review article perspectives on molecular biomarkers of...

Review ArticlePerspectives on Molecular Biomarkers of Oxidative Stress andAntioxidant Strategies in Traumatic Brain Injury

Andreacute Mendes Arent123 Luiz Felipe de Souza1 Roger Walz4 and Alcir Luiz Dafre1

1 Department of Biochemistry Federal University of Santa Catarina Biological Sciences Centre 88040-900 Florianopolis SC Brazil2 Faculty of Medicine University of South Santa Catarina (Unisul) 88137-270 Palhoca SC Brazil3 Neurosurgery Service Sao Jose Regional Hospital (HRSJ-HMG) 88103-901 Sao Jose SC Brazil4 Applied Neurosciences Centre (CeNAp) and Department of Medical Clinics University HospitalFederal University of Santa Catarina 88040-900 Florianopolis SC Brazil

Correspondence should be addressed to Alcir Luiz Dafre alcirdafreufscbr

Received 20 August 2013 Revised 4 December 2013 Accepted 9 December 2013 Published 13 February 2014

Academic Editor Fausto Catena

Copyright copy 2014 Andre Mendes Arent 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

Traumatic brain injury (TBI) is frequently associated with abnormal blood-brain barrier function resulting in the release of factorsthat can be used as molecular biomarkers of TBI among them GFAP UCH-L1 S100B and NSE Although many experimentalstudies have been conducted clinical consolidation of these biomarkers is still needed to increase the predictive power and reducethe poor outcome of TBI Interestingly several of these TBI biomarkers are oxidatively modified to carbonyl groups indicating thatmarkers of oxidative stress could be of predictive value for the selection of therapeutic strategies Some drugs such as corticosteroidsand progesterone have already been investigated in TBI neuroprotection but failed to demonstrate clinical applicability in advancedphases of the studies Dietary antioxidants such as curcumin resveratrol and sulforaphane have been shown to attenuate TBI-induced damage in preclinical studiesThese dietary antioxidants can increase antioxidant defenses via transcriptional activation ofNRF2 and are also known as carbonyl scavengers two potential mechanisms for neuroprotectionThis paper reviews the relevanceof redox biology in TBI highlighting perspectives for future studies

1 Introduction

According to theWorldHealthOrganization traumatic braininjury (TBI) is the leading cause of death in young adultsTBI will surpass many diseases and will become the thirdcause of death and disability in the general population by theyear 2020 [1 2] The high medical costs of these patients cancompromise the entire health care system [3]

The International Mission for Prognosis and Analysisof Critical Trials in TBI (IMPACT study) has developed aprognosis calculator based on admission data of more than8500 patients [4] validation studies has shown it to performwith reasonable accuracy [5] However the predictive powerof this outcome calculator can be improved by the use of braininjury biomarkers [6] while post-TBI prognosis itself can beimproved through the development of new neuroprotectivestrategies To determine a good biomarker it seems essential

that pathophysiologic mechanisms involved in the initialphase of TBI should be known in detail while a moreextended understanding of regulatory mechanisms is alsorequired for effectively promoting neuroprotection

2 Pathophysiology

21 Clinical Parameters The clinical outcomes of TBI aredirectly related to the severity of the primary and secondarylesions sustained by the patient Primary lesions are thoserelated to the initial impact (lacerations contusion fracturesand diffuse axonal injury) Secondary lesions are those whichdeveloped after the initial trauma including hematomasedema and pathological processes cascades that causeischemia resulting in aworsening of the clinical condition [7]The development of the secondary injury in TBI is a complexprocess involving oxidative stress glutamate excitotoxicity

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 723060 18 pageshttpdxdoiorg1011552014723060

2 BioMed Research International

inflammatory damage and the toxicity of metabolites thatcan be disseminated by the circulatory system [8 9]

The therapeutic management of intracranial trauma aimsto avoid the development of secondary lesions and to thisend the control of physiological parameters such as cerebralperfusion pressure (CPP) intracranial pressure (ICP) andcerebral blood flow (CBF) is crucial to minimize ischemiaand tissue damage [10] The clinical use of CPP as a clinicalparameter is based on theoretical suggestions indicatingthat optimal cerebral blood flow is necessary to meet themetabolic needs of the injured brain [11] The therapeuticmanagement goal is to keep the CBF stable and maintain abalance between CPP and ICP in order to rescue the ischemicpenumbra area Cells in this area are potentially salvabletherefore they comprise the most essential area for medicalintervention making the prevention of secondary insults inthis region crucial for a better outcome [12]

22 Brain Swelling Among secondary injuries cerebraledema is of special significance as it can greatly aggravatebrain damage and is the main condition related to increasedICP excluding conditions potentially leading to surgicalinterventions such as hematoma and contusion IncreasedICP leads to a decrease in CPP and CBF worsening tissuedamage as a consequence of brain ischemia Edema occursby two basic mechanisms cytotoxic edema related to thedepletion of cell energy and vasogenic edema related todisruption of the brain-blood barrier (BBB) [13 14]

In vasogenic brain edema BBB integrity is compromisedby mechanical or autodigestive disruption or functionalbreakdown of the endothelial cell layer of brain vesselswhich is critical for maintenance of the BBB Disintegrationof the cerebral vascular endothelial wall allows for uncon-trolled ion and protein transfer from the intravascular to theextracellular (interstitial) brain compartment leading to fluidaccumulation which increases the volumeof the extracellularspace [15 16] The intact BBB prevents diffusion of mostwater-soluble molecules above 500Da [17] However whenthe BBB is disrupted brain-related proteins can be measuredin the peripheral circulation [18 19] The BBB leakageassociated with TBI not only allows brain-related moleculesto reach the bloodstream but also permitsmolecules from theperiphery to enter cerebrospinal fluid (CSF) Both situationseither peripheral proteins entering the CSF or CSF leakage ofproteins can be used as biomarkers of TBI [20 21]

Cytotoxic brain edema is characterized by intracel-lular water accumulation inside neurons astrocytes andmicroglia This pathology is caused by an increased cellmembrane permeability ionic pump failure due to energydepletion and intracellular accumulation of osmoticallyactive solutes [16 22]This edema-driven energy impairmentgenerates an ldquoischemia-likerdquo pattern which increases glycol-ysis flux leading to lactic acid accumulation associated withincreased membrane permeability intensifying edema andthe establishment of a destructive positive feed-back loop

Thenext step of this pathophysiological cascade is charac-terized by excitoxicity TBI is associatedwith amassive release

of excitatory amino acid neurotransmitters particularly glu-tamate [23 24]The extracellular glutamate availability affectsneurons and astrocytes and results in overstimulation ofionotropic and metabotropic glutamate receptors increasingCa2+ Na+ and K+ influxes [25 26] Although these eventstrigger catabolic processes the cellular attempt to compensatefor ionic gradients increases Na+K+-ATPase activity andtherefore metabolic demand creating a vicious circle of flow-metabolism uncoupling This condition can destroy vascularand cellular structures and ultimately induces necrotic orprogrammed cell death [27]

3 Reactive Oxygen Species andTraumatic Brain Injury

Reactive oxygen species (ROS) and reactive nitrogen species(RNS) are generated during normal physiological processesThey are highly reactive molecules which can cause damageto key cellular components such as DNA lipids and proteinsUnder physiological conditions the endogenous defensesystem is able to prevent the formation of or scavenge theseharmfulmolecules protecting tissues fromoxidative damageIn TBI there is a considerable increase in the production offree radicals supporting the idea that oxidative stress plays adecisive role in the pathology [28 29]

It is generally believed that 1-2 of the oxygen reducedby mitochondria is converted to superoxide anion (O

2

∙minus) atthe level of complex I or at the level of ubiquinone [30ndash32] However certain enzymatic components are looselyassociated with the inner mitochondrial membrane andunder conditions of cellular stress can be released or inac-tivated greatly diminishing the reducing capacity of theelectron transport chain (ETC) The electrons will sub-sequently be monoelectronically donated to oxygen (O

2)

yielding increased production of O2

∙minus Another importantsource of mitochondrial O

2

∙minusdepends on Ca2+ influx oftensecondary to glutamatergic excitotoxicity which leads tostructural alterations of the inner mitochondrial membraneThese alterationsmay increase ROS formation due to disorga-nization of the ETC [33] Under severe Ca2+ loads howeveropening of the mitochondrial permeability transition pore(mPTP) results in the extrusion of mitochondrial Ca2+and other high- and low-molecular weight componentsThis catastrophic event discharges and uncouples the ETCpreventing ATP production which can lead to necrotic orapoptotic cell death [34]

Other sources of free radicals in TBI in addition tomitochondrial dysfunction and excitotoxicity mediated byglutamate include the formation of bradykininThis cytokinecan activate phospholipase A2 releasing arachidonic acidthat can serve as a source of free radicals [35 36] Arachidonicacid may also facilitate NADPH oxidase activity thus furtherincreasing ROS production [37] Apart from increasingarachidonic acid production frommembrane phospholipidsbradykinin can induce free radical production by causing aCa2+ overload [38] Another source of ROS in TBI may bemacrophagesmicroglia and neutrophils activated as part ofan inflammatory process triggered by the initial injury [28]

BioMed Research International 3

The extremely short half-life of ROS in biological systemsmakes direct measurement virtually impossible in a clinicalsetup Therefore several indirect approaches have been usedfor the estimation of ROS These include measurement of (1)products of enzymes known to coproduce ROS (2) stableadducts formed by the reaction between ROS and endoge-nous or exogenous trapping agents and (3) endogenous scav-engers [39] The brain is highly sensitive to oxidative stressbecause this 1300 g organ consumes about 20ndash30of inspiredoxygen and contains high levels of both polyunsaturated fattyacids and redox transitionmetalsmaking it an ideal target fora free radical attack [40]

Free radical acting on polyunsaturated fatty acids leadsto the formation of highly reactive electrophilic aldehydesincluding malondialdehyde (MDA) 4-hydroxy-2-nonenal(4-HNE) which are the most abundant products andacrolein the most reactive product [41ndash43] Lipid peroxi-dation products such as 4-HNE and thiobarbituric acid-reactive substances are studied in order to identify anoxidative stress condition in experimental models of TBI[44ndash46] Reactive aldehydes are a noxious byproduct of lipidperoxidation which among other things increase BBB per-meability [47] contribute to cytoskeletal changes in neurons[48] and affect glucose transport across membranes [49 50]

Oxidative stress also damages nucleic acids both byinducing DNA fragmentation which consists of single- anddouble-stranded DNA breaks the latter being irreversibleand occurring a few hours after brain injury [51 52] and viaoxidative damage leading to modification and loss of DNAbases The predominant base modification used as an indexof DNA-oxidative damage is 8-hydroxy-21015840-deoxyguanosine(8-OHdG) Single-strand breaks and base oxidation canbe repaired [53] but an inefficient DNA repair may delayneurobehavioral recovery after TBI [54] Some experimentalwork has demonstrated that oxidative damage toDNAoccursearly in TBI and can be targeted by therapeutic strategies [5556] However intriguingly in a study using administrationof the ROS scavenger alpha-phenyl-N-tert-butyl-nitrone theauthors found an improvement inmemory (water maze task)accompanied by a paradoxical increase in neuronal DNAfragmentation These data suggest that DNA fragmentationwould not be a good marker for TBI [57] On the other handimmunohistochemical analysis of DNA damage markers inautopsy samples has suggested the validity of single-strandbreaks as markers of TBI Given these findings DNA single-stranded breaks may be more helpful when used in con-junction with other biomarkers such as glial fibrillary acidicprotein (GFAP) and basic fibroblast growth factor (bFGF)in providing clues on different cell death mechanisms ofsucceeding TBI [58] However there is a need for guidelinesto support the use of DNA modifications as a marker of TBI

4 Antioxidant Defenses

Antioxidants act in a concerted fashion in the normal brainand can be classified into two major groups enzymes andlow-molecular-weight antioxidants The enzymes include a

number of proteins including SOD catalase and peroxi-dases as well as some supporting enzymes The expressionof these enzymes and their activity diverge in different brainregions [59] The protective role of endogenous antioxidantenzymes in ischemic brain injury has been well establishedin the literature [60] Trauma not only interferes with theregulation of antioxidant mechanisms but may also convertthese mechanisms into prooxidative ones through its abilityto disrupt cell compartmentalization [61]

