapy is anovel therapeutic strategy and neuroscientists are increas-ingly interested in the participation of ROS towards thepathology involved in neurodegenerative disorders It ishowever difficult to determine targets for treatment and todistinguish betweenwhatmay be harmful or beneficial for thebrain without precise knowledge of the pathways involved inthe progression of neuronal diseases [178]

Modulation of prooxidant-antioxidant balance plays animportant role in mitochondrial dysfunction and providesan additional therapeutic option which can be used toimprove neuroprotection and cognitive functions in responseto oxidative stress Anti-ROS drugs could probe pathologi-cal pathways associated with neurodegeneration psychiatricdisorders However there are only few well-established drugsof such a kind and the risks and benefits are still not fully

clarified Most likely multiple distinct pathways should betargeted for an efficient therapeutic purpose Therefore it isnot surprisingly that many drugs exert their beneficial effectson neurotransmission indirectly by modulating inflamma-tion oxidative stress or apoptosis [179] Meta-analyses havesuggested that antidepressants (fluvoxamine reboxetine orimipramine) and antipsychotics (clozapine and risperidone)reduce the levels of the proinflammatory cytokines IL-6and NO and suppress the macrophage production [177] andupregulate signaling pathway associated with neurotrophicfactors like BDNF [180 181] Likewise fluoxetine may exertits neuroprotective effects via downregulating the expressionof inhibiting key players involved in inflammation includingNFkappaB [182] IL-1120573 TNF-120572 and COX-2 [183] Howeverthe available drugs have pleiotropic actions and are not fullycharacterized in the clinic

Authorsrsquo Contribution

Aurel Popa-Wagner SmarandaMitran Senthil Kumar EdwinChang and AnandashMaria Buga have equally contributed to thiswork

Acknowledgments

This study was supported by UEFISCDI PN-II-PCCA-2011Grant no 80 to Aurel Popa-Wagner and UEFISCDI FLARE2to AnandashMaria Buga

References

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[2] N A Campbell and J B Reece Biology Pearson-BenjaminCummings 7th edition 2005


[3] P R Rich ldquoThe molecular machinery of Keilinrsquos respiratorychainrdquo Biochemical Society Transactions vol 31 no 6 pp 1095ndash1105 2003

[4] M Guglielmotto E Tamagno and O Danni ldquoOxidative stressand hypoxia contribute to Alzheimerrsquos disease pathogenesistwo sides of the same coinrdquo TheScientificWorldJournal vol 9no 1 pp 781ndash791 2009

[5] S-D Chen D-I Yang T-K Lin F-Z Shaw C-W Liou andY-C Chuang ldquoRoles of oxidative stress apoptosis PGC-1 andmitochondrial biogenesis in cerebral ischemiardquo InternationalJournal of Molecular Sciences vol 12 no 10 pp 7199ndash7215 2011

[6] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007

[7] T M Michel D Pulschen and J Thome ldquoThe role of oxidativestress in depressive disordersrdquo Current Pharmaceutical Designvol 18 no 36 pp 5890ndash5899 2012

[8] X Wang and X Zhao ldquoContribution of oxidative damage toantimicrobial lethalityrdquo Antimicrobial Agents and Chemother-apy vol 53 no 4 pp 1395ndash1402 2009

[9] W Droge ldquoFree radicals in the physiological control of cellfunctionrdquo Physiological Reviews vol 82 no 1 pp 47ndash95 2002

[10] S-P LuM-H Lin Feng H-L Huang Y-C HuangW-I TsouandM-Z Lai ldquoReactive oxygen species promote raft formationin T lymphocytesrdquo Free Radical Biology ampMedicine vol 42 no7 pp 936ndash944 2007

[11] C M Atkins and J D Sweatt ldquoReactive oxygen species mediateactivity-dependent neuron-glia signaling in output fibers of thehippocampusrdquo The Journal of Neuroscience vol 19 no 17 pp7241ndash7248 1999