The low-molecular-weight antioxidants comprise a con-certed system of water- and lipid-soluble molecules like glu-tathione (GSH) ascorbic acid histidine-related compounds(carnosine homocarnosine and anserine) melatonin uricacid lipoic acid and tocopherols [59] These are extremelyimportant in minimizing oxidative stress However cells cansynthesize only a limited number of these molecules (egGSH and carnosine) The majority of low-molecular-weightantioxidants are derived from dietary sources The concen-tration of ascorbate which has a relatively high antioxidantpotential is unusually high in the brain [62] However thereis a very limited literature about the importance of thisantioxidant in TBI Brain ascorbic acid was shown to bedecreased in experimental blast-induced TBI and has beenassociated with decreases in GSH and protein thiols and anincrease in oxidative markers [63ndash65]

Cells are equipped with enzymes that can eliminateperoxidation end products such as the aldehyde 4-HNEThese enzymes include aldehyde dehydrogenases aldo-keto reductases carbonyl reductase and glutathione S-transferases (GST) [66] GST is an enzyme that displaysglutathione peroxidase activity and has by far the highestdetoxifying capability of highly toxic aldehydes such as 4-HNE Naturally occurring variation in the GST expressionaffects neurodegeneration after experimental TBI confirm-ing the importance of lipid peroxidation as an importantpathophysiological mechanism in TBI [67]

5 Biomarkers of TBI

Biochemical biomarkers can be analyzed from serum orwhole blood Disadvantages of this approach include lack ofspecificity to brain tissue high variability in the extent of BBBdisruption and low sensitivity to early injury Alternativelywe can assess CSF markers that may be more specific tocentral nervous system (CNS) tissue and sensitive to earlyinjury although CSF collection is more invasive and notroutinely available inmedical practice Another optionwouldbe the measurement of parenchymal interstitial fluid viamicrodialysis High lactate to pyruvate ratio increased levelsof glycerol and low levels of glucose have been correlatedwith poor clinical outcomeHowever cutoff points for certainparameters are broad and poorly validated One rationalapproach that may lead to identification of blood or CSFmarkers would be to evaluate biochemical processes knownto play a central role in CNS injury including markers ofinflammation glial activation neuronal dysfunction andoxidative stress [68]


TBI biomarkers can reveal structural brain damage butare also markers of secondary injury cascades TBI promotesgenomic proteomic and lipidomic changes as well as oxida-tive stress neurotransmitter dysfunction mitochondrial fail-ure and other processes [69] Therefore TBI biomarkerscan also indicate appropriate therapeutic strategies to mini-mize secondary brain injury and long-term sequelae UsingTBI biomarkers increases the predictive value of outcomecalculators and improves the development of individualizedtreatment courses thereby reducing outcome severity [70]The detection of oxidatively modified biomolecules could beused as biomarkers to demonstrate the extension of cellulardamage or changes in the cascade of secondary brain damageand repair [39 65]

Severalmolecules have been investigated as biomarkers ofTBI CNS-specific molecules include creatine kinase [71 72]lactate dehydrogenase [71 72] glial fibrillary acid protein(GFAP) [72ndash75] myelin basic protein [72 76] neuron-specific enolase [77ndash79] S-100120573protein [72 75 80] brain andheart type fatty acid-binding proteins [81] tau proteins [8283] brain-derived neurotrophic factor (BDNF) [84 85] andubiquitin carboxy-terminal hydrolase-L1 [86 87] The mostcommonly used inflammatory serum biochemical markersinclude heat shock protein 70 kDa (Hsp70) [88] regulated onactivation normal T cell expressed and secreted (RANTES)[89] tumor necrosis factor alpha (TNF-120572) and interleukins[90]

N-acetylaspartate (NAA) a nervous system-specificmetabolite is synthesized from aspartate and acetyl-coenzyme A in neurons NAA has been shown to be amarker with diagnostic relevance in monitoring metabolicstate after TBI [65] NAA is the second most concentratedmetabolite in the brain after the amino acid glutamate Itis only detected in adult brain neurons and is synthesizedin the mitochondria NAA and ATP metabolism appear tobe linked indirectly whereby acetylation of aspartate mayfacilitate its removal from neuronal mitochondria thusfavoring conversion of glutamate to 120572-ketoglutarate whichcan enter the tricarboxylic acid cycle for energy production[91] Accumulating evidence in the last decade suggests thatNAA is a marker of mitochondrial dysfunction in the brainA close relationship has been demonstrated between traumaseverity depression of energy metabolism and NAA [92 93]Alterations in NAA levels have also been demonstrated inmany cerebral pathologies and their noninvasive in vivoquantification by 1H-NMR spectroscopy makes them aparticularly attractive biomarker [94ndash96]

The activity of the most studied antioxidant enzymesin TBI CAT SOD and GPx presents random changes inanimal models of TBI In some cases an increase [97 98]and in others a decrease [99 100] or no change [101 102]Theheterogeneity in sampling time points and animalmodelsmay be related to this lack of consistency across studiesWhatever the reason to date there is little consistency in dataregarding antioxidant enzymes to justify their use as markersof TBI and as a predictive tool of outcome

Glutathione the major nonprotein thiol of cells usuallydecreases after TBI in rats [64 99] but not in mice [64

99 103ndash105] demonstrating species-specific characteristicsthat should be taken into account when using informationobtained from animal studies

The peroxidation of membrane lipids can change themembrane function by modifying its fluidity permeabilitymetabolic processes and ionic equilibrium [106] Damage tomitochondrial membranes can also increase the productionof ROS besides generating mitochondrial dysfunction Thedamage to brain membrane lipids is an early event In thirtyminutes after trauma higher levels of MDA and 4-HNEcan be detected whose levels are maintained elevated 72 hafter the injury onset [107ndash109] Most studies analyzing theoxidative damage to lipids in animalmodels find a correlationbetween this parameter in conjunction with cognitive dam-age installation of edema and volume of injury These datasuggest that the damage to lipids of biologicalmembranes canbe an important event in this pathology [110 111]

Oxidative damage to DNA is also an early event in TBIIn animal models the appearance of 8-OHdG oxidativemarker of DNA damage is increased within the first 15minutes after trauma demonstrating that the TBI-inducedROS production can interfere with the integrity of DNA[55] On the other hand the administration of edaravonean antioxidant proved to be capable of blocking the DNAdamage resulting in improvement in behavioral tests in mice[112ndash114]

It has been shown that after a mild TBI rats showedincreased protein carbonylation another marker of oxida-tive stress This event correlated with poor performancein behavioral tests (Morris water maze test) accompaniedby decrease in the levels of the neurotrophic factor BDNFThese alterations were neutralized by the administration ofantioxidant vitamin E showing that oxidative damage toproteins may have a key role in neuronal death in TBI [115]Evidence also points to the involvement of peroxynitrite onthe pathophysiology of TBI A number of studies showedprecocious (1 h) increase in protein nitration markers suchas 3-nitrotyrosine [116 117] By contrast protein carbonyland lipid peroxidation levels were increased in mild TBI indifferent parts of the brain However these oxidative changeswere not observed or even decreased in severe TBI [46]These results were somewhat corroborated by Schwarzboldand collaborators showing that the oxidative damage doesnot completely correlate with the degree of trauma severity[98]

Several lines of evidence point to the occurrence of oxida-tive stress in brain trauma Bayir and collaborators showedthat children who have suffered severe TBI presented aclinical evolution that is marked by progressive impairmentin antioxidant defenses and increase in lipid peroxidationThese findings correlate with the clinical evolution of thesepatients Among the endpoints analyzed authors relate ascor-bate depletion in the cerebrospinal fluid followed by theascorbyl radical formation in addition to a decrease in thelevels of GSH and antioxidant capacity [118] Arachidonicacid derivatives used as markers of lipid peroxidation suchas F2-isoprostanes are found at high levels in cerebrospinalfluid after TBI In fact they are positively correlated withneuron-specific enolase a marker of neuronal damage [119


120] However the clinical applicability of this technique islimited and not all patients can be analyzed due to the needof sampling of CSF

The 8-iso-prostaglandin F2120572 (8-iso-PGF2120572) is derivedfrom either enzymatic by cyclooxygenase or nonenzymaticoxidation of arachidonic acid [121] This isoprostane is con-sidered an excellent marker of oxidative stress in vivo Recentdata correlate plasma levels of this marker with the Glasgowcoma scale (GCS) This finding is very important because itwould be a predictive factor of mortality and outcome withsensitivity similar to GCS [122 123]Thus this marker can bea tool in predicting the prognosis of patients with TBI andused as a marker of lipid peroxidation which can be dosed inperipheral blood sample

Nitrosative stress mainly detected by the presence of 3-NT has been demonstrated in TBI [124 125] Darwish andcollaborators [126] detected 3-NT in theCSF of 7 out of 10 TBIpatients but it was not found in control samples High levelsof 3-NT were also associated with a negative neurologicaloutcome measured by the Glasgow outcome scale but againa marker obtained from the cerebrospinal fluid has limitedapplicability

In spite of solid evidence of increased oxidative stressmarkers in TBI the correlation of these changes with theseverity of TBI as measured by the GCS is still controversialFor example higher levels of lipid peroxidation decreasein the levels of GSH and increased activity of SOD wereobserved in erythrocyte of patients with severe TBI com-pared to patients who are victims of mild TBI [127ndash129]Another work of the same group however showed increasedlipid peroxidation in erythrocytes of patients with TBI butthis was not correlated with GCS [130] Plasma levels oflipid peroxidation and protein carbonylation were also notpredictive factors associated with hospital mortality or ascognitive impairment in TBI patients [131 132]

Although the literature demonstrates the unequivocalcorrelation of markers of oxidative stress with trauma thecorrelation of levels of 4-HNE andMDAwith the outcome ofthe TBI presents divergent data necessitating further studiesto determine if there is in fact some association with theprognosis and outcome This divergence may be related to ahigher incidence of ischemia reperfusion in the mild traumacompared to severe trauma [46] One of the main sources ofROS in TBI occurs during tissue reperfusion after ischemiawhich is an event secondary to trauma In severe traumahowever there is a large area of primary tissue injury causingextensive cell death However in mild trauma more viablecells that can benefit from reperfusion present higher ROSproduction which may favor the use of markers of lipidperoxidation as predictive biomarkers of outcome

Overall it seems that the oxidative stress occurs simul-taneously in various conditions during and after the braintrauma but its correlation with the severity and outcomeis still not very well understood Despite all the lines ofevidence that indicate a central role of ROS in the cascadesof secondary damage the actual implication of them forneuronal death is not yet clear As a general picture fromthe literature data oxidative damage is not directly correlatedwith the severity of TBI An area of study that may shed

light on the use of oxidative stress biomarkers needs to takeinto account changes in redox signaling pathways besidesassessing direct oxidative damage to macromolecules whichmay regulate determining factors that contribute to the finaloutcome

6 Oxidative Stress-Mediated Factors in TBI

Age is another important factor in TBI Elderly patientswith TBI have a worse clinical outcome when compared toyounger patients [133] The influence of oxidative stress onthe development of aging has also been demonstrated Forinstance older rats showed higher levels of lipid peroxidationend product (4-HNE) along with lower antioxidant defenses[134] A worse cognitive outcome also demonstrated in olderrats was correlated with lower mitochondrial antioxidantenzymes and high levels of 8-OHdG 4-HNE single-strandDNA breaks and malondialdehyde suggesting the involve-ment of ROS [135]

Post-TBI complications such as seizures and cognitivedeficits also appear to be mediated by ROS in experimentalmodels [136ndash138]There is evidence that suggests that antiox-idant therapy may reduce lesions induced by oxidative freeradicals in some animal seizure models [139]

Interestingly physical conditioning seems to decreaseoxidative damage to lipids formed after TBI in rats [140]Both the use of amphetamines as well as physical exercisecan reduce oxidative damage after TBI [141]There is preclin-ical evidence suggesting that exercise can improve cognitiveoutcomes in experimental TBI [142]

7 Antioxidant Strategies for Neuroprotection

The relationship between oxidative stress and TBI has gener-ated considerable interest in the development of antioxidanttherapies for neuroprotection Despite the promising resultsin the treatment of TBI in animal models evidence of suc-cessful antioxidant therapy in clinical practice is limited [143]There are a number of drawbacks to the use of exogenousantioxidants for example the limited penetrability throughthe BBB the rapid metabolism and instability of thesecompounds short therapeutic windows and a very narrowtherapeutic dosage range resulting in toxicity at higher doses[143 144] Despite these limitations natural antioxidants andmodified antioxidants are promising candidates for futuredrugs to treat TBI

71 Free Radicals Scavengers Modified SOD has been usedin different models as a scavenger of O

2

∙minus as this radical hasincreased production after TBI Lecithinized SOD displayshigh affinity to cell membranes and was able to increaseneuronal counts in an animal model of TBI [145 146]Another superoxide scavenger OPC-14117 reduced edemaformation neurological deficit and infarct area caused byTBI [147ndash149]

Polyethylene glycol-conjugated superoxide dismutase(PEG-SOD) has been tested in clinical trials Initially somebenefits in a phase II study of PEG-SOD were demonstrated


including the reduction of persistent vegetative state anddeath outcomes when compared to placebo [150] but theseobservations were not confirmed in the phase III trialFailures such as these have been attributed to a narrowtherapeutic window [151] In this way strategies aimed atdirectly scavenging ROS are restricted due to the extremelyshort half-life of free radicals and the small therapeuticwindow in a TBI event

Nitrones and derivatives are used in neuroprotectionmodels Tempol (4-hydroxy-2266-tetramethylpiperidin-1-oxyl) is a long-known radical scavenger that displays neu-roprotective properties [152] including maintaining mito-chondrial function in brain cells affected by TBI [153] Otherradical scavengers such as 120572-phenyl-N-tert-butyl nitrone(PBN) or its sulfated form are able to improve cerebral bloodflow and glucose metabolism which are accompanied byimprovement in neurologic scores [154ndash157] However thetherapeutic window is relatively short due to initial burstof ROS in the first moments after the trauma Thereforestrategies to increase the therapeutic windows are necessaryto allow the efficient use of these radical scavengers [158]

The antioxidant 120572-tocopherol is hydrophobic and is ableto prevent membrane lipids from undergoing peroxidationTheuse of120572-tocopherol contributed to a lower lipid peroxida-tion [159] edema [160 161] and improvement in histologicalmarkers in experimental models of TBI [162]

Melatonin displays radical scavenger properties toward∙OH O

2

∙minus singlet oxygen and peroxynitrite [163] Admin-istration of melatonin shortly after TBI decreases brainedema neuronal death andmemory deficits [164 165]Thesechanges are correlated with improvements in markers ofoxidative damage (lipid peroxidation) and in the levels of lowmolecular weight antioxidants such as vitamin C [166ndash169]However improvement is not always observed with the useof melatonin [170]

72 Carbonyl Scavengers Besides the lipid peroxidation endproducts aldehydes likeMDA and 4-HNE cells also producecontinually a series of 120572-dicarbonyl species For instancemethylglyoxal is continuously produced during glycolysis butcan also be produced nonenzymatically from carbohydratesand glycation of proteins besides other endogenous sources[171] The production of methylglyoxal the main dicarbonylbyproduct of glycolysis is responsible for significant por-tion of protein glycation and consequently the inductionof cellular toxicity [66] Methylglyoxal modifies proteinsto form advanced glycation end product (AGE) residuesThese modified proteins can activate receptors of AGE(RAGE) leading to the upregulation and the expression ofproinflammatory mediators [172 173] This proinflammatorycascade involving RAGE has been recently shown to berelevant to TBI RAGE is upregulated in human brain asshort as 30min after TBI and maintained elevated up to6 days presenting maximal values at 24 h after TBI [174]Importantly the inflammatory cytokine high-mobility groupbox 1 (HMGB1) a RAGE ligand was increased in CSF andcould be associated with poor outcome after TBI in infantsand children [175] Since HMGB1 is released in the CSF an

anti-HMGB1 antibody strategy has proven to be effective ininhibiting fluid percussion-induced brain damage in mice[176]

This successful strategy brings attention to the potentialimportance of AGE on TBI To prevent AGE productionand consequent RAGEactivation120572-dicarbonyls likemethyl-glyoxal need to be eliminated or sequestered in order toavoid a negative impact in TBI outcome Carbonyl scavengershave been used with the aim of reducing the ldquoaldehydeloadrdquo [177] and have been investigated in vivo and in vitroregarding their effects on neuroprotection but there is lim-ited literature with regard to TBI [178 179] The carbonylscavenger D-penicillamine binds primarily to aldehydes inan irreversible manner which inhibits their damaging effectsand has also been shown to scavenge peroxynitrite as well[180] Acute penicillamine administration has previouslybeen shown to improve neurological recovery in the mouseconcussive head injury model [181] and to protect brainmitochondria [180] Carnosine is also a dicarbonyl scavengerwith neuroprotective properties in TBI [182] Hydralazinean acrolein scavenger decreased cell membrane leakage andpermeability in spinal cord injury [183] Aminoguanidineanother carbonyl scavenger and an inhibitor of induciblenitric oxide synthase (iNOS) was able to reduce carbonylstress in diabetes preserving neurological scores [184 185]preventing the decrease in cortical necrotic neuron counts[186] and reducing infarct volume [185] in animal models ofTBI Aminoguanidine treatment is also able to reduce infarctsize and preserve BBB in a middle cerebral artery occlusionmodel of ischemia [187] and reduce damage area in traumaticspinal cord injury [188] effects that are relevant to TBI

73 Glutathione-Promoting Drugs Strategies that aim atincreasing the GSH levels have also been tested in ani-mal models GSH-promoting agents like N-acetylcysteine(NAC) and 120574-glutamylcysteine ethyl ester are effective neu-roprotectants in preclinical studies Administration of 120574-glutamylcysteine ethyl ester after TBI in mice preservesGSH decreases autophagy and improves both behavioral andhistological outcomes [189] 120574-glutamylcysteine ethyl esterdecreased levels of protein carbonyls and 3-nitrotyrosineafter sever TBI [117] as well as preserved glutathione statusendotelial function and BBB [190]

Studies with NAC showed efficacy of this drug indecreasing the TBI-mediated oxidative stress and limiting thevolume of injury in rats [191] NAC also restored respiratoryfunction and calcium transport when administrated 1 h aftertrauma [192] In contrast this protective effect was notpresent when NAC was administrated 2 h after the lesionindicating that it must act in the early stages of the lesionNAC was able to restore brain GSH levels from 1 h to 14days after TBI suggesting that this protective effect may berelated to the maintenance of the GSH levels Other studiesalso showed anti-inflammatory properties of NAC NACadministration decreased several inflammatory cytokinesand the activation of NF-120581B which reduced brain edemaBBB permeability and apoptotic index in the injured brain[193]


NAC was also tested in a randomized double blindplacebo-controlled study with soldiers who were exposed toordnance blast and met the criteria for mild TBI Patientsreceived placebo or NAC for seven days and the treatmentshowed improvement in symptoms such as dizziness mem-ory loss and sleep disturbances [194]Given the fact thatNACis already approved by the FDA this is a good candidate forfuture clinical trials

74 Steroids Corticosteroids have been shown to inhibit thephospholipase A2 cyclooxygenase and lipoxygenase path-ways limiting the release of arachidonic acid and its metabo-lites downregulating proinflammatory cytokines and damp-ening the inflammatory response [195] Methylprednisoloneis able to attenuate cellular damage by a direct antioxidanteffect thereby inhibiting lipid peroxidation and protectingcellular membranes [195] Preclinical data showed that thissteroid affects the outcome Methylprednisolone was able toimprove brain edema in rats and this was dependent ondosing time of administration and method of treatment[196]

The indiscriminate use of corticosteroids was long per-formed without an evaluation of their devastating effectsas evidenced by clinical trials However The Brain TraumaFoundation guidelines published in 2000 state that ldquothe use ofcorticosteroids is not recommended for improving outcomeor reducing intracranial pressure in patients with severe braininjuryrdquo and ldquothe major of available evidence indicates thatsteroids do nor improve outcome or lower ICP in severelyhead injured patients and the routine use of steroids forthese purposes is not recommendedrdquo [197] In 2004 thecorticosteroid randomization after significant head injury(CRASH) study demonstrated greater mortality in patientsreceiving high doses of methylprednisolone compared toplacebo [198] ACochranemeta-analysis correlated the use ofcorticosteroids with increased risk of gastrointestinal bleed-ing hyperglycemia and also higher mortality rates [199]

Preclinical studies however suggested a possible antiox-idant and neuroprotective effect of physiological doses ofsex hormones following TBI [200 201] Progesterone hasbeen shown to decrease cerebral edema in a pluripotentmanner reducing lipid peroxidation aquaporin expressionproinflammatory cytokine release and complement activa-tion [202]Unfortunately studies in humans have not demon-strated a significant association between gender and progno-sis [203 204] Nevertheless clinical trials have demonstratedbetter outcomes in patients treated with progesterone [205206] In a phase II study progesterone showed significantreduction in mortality and improvement in the Glasgowoutcome scale at 3 and 6 months after TBI however resultsfrom a phase III multicentre randomized clinical trial arepending [207] A Cochrane systematic review concluded thatldquoProgesterone may improve neurologic outcome of patientssuffering TBIrdquo ldquo evidence is insufficient and there is a needfor further studies to support the use of progesterone in themanagement of TBI Further large and multicentre clinicaltrials on progesterone are required to assess the effect ofprogesterone in people with acute TBIrdquo [206]

Another strategy to prevent ROS-mediated damage is toblock the propagation of lipid peroxidation Lazaroids (21-aminosteroids) are a class of compoundswith themembrane-stabilizing properties similar to the effect of glucocorticoidsTirilazad inhibits lipid peroxidation through its membrane-stabilizing properties which prevent the propagation of thereaction between one oxidized fatty acid to the next andthrough free radical scavenging

In an animal model of TBI administration of the lazaroidtirilazad improved neurological score and survival rate whenadministrated shortly after the trauma (5ndash60min) [208] Ina weight drop TBI model in rats tirilazad also diminishedneuron loss at 24 h and increased neuronal survival 14days after the injury [209] Furthermore administration oftirilazad reduced extracellular O

2

∙minus after TBI which maycontribute to its neuroprotective effect [210] The protectiveeffect of tirilazad has also been demonstrated in animalmodels of ischemia and subarachnoid haemorrhage bothevents linkedwith the secondary injury pathways inTBI [211]

Tirilazad attenuated cerebral edema after TBI [212] andprotected against arachidonic acid-induced vasogenic brainedema in rats by inhibiting lipid peroxidation [213] Sincetirilazad does not penetrate the BBB effectively it is foundmainly in the membranes of endothelial cells where it couldexert its action However it is possible that tirilazad can reachneuronal cells during the phase of increased permeability ofthe BBB in TBI which can allow tirilazad to penetrate brainareas where it can act as a neuroprotectant [214]

In the 90s tirilazad entered a phase III multicentertrial The study comprised 1120 head-injured patients withmoderate or severe TBI Patients received tirilazad or placebowithin 4 h after injury at a dose of 25mgkg every 6 hfor 5 days The trial failed to show a beneficial effect ofthe treatment in either moderate or severe injured groupsHowever post hoc analysis showed that male patients thatalso had subarachnoid hemorrhage had significantly lessmortality [215] Meta-analysis studies questioned the efficacyof tirilazad in subarachnoid hemorrhage [216 217] In otherclinical studies tirilazad significantly contributed to recoveryafter spinal cord injury [218] but recent studies are notavailable The poor penetration through the BBB might beresponsible for the negative result as well as the nature of thehead injury

75 Calcium Blockers and Immunosuppressants Calciumblockers and immunosuppressants that could limit the pro-duction of ROSRNS by membrane stabilization or reduc-tion of inflammation have also been investigated Calcium-channel antagonists such as nimodipine would block theeffects of the influx of calcium into the cell after TBI Unfor-tunately in an extensive Cochranemeta-analysis nimodipineonly reduced the risk of death in a subgroup of patients withsubarachnoid hemorrhage [219] Cyclosporine A a knownimmunosuppressant is thought to mediate neuroprotectionby decreasing the mitochondrial permeability and thereforethe influx of Ca2+ organelle swelling and cell death [34]Cyclosporine A also showed promising results in a phase


II study however validation by a multicentre randomizedphase III clinical trial is pending [207]

76 Other Drugs Interference of other pathways which resultin the production of ROSRNS has thus far failed to producegood clinical outcomes Bradykinin antagonists such asDeltibant [220] modulators of excitotoxicity and glutamatesuch as dexanabinol [221 222] magnesium sulfate [223] andselfotel [224] have all been proven to be ineffective in clinicaltrials [207]