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[19] M J Hansson R Mansson S Morota et al ldquoCalcium-inducedgeneration of reactive oxygen species in brain mitochondria ismediated by permeability transitionrdquo Free Radical Biology ampMedicine vol 45 no 3 pp 284ndash294 2008

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[34] E Ben-David and S Shifman ldquoNetworks of neuronal genesaffected by common and rare variants in autism spectrumdisordersrdquoPLoSGenetics vol 8 no 3 Article ID e1002556 2012

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[38] X Wang A Pinto-Duarte T J Sejnowski and M M BehrensldquoHowNox2-containingNADPHoxidase affects cortical circuitsin the NMDA receptor antagonist model of schizophreniardquoAntioxidants amp Redox Signaling vol 18 no 12 pp 1444ndash14622013

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[56] R Gill A Tsung and T Billiar ldquoLinking oxidative stressto inflammation toll-like receptorsrdquo Free Radical Biology ampMedicine vol 48 no 9 pp 1121ndash1132 2010

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oxidative tissue damage and mitochondrial injuryrdquo Brain vol135 no 3 pp 886ndash899 2012

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[91] J T Morgan G Chana C A Pardo et al ldquoMicroglial activationand increased microglial density observed in the dorsolateralprefrontal cortex in autismrdquo Biological Psychiatry vol 68 no 4pp 368ndash376 2010

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[94] A Monji T A Kato Y Mizoguchi et al ldquoNeuroinflammationin schizophrenia especially focused on the role of microgliardquoProgress in Neuro-Psychopharmacology amp Biological Psychiatryvol 42 pp 115ndash121 2013

[95] K Liaury T Miyaoka T Tsumori et al ldquoMorphologicalfeatures of microglial cells in the hippocampal dentate gyrus ofGunn rat a possible schizophrenia animal modelrdquo Journal ofNeuroinflammation vol 9 article 56 2012

[96] R M Post ldquoKindling and sensitization as models for affectiveepisode recurrence cyclicity and tolerance phenomenardquo Neu-roscience and Biobehavioral Reviews vol 31 no 6 pp 858ndash8732007

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[101] XMingM Brimacombe J Chaaban B Zimmerman-Bier andG C Wagner ldquoAutism spectrum disorders concurrent clinicaldisordersrdquo Journal of Child Neurology vol 23 no 1 pp 6ndash132008

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[105] A Jorgensen J Krogh K Miskowiak et al ldquoSystemic oxida-tively generatedDNARNAdamage in clinical depression asso-ciations to symptom severity and response to electroconvulsivetherapyrdquo Journal of Affective Disorders vol 149 no 1ndash3 pp 355ndash362 2013

[106] T Durand C De Felice C Signorini et al ldquoF(2)-Dihomo-isoprostanes and brain white matter damage in stage 1 Rettsyndromerdquo Biochimie vol 95 pp 86ndash90 2013

[107] J Flatow P Buckley and B J Miller ldquoMeta-analysis of oxidativestress in schizophreniardquo Biological Psychiatry vol 74 no 6 pp400ndash409 2013

[108] M Bulut S Selek H S Gergerlioglu et al ldquoMalondialdehydelevels in adult attention-deficit hyperactivity disorderrdquo Journalof Psychiatry and Neuroscience vol 32 no 6 pp 435ndash438 2007

[109] Y Dwivedi H S Rizavi R R Conley R C Roberts C ATamminga andGN Pandey ldquoAltered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase Bin postmortem brain of suicide subjectsrdquo Archives of GeneralPsychiatry vol 60 no 8 pp 804ndash815 2003

[110] P Sklar S B Gabriel M G McInnis et al ldquoFamily-basedassociation study of 76 candidate genes in bipolar disorderBDNF is a potential risk locusrdquoMolecular Psychiatry vol 7 no6 pp 579ndash593 2002

[111] S Sen RMNesse S F Stoltenberg et al ldquoA BDNF coding vari-ant is associated with the NEO personality inventory domainneuroticism a risk factor for depressionrdquo Neuropsychopharma-cology vol 28 no 2 pp 397ndash401 2003

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[114] S Sen R Duman and G Sanacora ldquoSerum brain-derived neu-rotrophic factor depression and antidepressant medicationsmeta-analyses and implicationsrdquo Biological Psychiatry vol 64no 6 pp 527ndash532 2008

[115] A Versace A C Andreazza L T Young et al ldquoElevatedserum measures of lipid peroxidation and abnormal prefrontalwhite matter in euthymic bipolar adults toward peripheralbiomarkers of bipolar disorderrdquoMolecular Psychiatry 2013

[116] S Najjar DM Pearlman S Hirsch et al ldquoBrain biopsy findingslinkmajor depressive disorder to neuroinflammation oxidativestress and neurovascular dysfunction a case reportrdquo BiologicalPsychiatry 2013

[117] E A KosenkoGAliev L A Tikhonova Y Li A C Poghosyanand Y G Kaminsky ldquoAntioxidant status and energy state oferythrocytes inAlzheimer dementia probing formarkersrdquoCNSampNeurological DisordersDrugTargets vol 11 no 7 pp 926ndash9322012

[118] S M Cardoso M T Proenca S Santos I Santana and C ROliveira ldquoCytochrome c oxidase is decreased in Alzheimerrsquosdisease plateletsrdquo Neurobiology of Aging vol 25 no 1 pp 105ndash110 2004

[119] F Bosetti F Brizzi S Barogi et al ldquoCytochrome c oxidaseand mitochondrial F1F0-ATPase (ATP synthase) activities inplatelets and brain from patients with Alzheimerrsquos diseaserdquoNeurobiology of Aging vol 23 no 3 pp 371ndash376 2002

[120] M Mancuso M Filosto F Bosetti et al ldquoDecreased plateletcytochrome c oxidase activity is accompanied by increasedblood lactate concentration during exercise in patients withAlzheimer diseaserdquo Experimental Neurology vol 182 no 2 pp421ndash426 2003

[121] K Leuner K Schulz T Schutt et al ldquoPeripheral mitochondrialdysfunction in Alzheimerrsquos disease focus on lymphocytesrdquoMolecular Neurobiology vol 46 no 1 pp 194ndash204 2012

[122] MC Puertas JMMartınez-MartosM P CoboM P CarreraM D Mayas and M J Ramırez-Exposito ldquoPlasma oxidativestress parameters inmen andwomenwith early stageAlzheimertype dementiardquo Experimental Gerontology vol 47 no 8 pp625ndash630 2012

[123] E Okun T V Arumugam S-C Tang et al ldquoThe organotel-lurium compound ammonium trichloro(dioxoethylene-001015840)tellurate enhances neuronal survival and improves functionaloutcome in an ischemic stroke model in micerdquo Journal ofNeurochemistry vol 102 no 4 pp 1232ndash1241 2007

[124] S Nagotani T Hayashi K Sato et al ldquoReduction of cerebralinfarction in stroke-prone spontaneously hypertensive rats bystatins associated with amelioration of oxidative stressrdquo Strokevol 36 no 3 pp 670ndash672 2005

[125] W C Lee H Y Wong Y Y Chai et al ldquoLipid peroxidationdysregulation in ischemic stroke plasma 4-HNE as a potentialbiomarkerrdquoBiochemical and Biophysical Research Communica-tions vol 425 no 4 pp 842ndash847 2012

[126] M L Selley ldquo(E)-4-Hydroxy-2-nonenal may be involved inthe pathogenesis of Parkinsonrsquos diseaserdquo Free Radical Biology ampMedicine vol 25 no 2 pp 169ndash174 1998