77 Nrf2ARE A Putative Therapeutic and Biomarker RouteActivation of the antioxidant response element (ARE) hasbeen implicated in neuroprotection as this induces expres-sion of genes involved in decreasing oxidative stress inflam-matory damage and accumulation of toxicmetabolites [225]Several transcriptional factors can bind to ARE includingthe nuclear factor-erythroid 2-related (Nrf2) protein thatactivates transcription in response to oxidative stress orelectrophilic attack [226] Nrf2 is a basic leucine zipper redox-sensitive transcription factor reported to be a pleiotropicregulator of cell survival mechanisms [227] Recent studieshave demonstrated that Nrf2 plays an indispensable role inthe upregulation ofNrf2-dependent antioxidant enzymes andthe reduction of oxidative damage after TBI [228] Underbasal conditions Nrf2 is sequestered in the cytoplasm by thecytosolic regulatory protein Keap1 In conditions of oxidativeor xenobiotic stress Nrf2 translocates to the nucleus whereit binds to ARE neutralizing the BACH1 competitive inhibi-tion activating this promoter and resulting in transcriptionof a number of antioxidant proteins [229 230]

Several antioxidants from the diet which have been stud-ied for their neuroprotective properties are proposed to func-tion via the activation of Nrf2ARE Caffeic acid phenethylester is an active component of bee propolis extracts whichdisplays anti-inflammatory immunomodulatory antiprolif-erative and antioxidant properties Caffeic acid phenethylester treatment decreasedMDA levels and increasedGPx andSOD activity in a rat experimental model of TBI [231] Greentea is rich in polyphenols that have important antioxidantactivity Epigallocatechin gallate treatment in rat models ofTBI decreased the free radical burden (eg O

2

∙minus and ∙OH)induced by brain injury This antioxidant effect decreasedtissue damage induced by free radicals including a decreaseof neuronal cell degeneration apoptotic cell death aroundthe damaged area and improved brain function (watermaze) [232ndash234] Ginseng from the root of Panax ginsengis a well-known traditional herbal medicine that has beenused widely for thousands of years The ginseng saponinsare generally considered as the principal bioactive ingredi-ents Preclinical studies suggested that the neuroprotectiveeffects of ginseng saponins are potentially associated withprotection against oxidative stress damage [235ndash238] Theflavonoid quercetin improved neuronal electrical activity anddecreased proinflammatory effects in a model of TBI [239]Resveratrol is a polyphenolic compound enriched in grapesand red wine Resveratrol has been shown to be a promisingneuroprotective agent in TBI models possibly inhibiting

lipid peroxidation [240ndash242] The use of resveratrol in anexperimental model of TBI was able to counteract oxidativedamage and prevent the depletion of the antioxidant glu-tathione and also resulted in a reduction of infarct area [110]Polyphenolic derivatives of curcumin have also been shownto protect the brain against the effects of experimental TBIby decreasing oxidative stress [44 45 243 244] howeverthe observed effects may be attributable not only to theantioxidant properties of flavonoids but also to a responseoccurring secondary to Nrf2ARE activation Sulforaphanesimilar to other flavonoids is anNrf2ARE signaling activatorand is present in cruciferous vegetables such as broccoliNrf2ARE activation by sulforaphane treatment after exper-imental TBI was confirmed by induction of target genessuch as glutathione S-transferase 1205723 and heme oxigenase-1and associated with an improvement in BBB integrity [245]The administration of sulforaphane is also neuroprotective invarious animal models of TBI specifically reducing cerebraledema and oxidative stress and thus decreasing cognitivedeficits [246 247] In the spinal cord model sulforaphanewas able to produce both rapid (30min) and long-lasting(3 days) responses also corroborated by the induction ofNrf2ARE target proteins including the rate-limiting enzymefor glutathione synthesis (GCL) heme oxygenase 1 andNADPH quinonereductase-1 which cooperate to decreaselevels of the proinflammatory markers TNF-120572 and IL-1120573[248]

There is some evidence to support the idea that Nrf2activation is able to protect against dicarbonyl stress byinduction of glyoxalase 1 [249] the enzyme catalyzing thereaction of methylglyoxal with glutathione It has been sug-gested that methylglyoxal and glyoxalase 1 can also modulateseizure intensity as metabolic sensors [250] which may haveimplications in TBI since hyperglycolysis (high flux throughanaerobic glycolysis) after TBI is associated with a negativeoutcome [251ndash253] Hyperglycolysis may lead to increasedproduction of methylglyoxal [254 255] Nrf2 activationwould alleviate dicarbonyl stress by inducing glyoxalase 1 andglutathione synthesis [249] In fact resveratrol was effectivein protecting hepatic (Hep G2) cells against methylglyoxaltoxicity due induction of Nrf2 which leads to increasedexpression of glyoxalase I and antioxidant defenses [256]Theflavones Fisetin was highly protective against carbonyl stressin the Akita mice a model of diabetes type 1 by inducingNrf2-dependent enzymes such as glyoxalase and glutamate-cysteine ligase the rate limiting enzyme in glutathione syn-thesis [257] Fisetin was also neuroprotective in an ischemiamodel [258] Quercetin displays a strong antiglycation actionwhen albumin was incubated withmethylglyoxal Curcumindespite being a potent Nrf2 inducer and effective as aneuroprotectant in TBI is a strong inhibitor (IC(50) sim10 120583M)of glyoxalase I [259] which would jeopardize its possibleantiglycation properties Nevertheless curcumin is as potentdicarbonyl scavenger [260] Caffeic acid was effective inprotecting proteins against AGE formation in vitro [261] andepigallocatechin-3-gallate has been proposed as a dicarbonylscavenger [262] as well as other phenolic antioxidants [263]In this regard flavonoids are added to the list of carbonylscavengers acting directly as scavenger or indirectly through


activation Nrf2-dependent antiglycation enzymes such asglyoxalase I

The use of antioxidants which sequester ROS and otherharmful molecules is a promising strategy to increase neuro-protection in TBI [211 240] however part of the antioxidanteffect of such exogenous substances like flavonoids maybe due to the induction of endogenous antioxidants Nrf2activators may be prime candidates for the attenuation ofoxidative stress and subsequent neurotoxicity induced byTBI

8 Concluding Remarks

Improving TBI outcomes will greatly reduce the heavysocietal and economic burden currently associated withthis condition Oxidative stress appears to be a primarydriver of TBI pathophysiology and while several stress-related markers and new therapeutic drugs with distinctantioxidative stress mechanisms have been proposed forthe diagnosis and treatment of TBI clinical consolidationbased on proven efficacy is still necessary Research prospectsfor new biomarkers of TBI should focus on demonstrationof functionality in converging pathways that can impactmultiple pathophysiological cascades

As part of a consistent and clinically applicable interven-tion we believe it would be crucial to not only limit thedevelopment of secondary damage following TBI but alsoto activate major neuroprotective pathways The identifica-tion of relevant biochemical markers along with successfultherapeutic targeting in experimental models of TBI hasdemonstrated the importance of several regulatory pathwaysin neuroprotection in particular Nrf2ARE This pathwayis activated by oxidative stress and nitric oxide productionwhich are also both points of convergence in TBI-relatedpathophysiological cascades

Regarding the inhibition of secondary damage the toxiceffect of aldehydes can be mitigated by aldehyde scavengersbut also by upregulation of endogenous detoxification andantioxidant defenses which can limit damage to DNA lipidsand proteins However other pathophysiological routes likeinflammation also need to be targeted to reduce damage

Our opinion is that the ideal clinically feasible TBItherapy would involve the targeting of a pathway whichconverges on multiple pathophysiologic processes in TBIsuch as Nrf2ARE and which can also be modulated byexternal factors like dietary substances Such a pleiotropicdrug would have the potential to usher in a new era ofeffective neuroprotection for traumatic brain injury

Conflict of Interests

The authors have no actual or potential conflict of interestsincluding any financial personal or other relationships withrelevant people or organizationsThe work described has notbeen published previously and it is not under considerationfor publication elsewhere The publication of this work isapproved by the authors and tacitly or explicitly by theresponsible authorities where the work was performed

Acknowledgments

This work was supported by National Council for ResearchDevelopment (CNPq) and Foundation for the Support ofScientific and Technological Research in the State of SantaCatarina (FAPESC) Alcir Luiz Dafre and Roger Walz areresearch fellows of CNPq The authors also wish to thankKaren Chiang who kindly revised the paper This work wassupported by Programa de Apoio a Nucleos de ExcelenciaPRONEX-FAPESCCNPq (NENASC Project) and Programade Pesquisa para o SUS PPSUS-FAPESCMS-CNPqSES-SC

References

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[2] C J L Murray and A D Lopez ldquoGlobal mortality disabilityand the contribution of risk factors global burden of diseasestudyrdquoThe Lancet vol 349 no 9063 pp 1436ndash1442 1997

[3] F Tagliaferri C Compagnone M Korsic F Servadei and JKraus ldquoA systematic review of brain injury epidemiology inEuroperdquoActaNeurochirurgica vol 148 no 3 pp 255ndash267 2006

[4] E W Steyerberg N Mushkudiani P Perel et al ldquoPredictingoutcome after traumatic brain injury development and inter-national validation of prognostic scores based on admissioncharacteristicsrdquo PLoSMedicine vol 5 no 8 pp 1251ndash1261 2008

[5] B Roozenbeek H F Lingsma F E Lecky et al ldquoPredictionof outcome after moderate and severe traumatic brain injuryexternal validation of the international mission on prognosisand analysis of clinical trials (IMPACT) and corticoid ran-domisation after significant head injury (CRASH) prognosticmodelsrdquo Critical Care Medicine vol 40 no 5 pp 1609ndash16172012

[6] E Czeiter S Mondello N Kovacs et al ldquoBrain injury biomark-ers may improve the predictive power of the IMPACT outcomecalculatorrdquo Journal of Neurotrauma vol 29 pp 1770ndash1778 2012

[7] J Sahuquillo M A Poca and S Amoros ldquoCurrent aspects ofpathophysiology and cell dysfunction after severe head injuryrdquoCurrent Pharmaceutical Design vol 7 no 15 pp 1475ndash15032001

[8] P Fernandez andDDiaz ldquoExperimental animalmodels of trau-matic brain injury medical and biomechanical mechanismrdquoCritical Reviews in Neurosurgery vol 9 pp 44ndash52 1999

[9] L Wang X S Ji X Y Hong Y M Chi and R Z Qing ldquoTheinfluence of subarachnoid hemorrhage on neurons an animalmodelrdquo Annals of Clinical and Laboratory Science vol 35 no 1pp 79ndash85 2005

[10] S H North L C Shriver-Lake C R Taitt and F S LiglerldquoRapid analytical methods for on-site triage for traumatic braininjuryrdquoAnnual Review of Analytical Chemistry vol 5 pp 35ndash562012

[11] G S F Ling and C J Neal ldquoMaintaining cerebral perfusionpressure is a worthy clinical goalrdquoNeurocritical Care vol 2 no1 pp 75ndash81 2005

[12] P-O Grande P Reinstrup and B Romner ldquoActive cooling intraumatic brain-injured patients a questionable therapyrdquo ActaAnaesthesiologica Scandinavica vol 53 no 10 pp 1233ndash12382009


[13] H Bayir P M Kochanek and R S B Clark ldquoTraumatic braininjury in infants and childrenmechanisms of secondary damageand treatment in the intensive care unitrdquo Critical Care Clinicsvol 19 no 3 pp 529ndash549 2003

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myelin basic protein assay in patients with acute head injuryrdquoSurgical Neurology vol 43 no 3 pp 267ndash271 1995

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[79] S Bandyopadhyay H Hennes M H Gorelick R G Wellsand C M Walsh-Kelly ldquoSerum neuron-specific enolase asa predictor of short-term outcome in children with closedtraumatic brain injuryrdquo Academic Emergency Medicine vol 12no 8 pp 732ndash738 2005

[80] M Olivecrona M Rodling-Wahlstrom S Naredi and L-OD Koskinen ldquoS-100B and neuron specific enolase are pooroutcome predictors in severe traumatic brain injury treated byan intracranial pressure targeted therapyrdquo Journal of NeurologyNeurosurgery and Psychiatry vol 80 no 11 pp 1241ndash1247 2009

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[85] S Giacoppo P Bramanti M Barresi et al ldquoPredictive biomark-ers of recovery in traumatic brain injuryrdquo Neurocritical Carevol 16 pp 470ndash477 2012

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[89] K Lumpkins G V Bochicchio B Zagol et al ldquoPlasma levelsof the beta chemokine regulated upon activation normal T cellexpressed and secreted (RANTES) correlate with severe braininjuryrdquo Journal of Trauma vol 64 no 2 pp 358ndash361 2008

[90] D M Stein A Lindell K R Murdock et al ldquoRelationshipof serum and cerebrospinal fluid biomarkers with intracranialhypertension and cerebral hypoperfusion after severe traumaticbrain injuryrdquo Journal of Trauma vol 70 no 5 pp 1096ndash11032011

[91] J R Moffett B Ross P Arun C N Madhavarao and A M ANamboodiri ldquoN-Acetylaspartate in the CNS from neurodiag-nostics to neurobiologyrdquo Progress in Neurobiology vol 81 no 2pp 89ndash131 2007