[127] T V Ilic M Jovanovic A Jovicic and M Tomovic ldquoOxidativestress indicators are elevated in de novo Parkinsonrsquos diseasepatientsrdquo Functional Neurology vol 14 no 3 pp 141ndash147 1999

[128] M Bulut S Selek Y Bez et al ldquoLipid peroxidation markers inadult attention deficit hyperactivity disorder new findings foroxidative stressrdquo Psychiatry Research vol 209 no 3 pp 638ndash642 2013


[129] O Akyol H Herken E Uz et al ldquoThe indices of endoge-nous oxidative and antioxidative processes in plasma fromschizophrenic patients the possible role of oxidantantioxidantimbalancerdquo Progress in Neuro-Psychopharmacology amp BiologicalPsychiatry vol 26 no 5 pp 995ndash1005 2002

[130] M Ceylan S Sener A C Bayraktar and M KavutculdquoOxidative imbalance in child and adolescent patients withattention-deficithyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no 8 pp1491ndash1494 2010

[131] L H Sanders and J Timothy Greenamyre ldquoOxidative dam-age to macromolecules in human Parkinson disease and therotenone modelrdquo Free Radical Biology amp Medicine vol 62 pp111ndash120 2013

[132] M Gulec H Ozkol Y Selvi et al ldquoOxidative stress in patientswith primary insomniardquoProgress inNeuro-Psychopharmacologyamp Biological Psychiatry vol 37 no 2 pp 247ndash251 2012

[133] J Kalra A H Rajput S V Mantha A K Chaudhary andK Prasad ldquoOxygen free radical producing activity of poly-morphonuclear leukocytes in patients with Parkinsonrsquos diseaserdquoMolecular and Cellular Biochemistry vol 112 no 2 pp 181ndash1861992

[134] DO Cristalli N Arnal F AMarraM J T deAlaniz andCAMarra ldquoPeripheral markers in neurodegenerative patients andtheir first-degree relativesrdquo Journal of the Neurological Sciencesvol 314 no 1-2 pp 48ndash56 2012

[135] L Kouti M Noroozian S Akhondzadeh et al ldquoNitric oxideand peroxynitrite serum levels in Parkinsonrsquos disease correla-tion of oxidative stress and the severity of the diseaserdquo EuropeanReview for Medical and Pharmacological Sciences vol 17 no 7pp 964ndash970 2013

[136] C Haxaire F R Turpin B Potier et al ldquoReversal of age-related oxidative stress prevents hippocampal synaptic plasticitydeficits by protecting d-serine-dependent NMDA receptoractivationrdquo Aging Cell vol 11 no 2 pp 336ndash344 2012

[137] L Qin Y Liu J S Hong and F T Crews ldquoNADPH oxi-dase and aging drive microglial activation oxidative stressand dopaminergic neurodegeneration following systemic LPSadministrationrdquo Glia vol 61 no 6 pp 855ndash868 2013

[138] P Milani G Ambrosi O Gammoh F Blandini and C CeredaldquoSOD1 and DJ-1 converge at Nrf2 pathway a clue for antiox-idant therapeutic potential in neurodegenerationrdquo OxidativeMedicine and Cellular Longevity vol 2013 Article ID 83676012 pages 2013

[139] 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

[140] Y Li J D Paonessa and Y Zhang ldquoMechanism of chemicalactivation of Nrf2rdquo PLoS One vol 7 no 4 Article ID e351222012

[141] L Gan M R Vargas D A Johnson and J A JohnsonldquoAstrocyte-specific overexpression of Nrf2 delays motor pathol-ogy and synuclein aggregation throughout the CNS in thealpha-synuclein mutant (A53T) mouse modelrdquo The Journal ofNeuroscience vol 32 no 49 pp 17775ndash17787 2012

[142] T G Son EM Kawamoto Q S Yu N H GreigM PMattsonand S Camandola ldquoNaphthazarin protects against glutamate-induced neuronal death via activation of the Nrf2ARE path-wayrdquo Biochemical and Biophysical Research Communicationsvol 433 no 4 pp 602ndash606 2013