[92] P S Ariyannur C N Madhavarao and A M A NamboodirildquoN-acetylaspartate synthesis in the brain mitochondria vsmicrosomesrdquo Brain Research vol 1227 pp 34ndash41 2008

[93] R Vagnozzi B Tavazzi S Signoretti et al ldquoTemporal windowofmetabolic brain vulnerability to concussions mitochondrial-related impairmentmdashpart Irdquo Neurosurgery vol 61 no 2 pp379ndash389 2007

[94] A Carpentier D Galanaud L Puybasset et al ldquoEarly morpho-logic and spectroscopicmagnetic resonance in severe traumaticbrain injuries can detect ldquoinvisible brain stem damagerdquo andpredict lsquovegetative statesrsquordquo Journal of Neurotrauma vol 23 no5 pp 674ndash685 2006

[95] B A Holshouser K A Tong and S Ashwal ldquoProton MR spec-troscopic imaging depicts diffuse axonal injury in children withtraumatic brain injuryrdquo American Journal of Neuroradiologyvol 26 no 5 pp 1276ndash1285 2005

[96] A Marmarou S Signoretti P Fatouros G A Aygok and RBullock ldquoMitochondrial injury measured by proton magneticresonance spectroscopy in severe head trauma patientsrdquo ActaNeurochirurgica Supplementum no 95 pp 149ndash151 2005

[97] S T DeKosky K M Taffe E E Abrahamson C E Dixon PM Kochanek and M D Ikonomovic ldquoTime course analysisof hippocampal nerve growth factor and antioxidant enzymeactivity following lateral controlled cortical impact brain injuryin the ratrdquo Journal of Neurotrauma vol 21 no 5 pp 491ndash5002004

[98] M L SchwarzboldD Rial T de Bemet al ldquoEffects of traumaticbrain injury of different severities on emotional cognitiveand oxidative stress-related parameters in micerdquo Journal ofNeurotrauma vol 27 no 10 pp 1883ndash1893 2010

[99] F Dehghan M Khaksari Hadad G Asadikram H Najafipourand N Shahrokhi ldquoEffect of melatonin on intracranial pressureand brain edema following traumatic brain injury role ofoxidative stressesrdquo Archives of Medical Research vol 44 pp251ndash258 2013

[100] L F Silva M S Hoffmann R Gerbatin Rda et al ldquoTreadmillexercise protects against pentylenetetrazol-induced seizuresand oxidative stress after traumatic brain injuryrdquo Journal ofNeurotrauma no 30 pp 1278ndash1287 2013

[101] E Ozturk S Demirbilek A Koroglu et al ldquoPropofol and ery-thropoietin antioxidant properties in rat brain injured tissuerdquoProgress in Neuro-Psychopharmacology amp Biological Psychiatryvol 32 pp 81ndash86 2008

[102] M B Potts R Rola C P Claus D M Ferriero J R Fike andL J Noble-Haeusslein ldquoGlutathione peroxidase overexpressiondoes not rescue impaired neurogenesis in the injured immaturebrainrdquo Journal of Neuroscience Research vol 87 no 8 pp 1848ndash1857 2009

[103] B Blasiole H Bayr V A Vagni et al ldquoEffect of hyperoxia onresuscitation of experimental combined traumatic brain injuryand hemorrhagic shock in micerdquo Anesthesiology pp 649ndash6632013

[104] S Homsi F Federico N Croci et al ldquoMinocycline effectson cerebral edema relations with inflammatory and oxidativestress markers following traumatic brain injury in micerdquo BrainResearch vol 1291 pp 122ndash132 2009

[105] L Lomnitski S Chapman A Hochman et al ldquoAntioxidantmechanisms in apolipoprotein E deficient mice prior to and


following closed head injuryrdquoBiochimica et Biophysica Acta vol1453 no 3 pp 359ndash368 1999

[106] R M Adibhatla and J F Hatcher ldquoPhospholipase A2 reactiveoxygen species and lipid peroxidation in CNS pathologiesrdquoJournal of Biochemistry andMolecular Biology vol 41 no 8 pp560ndash567 2008

[107] X Ji W Liu K Xie et al ldquoBeneficial effects of hydrogen gasin a rat model of traumatic brain injury via reducing oxidativestressrdquo Brain Research vol 1354 pp 196ndash205 2010

[108] I Solaroglu O Okutan E Kaptanoglu E Beskonakli andK Kilinc ldquoIncreased xanthine oxidase activity after traumaticbrain injury in ratsrdquo Journal of Clinical Neuroscience vol 12 no3 pp 273ndash275 2005

[109] P G Sullivan J N KellerM PMattson and SW Scheff ldquoTrau-matic brain injury alters synaptic homeostasis implicationsfor impaired mitochondrial and transport functionrdquo Journal ofNeurotrauma vol 15 no 10 pp 789ndash798 1998

[110] O Ates S Cayli E Altinoz et al ldquoNeuroprotection by resver-atrol against traumatic brain injury in ratsrdquo Molecular andCellular Biochemistry vol 294 no 1-2 pp 137ndash144 2007

[111] M KhanH Sakakima T S Dhammu et al ldquoS-Nitrosoglutathi-one reduces oxidative injury and promotes mechanisms ofneurorepair following traumatic brain injury in ratsrdquo Journal ofNeuroinflammation vol 8 article 78 2011

[112] K Miyamoto H Ohtaki K Dohi et al ldquoTherapeutic timewindow for edaravone treatment of traumatic brain injuryin micerdquo BioMed Research International vol 2013 Article ID379206 13 pages 2013

[113] M Ohta Y Higashi T Yawata et al ldquoAttenuation of axonalinjury and oxidative stress by edaravone protects against cogni-tive impairments after traumatic brain injuryrdquo Brain Researchvol 1490 pp 184ndash192 2013

[114] G-H Wang Z-L Jiang Y-C Li et al ldquoFree-radical scavengeredaravone treatment confers neuroprotection against traumaticbrain injury in ratsrdquo Journal of Neurotrauma vol 28 no 10 pp2123ndash2134 2011

[115] A Wu Z Ying and F Gomez-Pinilla ldquoVitamin e protectsagainst oxidative damage and learning disability after mildtraumatic brain injury in ratsrdquo Neurorehabilitation and NeuralRepair vol 24 no 3 pp 290ndash298 2010

[116] Y Deng B M Thompson X Gao and E D Hall ldquoTem-poral relationship of peroxynitrite-induced oxidative damagecalpain-mediated cytoskeletal degradation and neurodegener-ation after traumatic brain injuryrdquo Experimental Neurology vol205 no 1 pp 154ndash165 2007

[117] T T Reed J Owen W M Pierce A Sebastian P G SullivanandDA Butterfield ldquoProteomic identification of nitrated brainproteins in traumatic brain-injured rats treated postinjury withgamma-glutamylcysteine ethyl ester insights into the role ofelevation of glutathione as a potential therapeutic strategy fortraumatic brain injuryrdquo Journal of Neuroscience Research vol87 no 2 pp 408ndash417 2009

[118] H Bayir V E Kagan Y Y Tyurina et al ldquoAssessment ofantioxidant reserves and oxidative stress in cerebrospinal fluidafter severe traumatic brain injury in infants and childrenrdquoPediatric Research vol 51 no 5 pp 571ndash578 2002

[119] T B Corcoran E Mas A E Barden et al ldquoAre isofurans andneuroprostanes increased after subarachnoid hemorrhage andtraumatic brain injuryrdquo Antioxidants and Redox Signaling vol15 no 10 pp 2663ndash2667 2011

[120] S Varma K L Janesko S R Wisniewski et al ldquoF2-isoprostaneand neuron-specific enolase in cerebrospinal fluid after severe

traumatic brain injury in infants and childrenrdquo Journal ofNeurotrauma vol 20 no 8 pp 781ndash786 2003

[121] D Pratico E M Smyth F Violi and G A FitzGerald ldquoLocalamplification of platelet function by 8-epi prostaglandin F2120572 isnot mediated by thromboxane receptor isoformsrdquo The Journalof Biological Chemistry vol 271 no 25 pp 14916ndash14924 1996

[122] F Clausen N Marklund A Lewen P Enblad S Basuand L Hillered ldquoInterstitial F2-isoprostane 8-Iso-PGF2120572 asa biomarker of oxidative stress after severe human traumaticbrain injuryrdquo Journal of Neurotrauma vol 29 no 5 pp 766ndash775 2012

[123] G F Yu Y Q Jie A Wu Q Huang W M Dai and X FFan ldquoIncreased plasma 8-iso-prostaglandin F2120572concentrationin severe human traumatic brain injuryrdquo Clinica Chimica Actavol 421 pp 7ndash11 2013

[124] A G Mustafa I N Singh J Wang K M Carrico and E DHall ldquoMitochondrial protection after traumatic brain injury byscavenging lipid peroxyl radicalsrdquo Journal of Neurochemistryvol 114 no 1 pp 271ndash280 2010

[125] R D Readnower M Chavko S Adeeb et al ldquoIncrease inblood-brain barrier permeability oxidative stress and activatedmicroglia in a rat model of blast-induced traumatic braininjuryrdquo Journal of Neuroscience Research vol 88 no 16 pp3530ndash3539 2010

[126] R S Darwish N Amiridze and B Aarabi ldquoNitrotyrosine as anoxidative stress marker evidence for involvement in neurologicoutcome in human traumatic brain injuryrdquo Journal of Traumavol 63 no 2 pp 439ndash442 2007

[127] C Nayak D Nayak A Raja and A Rao ldquoTime-level relation-ship between indicators of oxidative stress and Glasgow ComaScale scores of severe head injury patientsrdquo Clinical Chemistryand Laboratory Medicine vol 44 no 4 pp 460ndash463 2006

[128] C Nayak D Nayak A Raja and A Rao ldquoTime-relativechanges in the erythrocyte antioxidant enzyme activities andtheir relationship with glasgow coma scale scores in severe headinjury patients in the 21-day posttraumatic study periodrdquo IndianJournal of Medical Sciences vol 61 no 7 pp 381ndash389 2007

[129] C Nayak D Nayak A Raja and A Rao ldquoErythrocyte indica-tors of oxidative changes in patients with graded traumatic headinjuryrdquo Neurology India vol 56 no 1 pp 31ndash35 2008

[130] C Nayak D Nayak A Raja and A Rao ldquoRelationship betweenmarkers of lipid peroxidation thiol oxidation and Glasgowcoma scale scores of moderate head injury patients in the 7 daypost-traumatic periodrdquoNeurological Research vol 30 no 5 pp461ndash464 2008

[131] A Hohl J D S Gullo C C P Silva et al ldquoPlasma levels ofoxidative stress biomarkers and hospital mortality in severehead injury amultivariate analysisrdquo Journal of Critical Care vol27 pp 523e11ndash523e19 2012

[132] M E R de Oliveira Thais G Cavallazzi M L Schwarzboldet al ldquoPlasma levels of oxidative stress biomarkers and long-term cognitive performance after severe head injuryrdquo CNSNeuroscience ampTherapeutics vol 18 pp 606ndash608 2012

[133] A McIntyre S Mehta J Aubut M Dijkers and R W TeasellldquoMortality among older adults after a traumatic brain injury ameta-analysisrdquo Brain Injury vol 27 pp 31ndash40 2013

[134] C ShaoKN RobertsWRMarkesbery SW Scheff andMALovell ldquoOxidative stress in head trauma in agingrdquo Free RadicalBiology and Medicine vol 41 no 1 pp 77ndash85 2006

[135] T Itoh M Imano S Nishida et al ldquoIncreased apoptoticneuronal cell death and cognitive impairment at early phase


after traumatic brain injury in aged ratsrdquo Brain Structure andFunction vol 218 pp 209ndash220 2013

[136] L F A Silva M S Hoffmann L M Rambo et al ldquoThe involve-ment of Na+ K+-ATPase activity and free radical generationin the susceptibility to pentylenetetrazol-induced seizures afterexperimental traumatic brain injuryrdquo Journal of theNeurologicalSciences vol 308 no 1-2 pp 35ndash40 2011

[137] F D Lima M A Souza A F Furian et al ldquoNa+K+-ATPaseactivity impairment after experimental traumatic brain injuryrelationship to spatial learning deficits and oxidative stressrdquoBehavioural Brain Research vol 193 no 2 pp 306ndash310 2008

[138] A L L Saraiva A P O Ferreira L F A Silva et al ldquoCreatinereduces oxidative stress markers but does not protect againstseizure susceptibility after severe traumatic brain injuryrdquo BrainResearch Bulletin vol 87 no 2-3 pp 180ndash186 2012