[143] A T Dinkova-Kostova W D Holtzclaw R N Cole et alldquoDirect evidence that sulfhydryl groups of Keap1 are the sensorsregulating induction of phase 2 enzymes that protect againstcarcinogens and oxidantsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 99 no 18 pp11908ndash11913 2002

[144] F Hong M L Freeman and D C Liebler ldquoIdentificationof sensor cysteines in human Keap1 modified by the cancerchemopreventive agent sulforaphanerdquo Chemical Research inToxicology vol 18 no 12 pp 1917ndash1926 2005

[145] H Jiang X Tian Y GuoW Duan H Bu and C Li ldquoActivationof nuclear factor erythroid 2-related factor 2 cytoprotectivesignaling by curcumin protect primary spinal cord astrocytesagainst oxidative toxicityrdquo Biological and Pharmaceutical Bul-letin vol 34 no 8 pp 1194ndash1197 2011

[146] N A Kaidery R Banerjee L Yang et al ldquoTargeting Nrf2-mediated gene transcription by extremely potent synthetictriterpenoids attenuate dopaminergic neurotoxicity in theMPTP mouse model of Parkinsonrsquos diseaserdquo Antioxidants ampRedox Signaling vol 18 no 2 pp 139ndash157 2013

[147] F LrsquoEpiscopo C Tirolo N Testa et al ldquoAging-induced Nrf2-ARE pathway disruption in the subventricular zone drivesneurogenic impairment in Parkinsonian mice via PI3K-Wnt120573-Catenin dysregulationrdquoThe Journal of Neuroscience vol 33 no4 pp 1462ndash1485 2013

[148] I Perez-de-Puig A Martın R Gorina X de la Rosa EMartinez and A M Planas ldquoInduction of hemeoxygenase-1expression after inhibition of hemeoxygenase activity promotesinflammation and worsens ischemic brain damage in micerdquoNeuroscience vol 243 pp 22ndash32 2013

[149] A M Buga C J Scholz S Kumar et al ldquoIdentification of newtherapeutic targets by genome-wide analysis of gene expressionin the ipsilateral cortex of aged rats after strokerdquo PLoS One vol7 Article ID e50985 2012

[150] M Bousquet F Calon and F Cicchetti ldquoImpact of omega-3fatty acids in Parkinsonrsquos diseaserdquo Ageing Research Reviews vol10 no 4 pp 453ndash463 2011

[151] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006

[152] A J Richardson and P Montgomery ldquoThe Oxford-DurhamStudy a randomized controlled trial of dietary supplementa-tion with fatty acids in children with developmental coordina-tion disorderrdquo Pediatrics vol 115 no 5 pp 1360ndash1366 2005

[153] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008

[154] G Bjelakovic D Nikolova L L Gluud R G Simonettiand C Gluud ldquoMortality in randomized trials of antioxidantsupplements for primary and secondary prevention systematicreview and meta-analysisrdquoThe Journal of the American MedicalAssociation vol 297 no 8 pp 842ndash857 2007

[155] M Hoslashyer-Hansen S P S Nordbrandt and M JaattelaldquoAutophagy as a basis for the health-promoting effects ofvitamin Drdquo Trends inMolecularMedicine vol 16 no 7 pp 295ndash302 2010

[156] P Tuohimaa T Keisala A Minasyan J Cachat and AKalueff ldquoVitamin D nervous system and agingrdquo Psychoneu-roendocrinology vol 34 no 1 pp S278ndashS286 2009


[157] R K Kaundal and S S Sharma ldquoPeroxisome proliferator-activated receptor 120574 agonists as neuroprotective agentsrdquo DrugNews amp Perspectives vol 23 no 4 pp 241ndash256 2010