[139] C C T Aguiar A B Almeida P V P Araujo et al ldquoOxidativestress and epilepsy literature reviewrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 795259 12 pages 2012

[140] F D Lima M S Oliveira A F Furian et al ldquoAdaptationto oxidative challenge induced by chronic physical exerciseprevents Na+K+-ATPase activity inhibition after traumaticbrain injuryrdquo Brain Research vol 1279 pp 147ndash155 2009

[141] G S Griesbach D A Hovda F Gomez-Pinilla and R LSutton ldquoVoluntary exercise or amphetamine treatment butnot the combination increases hippocampal brain-derivedneurotrophic factor and synapsin I following cortical contusioninjury in ratsrdquo Neuroscience vol 154 no 2 pp 530ndash540 2008

[142] T Itoh M Imano S Nishida et al ldquoExercise inhibits neuronalapoptosis and improves cerebral function following rat trau-matic brain injuryrdquo Journal of Neural Transmission vol 118 no9 pp 1263ndash1272 2011

[143] J L Rigg E P Elovic and B D Greenwald ldquoA review of theeffectiveness of antioxidant therapy to reduce neuronal damagein acute traumatic brain injuryrdquo Journal of Head TraumaRehabilitation vol 20 no 4 pp 389ndash391 2005

[144] Y Gilgun-Sherki Z Rosenbaum E Melamed and D OffenldquoAntioxidant therapy in acute central nervous system injurycurrent staterdquo Pharmacological Reviews vol 54 no 2 pp 271ndash284 2002

[145] M Yunoki M Kawauchi N Ukita et al ldquoEffects of lecithinizedsuperoxide dismutase on traumatic brain injury in ratsrdquo Journalof Neurotrauma vol 14 no 10 pp 739ndash746 1997

[146] M Yunoki M Kawauchi N Ukita T Sugiura and T OhmotoldquoEffects of lecithinized superoxide dismutase on neuronal cellloss in CA3 hippocampus after traumatic brain injury in ratsrdquoSurgical Neurology vol 59 no 3 pp 156ndash160 2003

[147] N Aoyama Y Katayama T Kawamata et al ldquoEffects ofantioxidant OPC-14117 on secondary cellular damage andbehavioral deficits following cortical contusion in the ratrdquo BrainResearch vol 934 no 2 pp 117ndash124 2002

[148] T Kawamata Y Katayama T Maeda et al ldquoAntioxidantOPC-14117 attenuates edema formation and behavioral deficitsfollowing cortical contusion in ratsrdquo Acta NeurochirurgicaSupplement vol 1997 no 70 pp 191ndash193 1997

[149] T Mori T Kawamata Y Katayama et al ldquoAntioxidant OPC-14117 attenuates edema formation and subsequent tissue dam-age following cortical contusion in ratsrdquo Acta NeurochirurgicaSupplement vol 1998 no 71 pp 120ndash122 1998

[150] J P Muizelaar A Marmarou H F Young et al ldquoImproving theoutcome of severe head injury with the oxygen radical scav-enger polyethylene glycol-conjugated superoxide dismutase a

Phase II trialrdquo Journal of Neurosurgery vol 78 no 3 pp 375ndash382 1993

[151] J P Muizelaar J W Kupiec and L A Rapp ldquoPEG-SOD afterhead injuryrdquo Journal of Neurosurgery vol 83 no 5 p 942 1995

[152] R Zhang E Shohami E Beit-Yannai R Bass V Trembovlerand A Samuni ldquoMechanism of brain protection by nitroxideradicals in experimental model of closed-head injuryrdquo FreeRadical Biology and Medicine vol 24 no 2 pp 332ndash340 1998

[153] Y Deng-Bryant I N Singh K M Carrico and E D HallldquoNeuroprotective effects of tempol a catalytic scavenger ofperoxynitrite-derived free radicals in a mouse traumatic braininjury modelrdquo Journal of Cerebral Blood Flow and Metabolismvol 28 no 6 pp 1114ndash1126 2008

[154] F Clausen N Marklund A Lewen and L Hillered ldquoThenitrone free radical scavenger NXY-059 is neuroprotectivewhen administered after traumatic brain injury in the ratrdquoJournal of Neurotrauma vol 25 no 12 pp 1449ndash1457 2008

[155] N Marklund S Sihver B Langstrom M Bergstrom and LHillered ldquoEffect of traumatic brain injury and nitrone radicalscavengers on relative changes in regional cerebral blood flowand glucose uptake in ratsrdquo Journal of Neurotrauma vol 19 no10 pp 1139ndash1153 2002

[156] N Marklund F Clausen T K McIntosh and L HilleredldquoFree radical scavenger posttreatment improves functional andmorphological outcome after fluid percussion injury in the ratrdquoJournal of Neurotrauma vol 18 no 8 pp 821ndash832 2001

[157] N Marklund T Lewander F Clausen and L Hillered ldquoEffectsof the nitrone radical scavengers PBN and S-PBN on in vivotrapping of reactive oxygen species after traumatic brain injuryin ratsrdquo Journal of Cerebral Blood Flow and Metabolism vol 21no 11 pp 1259ndash1267 2001

[158] M Fujita Y Oda E P Wei and J T Povlishock ldquoThecombination of either tempol or FK506 with delayed hypother-mia implications for traumatically induced microvascular andaxonal protectionrdquo Journal of Neurotrauma vol 28 no 7 pp1209ndash1218 2011

[159] S Inci O E Ozcan and K Kilinc ldquoTime-level relationship forlipid peroxidation and the protective effect of 120572-tocopherol inexperimental mild and severe brain injuryrdquo Neurosurgery vol43 no 2 pp 330ndash336 1998

[160] Y Ikeda Y Mochizuki Y Nakamura et al ldquoProtective effectof a novel vitamin E derivative on experimental traumaticbrain edema in ratsndashpreliminary studyrdquo Acta NeurochirurgicaSupplement vol 76 pp 343ndash345 2000

[161] M A Petty P Poulet A Haas I J Namer and J WagnerldquoReduction of traumatic brain injury-induced cerebral oedemaby a free radical scavengerrdquo European Journal of Pharmacologyvol 307 no 2 pp 149ndash155 1996

[162] J Yang Y Han W Ye F Liu K Zhuang and G Wu ldquoAlphatocopherol treatment reduces the expression of Nogo-A andNgR in rat brain after traumatic brain injuryrdquo Journal of SurgicalResearch vol 182 pp e69ndashe77 2013

[163] O Ates S Cayli I Gurses et al ldquoEffect of pinealectomyand melatonin replacement on morphological and biochemicalrecovery after traumatic brain injuryrdquo International Journal ofDevelopmental Neuroscience vol 24 no 6 pp 357ndash363 2006

[164] A Bayir D A Kiresi H Kara et al ldquoThe effects ofmannitol andmelatonin on MRI findings in an animal model of traumaticbrain edemardquo Acta Neurologica Belgica vol 108 no 4 pp 149ndash154 2008

[165] S V Kabadi and T J Maher ldquoPosttreatment with uridine andmelatonin following traumatic brain injury reduces edema in


various brain regions in ratsrdquo Annals of the New York Academyof Sciences vol 1199 pp 105ndash113 2010

[166] S M Beni R Kohen R J Reiter D-X Tan and E ShohamildquoMelatonin-induced neuroprotection after closed head injuryis associated with increased brain antioxidants and attenuatedlate-phase activation of NF-kappaB and AP-1rdquo The FASEBJournal vol 18 no 1 pp 149ndash151 2004

[167] C Mesenge I Margaill C Verrecchia M Allix R G Bouluand M Plotkine ldquoProtective effect of melatonin in a model oftraumatic brain injury in micerdquo Journal of Pineal Research vol25 no 1 pp 41ndash46 1998

[168] D Ozdemir N Uysal S Gonenc et al ldquoEffect of melatonin onbrain oxidative damage induced by traumatic brain injury inimmature ratsrdquo Physiological Research vol 54 no 6 pp 631ndash637 2005

[169] D Ozdemir K Tugyan N Uysal et al ldquoProtective effect ofmelatonin against head trauma-induced hippocampal damageand spatial memory deficits in immature ratsrdquo NeuroscienceLetters vol 385 no 3 pp 234ndash239 2005

[170] M L KelsoNN Scheff SW Scheff and J R Pauly ldquoMelatoninand minocycline for combinatorial therapy to improve func-tional and histopathological deficits following traumatic braininjuryrdquo Neuroscience Letters vol 488 no 1 pp 60ndash64 2011

[171] M P Kalapos ldquoWhere does plasma methylglyoxal originatefromrdquo Diabetes Research and Clinical Practice vol 99 no 3pp 260ndash271 2013

[172] N Rabbani andP JThornalley ldquoMethylglyoxal glyoxalase 1 andthe dicarbonyl proteomerdquo Amino Acids vol 42 no 4 pp 1133ndash1142

[173] R Ramasamy S F Yan andAM Schmidt ldquoAdvanced glycationendproducts from precursors to RAGE round and round wegordquo Amino Acids vol 42 pp 1151ndash1161 2012

[174] T L Gao X T Yuan D Yang et al ldquoExpression of HMGB1 andRAGE in rat and human brains after traumatic brain injuryrdquoJournal of Trauma and Acute Care Surgery vol 72 pp 643ndash6492012

[175] A K Au R K Aneja M J Bell et al ldquoCerebrospinal fluidlevels of high-mobility group box 1 and cytochrome C predictoutcome after pediatric traumatic brain injuryrdquo Journal ofNeurotrauma vol 29 pp 2013ndash2021 2012

[176] Y Okuma K Liu H Wake et al ldquoAnti-high mobility groupbox-1 antibody therapy for traumatic brain injuryrdquo Annals ofNeurology vol 72 no 3 pp 373ndash384 2012

[177] G Aldini I Dalle-Donne R M Facino A Milzani and MCarini ldquoIntervention strategies to inhibit protein carbonylationby lipoxidation-derived reactive carbonylsrdquoMedicinal ResearchReviews vol 27 no 6 pp 817ndash868 2007

[178] P L Wood M A Khan S R Kulow S A Mahmood and JR Moskal ldquoNeurotoxicity of reactive aldehydes the conceptof ldquoaldehyde loadrdquo as demonstrated by neuroprotection withhydroxylaminesrdquo Brain Research vol 1095 no 1 pp 190ndash1992006

[179] B Saletu H V Semlitsch P Anderer F Resch O Presslich andP Schuster ldquoPsychophysiological research in psychiatry andneuropsychopharmacology IIThe investigation of antihypoxi-doticnootropic drugs (tenilsetam and co-dergocrine-mesylate)in elderlies with the Viennese Psychophysiological Test-System(VPTS)rdquo Methods and Findings in Experimental and ClinicalPharmacology vol 11 no 1 pp 43ndash55 1989

[180] I N Singh P G Sullivan and E D Hall ldquoPeroxynitrite-mediated oxidative damage to brain mitochondria protective

effects of peroxynitrite scavengersrdquo Journal of NeuroscienceResearch vol 85 no 10 pp 2216ndash2223 2007

[181] E D Hall N C Kupina and J S Althaus ldquoPeroxynitritescavengers for the acute treatment of traumatic brain injuryrdquoAnnals of the New York Academy of Sciences vol 890 pp 462ndash468 1999

[182] X Pei K Ni Y Zhou et al ldquoProtective effects of carnosineagainst closed head injury in micerdquo Journal of Zhejiang Univer-sity Science vol 42 pp 291ndash296 2013

[183] K Hamann A Durkes H Ouyang K Uchida A Pond andR Shi ldquoCritical role of acrolein in secondary injury followingex vivo spinal cord traumardquo Journal of Neurochemistry vol 107no 3 pp 712ndash721 2008

[184] G Louin C Marchand-Verrecchia B Palmier M PlotkineandM Jafarian-Tehrani ldquoSelective inhibition of inducible nitricoxide synthase reduces neurological deficit but not cerebraledema following traumatic brain injuryrdquo Neuropharmacologyvol 50 no 2 pp 182ndash190 2006

[185] J Lu S Moochhala M Shirhan et al ldquoNeuroprotection byaminoguanidine after lateral fluid-percussive brain injury inrats a combined magnetic resonance imaging histopathologicand functional studyrdquo Neuropharmacology vol 44 no 2 pp253ndash263 2003

[186] K Wada K Chatzipanteli S Kraydieh R Busto and W DDietrich ldquoInducible nitric oxide synthase expression after trau-matic brain injury and neuroprotection with aminoguanidinetreatment in ratsrdquo Neurosurgery vol 43 no 6 pp 1427ndash14361998