[158] S Polvani M Tarocchi and A Galli ldquoPPAR and oxidativestress Con(120573) catenating NRF2 and FOXOrdquo PPAR Researchvol 2012 Article ID 641087 15 pages 2012

[159] T Haraguchi K Iwasaki K Takasaki et al ldquoTelmisartan apartial agonist of peroxisome proliferator-activated receptor120574 improves impairment of spatial memory and hippocampalapoptosis in rats treated with repeated cerebral ischemiardquo BrainResearch vol 1353 no 1 pp 125ndash132 2010

[160] K Washida M Ihara K Nishio et al ldquoNonhypotensive doseof telmisartan attenuates cognitive impairment partially due toperoxisome proliferator-activated receptor-120574 activation in micewith chronic cerebral hypoperfusionrdquo Stroke vol 41 no 8 pp1798ndash1806 2010

[161] T Kishi Y Hirooka and K Sunagawa ldquoTelmisartan pro-tects against cognitive decline via up-regulation of brain-derived neurotrophic factortropomyosin-related kinase B inhippocampus of hypertensive ratsrdquo Journal of Cardiology vol60 no 6 pp 489ndash494 2012

[162] F Xu J Li W Ni Y W Shen and X P Zhang ldquoPeroxisomeproliferator-activated receptor-120574 agonist 15d-prostaglandinJ2 mediates neuronal autophagy after cerebral ischemia-reperfusion injuryrdquo PLoS One vol 8 no 1 Article ID e550802013

[163] K Tureyen R Kapadia K K Bowen et al ldquoPeroxisomeproliferator-activated receptor-120574 agonists induce neuropro-tection following transient focal ischemia in normotensivenormoglycemic as well as hypertensive and type-2 diabeticrodentsrdquo Journal of Neurochemistry vol 101 no 1 pp 41ndash562007

[164] S-W Park J-H Yi G Miranpuri et al ldquoThiazolidinedioneclass of peroxisome proliferator-activated receptor 120574 agonistsprevents neuronal damage motor dysfunction myelin lossneuropathic pain and inflammation after spinal cord injury inadult ratsrdquo Journal of Pharmacology and Experimental Thera-peutics vol 320 no 3 pp 1002ndash1012 2007

[165] M P Pereira O Hurtado A Cardenas et al ldquoThe nonthia-zolidinedione PPAR120574 agonist L-796449 is neuroprotective inexperimental strokerdquo Journal of Neuropathology and Experi-mental Neurology vol 64 no 9 pp 797ndash805 2005

[166] J Chungpaibulpatana T Sumpatanarax NThadakul C Chan-tharatreerat M Konkaew andM Aroonlimsawas ldquoHyperbaricoxygen therapy inThai autistic childrenrdquo Journal of the MedicalAssociation of Thailand vol 91 no 8 pp 1232ndash1238 2008

[167] D A Rossignol and L W Rossignol ldquoHyperbaric oxygentherapy may improve symptoms in autistic childrenrdquo MedicalHypotheses vol 67 no 2 pp 216ndash228 2006

[168] C Joseph A M Buga R Vintilescu et al ldquoProlonged gaseoushypothermia prevents the upregulation of phagocytosis-specificprotein annexin 1 and causes low-amplitude EEG activity in theaged rat brain after cerebral ischemiardquo Journal of Cerebral BloodFlow amp Metabolism vol 32 no 8 pp 1632ndash1642 2012

[169] Q Ji K Hui L Zhang X Sun W Li and M Duan ldquoTheeffect of hydrogen-rich saline on the brain of rats with transientischemiardquo Journal of Surgical Research vol 168 no 1 pp e95ndashe101 2011

[170] J Li YDongHChen et al ldquoProtective effects of hydrogen-richsaline in a rat model of permanent focal cerebral ischemia viareducing oxidative stress and inflammatory cytokinesrdquo BrainResearch vol 1486 no 1 pp 103ndash111 2012

[171] R Khairova R Pawar G Salvadore et al ldquoEffects of lithiumon oxidative stress parameters in healthy subjectsrdquo MolecularMedicine Reports vol 5 no 3 pp 680ndash682 2012

[172] D M Chuang Z Wang and C T Chiu ldquoGSK-3 as a targetfor lithium-induced neuroprotection against excitotoxicity inneuronal cultures and animal models of ischemic strokerdquoFrontiers in Molecular Neuroscience vol 4 article 15 2011

[173] M Pignitter A C F Gorren S Nedeianu K Schmidt and BMayer ldquoInefficient spin trapping of superoxide in the presenceof nitric-oxide implications for studies on nitric-oxide synthaseuncouplingrdquo Free Radical Biology amp Medicine vol 41 no 3 pp455ndash463 2006

[174] M Talarowska P Gałecki M Maes et al ldquoNitric oxide plasmaconcentration associated with cognitive impairment in patientswith recurrent depressive disorderrdquo Neuroscience Letters vol510 no 2 pp 127ndash131 2012

[175] T Yoshitomi A Hirayama and Y Nagasaki ldquoThe ROS scav-enging and renal protective effects of pH-responsive nitroxideradical-containing nanoparticlesrdquo Biomaterials vol 32 no 31pp 8021ndash8028 2011

[176] T M Michel A J Sheldrick S Camara E Grnblatt F Schnei-der and P Riederer ldquoAlteration of the pro-oxidant xanthineoxidase (XO) in the thalamus and occipital cortex of patientswith schizophreniardquoWorld Journal of Biological Psychiatry vol12 no 8 pp 588ndash597 2011

[177] XHuH ZhouD Zhang et al ldquoClozapine protects dopaminer-gic neurons from inflammation-induced damage by inhibitingmicroglial overactivationrdquo Journal of NeuroImmune Pharmacol-ogy vol 7 no 1 pp 187ndash201 2012

[178] C D Pandya K R Howell and A Pillai ldquoAntioxidants aspotential therapeutics for neuropsychiatric disordersrdquo Progressin Neuropsychopharmacology amp Biological Psychiatry vol 46pp 214ndash223 2013

[179] S Dodd M Maes G Anderson O M Dean S Moylan andM Berk ldquoPutative neuroprotective agents in neuropsychiatricdisordersrdquo Progress in Neuro-Psychopharmacology amp BiologicalPsychiatry vol 42 pp 135ndash145 2013

[180] R W Grillo G L Ottoni R Leke D O Souza L V Portelaand D R Lara ldquoReduced serum BDNF levels in schizophrenicpatients on clozapine or typical antipsychoticsrdquo Journal ofPsychiatric Research vol 41 no 1-2 pp 31ndash35 2007

[181] M Pedrini I Chendo I Grande et al ldquoSerum brain-derivedneurotrophic factor and clozapine daily dose in patients withschizophrenia a positive correlationrdquo Neuroscience Letters vol491 no 3 pp 207ndash210 2011

[182] C-M Lim S-W Kim J-Y Park C Kim S H Yoon andJ-K Lee ldquoFluoxetine affords robust neuroprotection in thepostischemic brain via its anti-inflammatory effectrdquo Journal ofNeuroscience Research vol 87 no 4 pp 1037ndash1045 2009

[183] N G Wehner M Skov G Shopp M S Rocca and J ClarkeldquoEffects of natalizumab an 1205724 integrin inhibitor on fertility inmale and female guinea pigsrdquo Birth Defects Research B vol 86no 2 pp 108ndash116 2009