[187] A Vakili F Hosseinzadeh and T Sadogh ldquoEffect ofaminoguanidine on post-ischemic brain edema in transientmodel of focal cerebral ischemiardquo Brain Research vol 1170 pp97ndash102 2007

[188] K Chatzipanteli R Garcia A E Marcillo K E Loor SKraydieh and W D Dietrich ldquoTemporal and segmental dis-tribution of constitutive and inducible nitric oxide synthasesafter traumatic spinal cord injury effect of aminoguanidinetreatmentrdquo Journal of Neurotrauma vol 19 no 5 pp 639ndash6512002

[189] R S B Clark H Bayir C T Chu S M Alber P M Kochanekand S C Watkins ldquoAutophagy is increased in mice aftertraumatic brain injury and is detectable in human brain aftertrauma and critical illnessrdquo Autophagy vol 4 no 1 pp 88ndash902008

[190] J Lok W Leung S Zhao et al ldquoGamma-glutamylcysteineethyl ester protects cerebral endothelial cells during injury anddecreases blood-brain barrier permeability after experimentalbrain traumardquo Journal ofNeurochemistry vol 118 no 2 pp 248ndash255 2011

[191] J-H Yi and A S Hazell ldquoN-acetylcysteine attenuates earlyinduction of heme oxygenase-1 following traumatic braininjuryrdquo Brain Research vol 1033 no 1 pp 13ndash19 2005

[192] YXiong P L Peterson andC P Lee ldquoEffect ofN-acetylcysteineon mitochondrial function following traumatic brain injury inratsrdquo Journal of Neurotrauma vol 16 no 11 pp 1067ndash1082 1999

[193] G Chen J Shi Z Hu and C Hang ldquoInhibitory effecton cerebral inflammatory response following traumatic braininjury in rats a potential neuroprotective mechanism of N-acetylcysteinerdquoMediators of Inflammation vol 2008 Article ID716458 8 pages 2008

[194] M E Hoffer C Balaban M D Slade J W Tsao and BHoffer ldquoAmelioration of acute sequelae of blast induced mild


traumatic brain injury by N-acetyl cysteine a double-blindplacebo controlled studyrdquo PloS One vol 8 Article ID e541632013

[195] M Segatore ldquoCorticosteroids and traumatic brain injury statusat the end of the decade of the brainrdquoThe Journal ofNeuroscienceNursing vol 31 no 4 pp 239ndash250 1999

[196] C O Park ldquoThe effects of methylprednisolone on preventionof brain edema after experimental moderate diffuse braininjury in ratsmdashComparison between dosage injection timeand treatment methodsrdquo Yonsei Medical Journal vol 39 no 5pp 395ndash403 1998

[197] ldquoThe Brain Trauma Foundation The American Association ofNeurological Surgeons The joint section on neurotrauma andcritical care Role of steroidsrdquo Journal of Neurotrauma vol 17pp 531ndash535 2000

[198] I Roberts D Yates P Sandercock et al ldquoEffect of intravenouscorticosteroids on death within 14 days in 10008 adults withclinically significant head injury (MRC CRASH trial) ran-domised placebo-controlled trialrdquo The Lancet vol 364 pp1321ndash1328 2004

[199] P Alderson and I Roberts ldquoCorticosteroids for acute traumaticbrain injuryrdquo Cochrane Database of Systematic Reviews ArticleID CD000196 2005

[200] N Shahrokhi M K Haddad S Joukar M Shabani ZKeshavarzi and B Shahozehi ldquoNeuroprotective antioxidanteffect of sex steroid hormones in traumatic brain injuryrdquoPakistan Journal of Pharmaceutical Sciences vol 25 no 1 pp219ndash225 2012

[201] H Bayir D W Marion A M Puccio et al ldquoMarked gendereffect on lipid peroxidation after severe traumatic brain injuryin adult patientsrdquo Journal of Neurotrauma vol 21 no 1 pp 1ndash82004

[202] D G Stein ldquoProgesterone exerts neuroprotective effects afterbrain injuryrdquo Brain Research Reviews vol 57 no 2 pp 386ndash3972008

[203] J Leitgeb W Mauritz A Brazinova et al ldquoEffects of gender onoutcomes after traumatic brain injuryrdquo Journal of Trauma vol71 no 6 pp 1620ndash1626 2011

[204] C Renner H Hummelsheim A Kopczak et al ldquoThe influenceof gender on the injury severity course and outcome oftraumatic brain injuryrdquoBrain Injury vol 26 pp 1360ndash1371 2012

[205] G Xiao J Wei W Yan W Wang and Z Lu ldquoImprovedoutcomes from the administration of progesterone for patientswith acute severe traumatic brain injury a randomized con-trolled trialrdquo Critical Care vol 12 no 2 article R61 2008

[206] J Ma S Huang S Qin and C You ldquoProgesterone foracute traumatic brain injuryrdquo Cochrane Database of SystematicReviews vol 10 Article ID 008409 2012

[207] K W McConeghy J Hatton L Hughes and A M CookldquoA review of neuroprotection pharmacology and therapies inpatients with acute traumatic brain injuryrdquo CNS Drugs vol 26pp 613ndash636 2012

[208] E D Hall P A Yonkers J M McCall and J M BraughlerldquoEffects of the 21-aminosteroid U74006F on experimental headinjury in micerdquo Journal of Neurosurgery vol 68 no 3 pp 456ndash461 1988

[209] C Gahm S Holmin S Rudehill and T Mathiesen ldquoNeu-ronal degeneration and iNOS expression in experimental braincontusion following treatment with colchicine dexamethasonetirilazad mesylate and nimodipinerdquo Acta Neurochirurgica vol147 no 10 pp 1071ndash1084 2005

[210] R H Fabian D S Dewitt and T A Kent ldquoThe 21-aminosteroidU-74389G reduces cerebral superoxide anion concentrationfollowing fluid percussion injury of the brainrdquo Journal ofNeurotrauma vol 15 no 6 pp 433ndash440 1998

[211] M Bains and E D Hall ldquoAntioxidant therapies in traumaticbrain and spinal cord injuryrdquo Biochimica et Biophysica Acta vol1822 no 5 pp 675ndash684 2012

[212] T K McIntosh M Thomas D Smith and M Banbury ldquoThenovel 21-aminosteroid U74006F attenuates cerebral edema andimproves survival after brain injury in the ratrdquo Journal ofNeurotrauma vol 9 no 1 pp 33ndash46 1992

[213] E D Hall and M A Travis ldquoInhibition of arachidonic acid-induced vasogenic brain edema by the non-glucocorticoid 21-aminosteroid U74006Frdquo Brain Research vol 451 no 1-2 pp350ndash352 1988

[214] R J Kavanagh and K P C A Kam PCA ldquoLazaroids efficacyand mechanism of action of the 21-aminosteroids in neuropro-tectionrdquo British Journal of Anaesthesia vol 86 no 1 pp 110ndash1192001

[215] L F Marshall A I R Maas S B Marshall et al ldquoA multicentertrial on the efficacy of using tirilazad mesylate in cases of headinjuryrdquo Journal of Neurosurgery vol 89 no 4 pp 519ndash525 1998

[216] G J Velat M M Kimball J D Mocco and B L HohldquoVasospasm after aneurysmal subarachnoid hemorrhagereview of randomized controlled trials and meta-analyses inthe literaturerdquoWorld Neurosurgery vol 76 no 5 pp 446ndash4542011

[217] D Ilodigwe G D Murray N F Kassell et al ldquoSlidingdichotomy compared with fixed dichotomization of ordinaloutcome scales in subarachnoid hemorrhage trials Clinicalarticlerdquo Journal of Neurosurgery vol 118 pp 3ndash12 2013

[218] M B Bracken M J Shepard T R Holford et al ldquoAdminis-tration of methylprednisolone for 24 or 48 hours or tirilazadmesylate for 48 hours in the treatment of acute spinal cordinjury results of the third national acute spinal cord injuryrandomized controlled trialrdquo The Journal of the AmericanMedical Association vol 277 no 20 pp 1597ndash1604 1997

[219] J Langham C Goldfrad G Teasdale D Shaw and K RowanldquoCalcium channel blockers for acute traumatic brain injuryrdquoCochraneDatabase of Systematic Reviews Article IDCD0005652003

[220] A Marmarou J Nichols J Burgess et al ldquoEffects of thebradykinin antagonist Bradycor(TM) (Deltibant CP-1027) insevere traumatic brain injury results of amulti-center random-ized placebo-controlled trialrdquo Journal of Neurotrauma vol 16no 6 pp 431ndash444 1999

[221] A I R Maas G Murray H Henney III et al ldquoEfficacy andsafety of dexanabinol in severe traumatic brain injury resultsof a phase III randomised placebo-controlled clinical trialrdquoTheLancet Neurology vol 5 no 1 pp 38ndash45 2006

[222] N Knoller L Levi I Shoshan et al ldquoDexanabinol (HU-211) in the treatment of severe closed head injury a random-ized placebo-controlled phase II clinical trialrdquo Critical CareMedicine vol 30 no 3 pp 548ndash554 2002

[223] N R Temkin G D Anderson H R Winn et al ldquoMagnesiumsulfate for neuroprotection after traumatic brain injury arandomised controlled trialrdquo The Lancet Neurology vol 6 no1 pp 29ndash38 2007

[224] G F Morris R Bullock S B Marshall A Marmarou AMaas and L F Marshall ldquoFailure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment


of severe head injury results of two phase III clinical trialsrdquoJournal of Neurosurgery vol 91 no 5 pp 737ndash743 1999

[225] W Yan H-D Wang Z-G Hu Q-F Wang and H-X YinldquoActivation of Nrf2-ARE pathway in brain after traumatic braininjuryrdquo Neuroscience Letters vol 431 no 2 pp 150ndash154 2008

[226] K Itoh T Chiba S Takahashi et al ldquoAn Nrf2small Mafheterodimer mediates the induction of phase II detoxifyingenzyme genes through antioxidant response elementsrdquo Bio-chemical and Biophysical Research Communications vol 236no 2 pp 313ndash322 1997

[227] E D Owuor and A-N T Kong ldquoAntioxidants and oxidantsregulated signal transduction pathwaysrdquo Biochemical Pharma-cology vol 64 no 5-6 pp 765ndash770 2002

[228] J-M Zhang Y Hong W Yan S Chen and C-R Sun ldquoTherole of Nrf2 signaling in the regulation of antioxidants anddetoxifying enzymes after traumatic brain injury in rats andmicerdquo Acta Pharmacologica Sinica vol 31 no 11 pp 1421ndash14302010

[229] A K Jain D A Bloom and A K Jaiswal ldquoNuclear importand export signals in control of Nrf2rdquo The Journal of BiologicalChemistry vol 280 no 32 pp 29158ndash29168 2005

[230] W O Osburn N Wakabayashi V Misra et al ldquoNrf2 regu-lates an adaptive response protecting against oxidative damagefollowing diquat-mediated formation of superoxide anionrdquoArchives of Biochemistry and Biophysics vol 454 no 1 pp 7ndash15 2006

[231] M Kerman M Kanter K K Coskun M Erboga and AGurel ldquoNeuroprotective effects of Caffeic acid phenethyl esteron experimental traumatic brain injury in ratsrdquo Journal ofMolecular Histology vol 43 no 1 pp 49ndash57 2012

[232] T Itoh M Imano S Nishida et al ldquo(-)-Epigallocatechin-3-gallate increases the number of neural stem cells around thedamaged area after rat traumatic brain injuryrdquo Journal of NeuralTransmission vol 119 pp 877ndash890 2012

[233] T Itoh M Imano S Nishida et al ldquo(-)-Epigallocatechin-3-gallate protects against neuronal cell death and improvescerebral function after traumatic brain injury in ratsrdquo Neuro-Molecular Medicine vol 13 no 4 pp 300ndash309 2011

[234] T Itoh M Imano S Nishida et al ldquo(-)-Epigallocatechin-3-gallate increases the number of neural stem cells around thedamaged area after rat traumatic brain injuryrdquo Journal of NeuralTransmission pp 1ndash14 2011

[235] L Xia Z-L Jiang G-H Wang B-Y Hu and K-F KeldquoTreatment with ginseng total saponins reduces the secondarybrain injury in rat after cortical impactrdquo Journal of NeuroscienceResearch vol 90 pp 1424ndash1436 2012

[236] B Y Hu Z L Jiang G H Wang X Li and H M ShenldquoEffective dose and time window of ginseng total saponinstreatment in rat after traumatic brain injuryrdquo Chinese Journalof Applied Physiology vol 28 pp 179ndash183 2012