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


Free radicalsOxidized proteinsGlycated productsLipid peroxidation

Altered neuronal signaling

NeuroinflammationActivation of cell death mechanisms

Exposure toproinflammatory

agentsOxidative stress

Parkinson ADHD Schizophrenia

Proinflammatory status

Oxidative stress

Stroke

Oxidative stress Mitochondrial

ROS

Alpha-synucleinaggregation

Lewis bodies

Alzheimer Depression

Abeta aggregationNeurofibrillary

tangles

Oxidative andnitrooxidative

BradykinesiaRigidity Tremor

NeurodegenerationMemory loss

Major depressionPsychosis

HyperactivityImpulsivityInattention

stress

Figure 1 Schematic representation of oxidative stress-related mechanisms underlying disease development in Alzheimerrsquos disease (AD)Parkinson disease (PD) stroke attention deficit and hyperactivity disorders (ADHD) schizophrenia and depression

of turnover in the mitochondrial respiratory chain Thehighly reactive nature of singlet oxygen can even be exploitedto make reactive peroxides that can serve as antimicrobialagents [8] Most of the physiological effects are in factmediated by reactive oxygen species (ROS) derivatives ofsuperoxide Similarly the superoxide anion (O

2

minus∙) throughits derivative the hydroxyl radical (∙OH) plays an essentialrole in cell physiology by stimulating the activation of guany-late cyclase and formation of the ldquosecond messengerrdquo cGMPin cells and activation of the transcription factor nuclearfactor kB (NF-kB) by hydrogen peroxide in mammaliancells [9] Under normal physiological conditions the NOradical (NO∙) regulates the vascular tone by smooth musclerelaxation

In the inflammatory response macrophages and neu-trophils are attracted by activated T lymphocytes and IL-2and produce high levels of O

2

minus which along with other ROSdestroy the engulfed bacteria (oxidative burst) [10] In braintissue ROS are generated by microglia and astrocytes andmodulate synaptic and nonsynaptic communication betweenneurons and glia ROS also interfere with increased neuronalactivity [11] by modifying the myelin basic protein and caninduce synaptic long-term potentiation a form of activity-dependent synaptic plasticity and memory consolidationFurthermore results from animal models suggest that therole of O

2

minus inmodulating synaptic plasticity memory forma-tion and learning is altered by age [12]

3 Deleterious Effects Associated with ROS

Activated oxygen species especially those that share elec-tronic orbital features with singlet oxygen are highly reactiveand therefore the evolutionary adaptation by organisms tomake oxygen wholly beneficial has never been completeConsequently there are many deleterious effects associatedwith excessive activated ROS ROS are thereby capable ofproducing membrane damage changes in the inner proteinsaffecting their structure and function lipids denaturationand structural damage to DNA In the brain those effectsappear when ROS are in excessive concentrations and thusthe ability of antioxidant mechanisms of neurons to counter-balance the damaging reactions is diminished [13]

The brain is especially susceptible to the assaults per-petrated by ROS This is because the brain as an organis a major metabolizer of oxygen (20 of the body con-sumption) and yet has relatively feeble protective antioxidantmechanisms Thus it is especially vulnerable to oxidativestress The brain contains a large amount of polyunsaturatedperoxidizable fatty acids along with high levels of iron thatact as a prooxidant and sometimes induce autophagic celldeath in hemorrhagic stroke Synaptic transmission involvingdopamine and glutamate oxidation may also occur in thebrain [13ndash15] In addition lipid peroxidation leads to theproduction of toxic compounds such aldehydes or dienals(eg 4-hydroxynonenal) which may cause in turn neuronalapoptosis [16]














2


2







































































9 Conclusions






Acknowledgments


References





































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























2


2







































































9 Conclusions






Acknowledgments


References





































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















































































9 Conclusions






Acknowledgments


References





































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































































9 Conclusions






Acknowledgments


References





































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































9 Conclusions






Acknowledgments


References





































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of











































9 Conclusions






Acknowledgments


References





































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























9 Conclusions






Acknowledgments


References





































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article ROS and Brain Diseases: The Good, the Bad ...downloads.hindawi.com/journals/omcl/2013/963520.pdf · Janus-faced properties of reactive oxygen species. It will describe