[237] L Xia Q Chen and G Cheng ldquoEffects of ginseng total saponinon traumatic brain edema of ratsrdquo Chinese Journal of IntegratedTraditional and Western Medicine vol 32 pp 1671ndash1674 2012

[238] Y C Ji Y B Kim S W Park et al ldquoNeuroprotective effect ofginseng total saponins in experimental traumatic brain injuryrdquoJournal of Korean Medical Science vol 20 no 2 pp 291ndash2962005

[239] E Schultke H Kamencic M Zhao et al ldquoNeuroprotectionfollowing fluid percussion brain trauma a pilot study usingquercetinrdquo Journal of Neurotrauma vol 22 no 12 pp 1475ndash1484 2005

[240] E D Hall R A Vaishnav and A G Mustafa ldquoAntioxidanttherapies for traumatic brain injuryrdquo Neurotherapeutics vol 7no 1 pp 51ndash61 2010

[241] R H Singleton H Q Yan W Fellows-Mayle and C E DixonldquoResveratrol attenuates behavioral impairments and reducescortical and hippocampal loss in a rat controlled cortical impactmodel of traumatic brain injuryrdquo Journal of Neurotrauma vol27 no 6 pp 1091ndash1099 2010

[242] U Sonmez A Sonmez G Erbil I Tekmen and B BaykaraldquoNeuroprotective effects of resveratrol against traumatic braininjury in immature ratsrdquo Neuroscience Letters vol 420 no 2pp 133ndash137 2007

[243] S Sharma Y Zhuang Z Ying A Wu and F Gomez-PinillaldquoDietary curcumin supplementation counteracts reduction inlevels of molecules involved in energy homeostasis after braintraumardquo Neuroscience vol 161 no 4 pp 1037ndash1044 2009

[244] A Wu Z Ying D Schubert and F Gomez-Pinilla ldquoBrain andspinal cord interaction a dietary curcumin derivative coun-teracts locomotor and cognitive deficits after brain traumardquoNeurorehabilitation and Neural Repair vol 25 no 4 pp 332ndash342 2011

[245] J Zhao A N Moore J B Redell and P K Dash ldquoEnhancingexpression of Nrf2-driven genes protects the blood-brain bar-rier after brain injuryrdquo The Journal of Neuroscience vol 27 no38 pp 10240ndash10248 2007

[246] P K Dash J Zhao S A Orsi M Zhang and A NMoore ldquoSul-foraphane improves cognitive function administered followingtraumatic brain injuryrdquoNeuroscience Letters vol 460 no 2 pp103ndash107 2009

[247] J Zhao A N Moore G L Clifton and P K Dash ldquoSul-foraphane enhances aquaporin-4 expression and decreasescerebral edema following traumatic brain injuryrdquo Journal ofNeuroscience Research vol 82 no 4 pp 499ndash506 2005

[248] X Wang J P de Rivero Vaccari H Wang et al ldquoActivationof the nuclear factor E2-related factor 2antioxidant responseelement pathway is neuroprotective after spinal cord injuryrdquoJournal of Neurotrauma vol 29 no 5 pp 936ndash945 2012

[249] MXueN RabbaniHMomiji et al ldquoTranscriptional control ofglyoxalase 1 byNrf2 provides a stress-responsive defence againstdicarbonyl glycationrdquo Biochemical Journal vol 443 no 1 pp213ndash222 2012

[250] M G Distler N Gorfinkle L A Papale et al ldquoGlyoxalase 1and its substrate methylglyoxal are novel regulators of seizuresusceptibilityrdquo Epilepsia vol 54 pp 649ndash657 2013

[251] M BergsneiderDAHovda E Shalmon et al ldquoCerebral hyper-glycolysis following severe traumatic brain injury in humans apositron emission tomography studyrdquo Journal of Neurosurgeryvol 86 no 2 pp 241ndash251 1997

[252] P J Hutchinson M T OrsquoConnell A Seal et al ldquoA combinedmicrodialysis and FDG-PET study of glucose metabolism inhead injuryrdquoActaNeurochirurgica vol 151 no 1 pp 51ndash61 2009

[253] KD Statler K L Janesko J AMelick R S B Clark LW Jenk-ins and P M Kochanek ldquoHyperglycolysis is exacerbated aftertraumatic brain injury with fentanyl vs isoflurane anesthesia inratsrdquo Brain Research vol 994 no 1 pp 37ndash43 2003

[254] D Schubert ldquoGlucose metabolism and Alzheimerrsquos diseaserdquoAgeing Research Reviews vol 4 no 2 pp 240ndash257 2005

[255] A Sartori and E J H Bechara ldquoIsmethylglyoxal an endogenoustoxinrdquo Quimica Nova vol 33 no 10 pp 2193ndash2201 2010

[256] A S Cheng Y H Cheng C H Chiou and T L ChangldquoResveratrol upregulates Nrf2 expression to attenuate


methylglyoxal-induced insulin resistance in Hep G2 cellsrdquoJournal of Agricultural and Food Chemistry vol 60 pp9180ndash9187 2012

[257] P Maher R Dargusch J L Ehren S Okada K Sharma andD Schubert ldquoFisetin lowers methylglyoxal dependent proteinglycation and limits the complications of diabetesrdquo PLoS ONEvol 6 no 6 Article ID e21226 2011

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

[259] M Liu M Yuan M Luo X Bu H-B Luo and X Hu ldquoBindingof curcumin with glyoxalase I molecular docking moleculardynamics simulations and kinetics analysisrdquo Biophysical Chem-istry vol 147 no 1-2 pp 28ndash34 2010

[260] T-Y Hu C-L Liu C-C Chyau and M L Hu ldquoTrapping ofmethylglyoxal by curcumin in cell-free systems and in humanumbilical vein endothelial cellsrdquo Journal of Agricultural andFood Chemistry vol 60 pp 8190ndash8196 2012

[261] A Gugliucci D H M Bastos J Schulze and M F F SouzaldquoCaffeic and chlorogenic acids in Ilex paraguariensis extractsare the main inhibitors of AGE generation by methylglyoxal inmodel proteinsrdquo Fitoterapia vol 80 no 6 pp 339ndash344 2009

[262] S Sang X Shao N Bai C-Y Lo C S Yang and C-T Ho ldquoTeapolyphenol (-)-epigallocatechin-3-gallate a new trapping agentof reactive dicarbonyl speciesrdquoChemical Research in Toxicologyvol 20 no 12 pp 1862ndash1870 2007

[263] Y Xie and X Chen ldquoStructures required of polyphenols forinhibiting advanced glycation end products formationrdquoCurrentDrug Metabolism vol 14 pp 414ndash431 2013

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


inflammatory damage and the toxicity of metabolites thatcan be disseminated by the circulatory system [8 9]

The therapeutic management of intracranial trauma aimsto avoid the development of secondary lesions and to thisend the control of physiological parameters such as cerebralperfusion pressure (CPP) intracranial pressure (ICP) andcerebral blood flow (CBF) is crucial to minimize ischemiaand tissue damage [10] The clinical use of CPP as a clinicalparameter is based on theoretical suggestions indicatingthat optimal cerebral blood flow is necessary to meet themetabolic needs of the injured brain [11] The therapeuticmanagement goal is to keep the CBF stable and maintain abalance between CPP and ICP in order to rescue the ischemicpenumbra area Cells in this area are potentially salvabletherefore they comprise the most essential area for medicalintervention making the prevention of secondary insults inthis region crucial for a better outcome [12]

22 Brain Swelling Among secondary injuries cerebraledema is of special significance as it can greatly aggravatebrain damage and is the main condition related to increasedICP excluding conditions potentially leading to surgicalinterventions such as hematoma and contusion IncreasedICP leads to a decrease in CPP and CBF worsening tissuedamage as a consequence of brain ischemia Edema occursby two basic mechanisms cytotoxic edema related to thedepletion of cell energy and vasogenic edema related todisruption of the brain-blood barrier (BBB) [13 14]

In vasogenic brain edema BBB integrity is compromisedby mechanical or autodigestive disruption or functionalbreakdown of the endothelial cell layer of brain vesselswhich is critical for maintenance of the BBB Disintegrationof the cerebral vascular endothelial wall allows for uncon-trolled ion and protein transfer from the intravascular to theextracellular (interstitial) brain compartment leading to fluidaccumulation which increases the volumeof the extracellularspace [15 16] The intact BBB prevents diffusion of mostwater-soluble molecules above 500Da [17] However whenthe BBB is disrupted brain-related proteins can be measuredin the peripheral circulation [18 19] The BBB leakageassociated with TBI not only allows brain-related moleculesto reach the bloodstream but also permitsmolecules from theperiphery to enter cerebrospinal fluid (CSF) Both situationseither peripheral proteins entering the CSF or CSF leakage ofproteins can be used as biomarkers of TBI [20 21]

Cytotoxic brain edema is characterized by intracel-lular water accumulation inside neurons astrocytes andmicroglia This pathology is caused by an increased cellmembrane permeability ionic pump failure due to energydepletion and intracellular accumulation of osmoticallyactive solutes [16 22]This edema-driven energy impairmentgenerates an ldquoischemia-likerdquo pattern which increases glycol-ysis flux leading to lactic acid accumulation associated withincreased membrane permeability intensifying edema andthe establishment of a destructive positive feed-back loop

Thenext step of this pathophysiological cascade is charac-terized by excitoxicity TBI is associatedwith amassive release

of excitatory amino acid neurotransmitters particularly glu-tamate [23 24]The extracellular glutamate availability affectsneurons and astrocytes and results in overstimulation ofionotropic and metabotropic glutamate receptors increasingCa2+ Na+ and K+ influxes [25 26] Although these eventstrigger catabolic processes the cellular attempt to compensatefor ionic gradients increases Na+K+-ATPase activity andtherefore metabolic demand creating a vicious circle of flow-metabolism uncoupling This condition can destroy vascularand cellular structures and ultimately induces necrotic orprogrammed cell death [27]

3 Reactive Oxygen Species andTraumatic Brain Injury

Reactive oxygen species (ROS) and reactive nitrogen species(RNS) are generated during normal physiological processesThey are highly reactive molecules which can cause damageto key cellular components such as DNA lipids and proteinsUnder physiological conditions the endogenous defensesystem is able to prevent the formation of or scavenge theseharmfulmolecules protecting tissues fromoxidative damageIn TBI there is a considerable increase in the production offree radicals supporting the idea that oxidative stress plays adecisive role in the pathology [28 29]

It is generally believed that 1-2 of the oxygen reducedby mitochondria is converted to superoxide anion (O

2

∙minus) atthe level of complex I or at the level of ubiquinone [30ndash32] However certain enzymatic components are looselyassociated with the inner mitochondrial membrane andunder conditions of cellular stress can be released or inac-tivated greatly diminishing the reducing capacity of theelectron transport chain (ETC) The electrons will sub-sequently be monoelectronically donated to oxygen (O

2)

yielding increased production of O2

∙minus Another importantsource of mitochondrial O

2

∙minusdepends on Ca2+ influx oftensecondary to glutamatergic excitotoxicity which leads tostructural alterations of the inner mitochondrial membraneThese alterationsmay increase ROS formation due to disorga-nization of the ETC [33] Under severe Ca2+ loads howeveropening of the mitochondrial permeability transition pore(mPTP) results in the extrusion of mitochondrial Ca2+and other high- and low-molecular weight componentsThis catastrophic event discharges and uncouples the ETCpreventing ATP production which can lead to necrotic orapoptotic cell death [34]

Other sources of free radicals in TBI in addition tomitochondrial dysfunction and excitotoxicity mediated byglutamate include the formation of bradykininThis cytokinecan activate phospholipase A2 releasing arachidonic acidthat can serve as a source of free radicals [35 36] Arachidonicacid may also facilitate NADPH oxidase activity thus furtherincreasing ROS production [37] Apart from increasingarachidonic acid production frommembrane phospholipidsbradykinin can induce free radical production by causing aCa2+ overload [38] Another source of ROS in TBI may bemacrophagesmicroglia and neutrophils activated as part ofan inflammatory process triggered by the initial injury [28]










5 Biomarkers of TBI




























2








2














2










2














Acknowledgments


References
































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























5 Biomarkers of TBI




























2








2














2










2














Acknowledgments


References
































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































2








2














2










2














Acknowledgments


References
































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















2














2










2














Acknowledgments


References
































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























2










2














Acknowledgments


References
































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















2














Acknowledgments


References
































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























Acknowledgments


References
































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article perspectives on molecular biomarkers of...

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