review article role of melatonin in traumatic brain...

Review ArticleRole of Melatonin in Traumatic Brain Injury andSpinal Cord Injury

Mehar Naseem and Suhel Parvez

Department of Medical Elementology and Toxicology Jamia Hamdard New Delhi 110062 India

Correspondence should be addressed to Suhel Parvez sparvezjamiahamdardacin

Received 31 July 2014 Revised 11 November 2014 Accepted 14 November 2014 Published 21 December 2014

Academic Editor Swapan Ray

Copyright copy 2014 M Naseem and S Parvez 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

Brain and spinal cord are implicated in incidences of two of the most severe injuries of central nervous system (CNS) Traumaticbrain injury (TBI) is a devastating neurological deficit involving primary and secondary injury cascadesTheprimary and secondarymechanisms include complex consequences of activation of proinflammatory cytokines cerebral edema upregulation of NF-120581120573disruption of blood-brain barrier (BBB) and oxidative stress Spinal cord injury (SCI) includes primary and secondary injurycascades Primary injury leads to secondary injury in which generation of free radicals and oxidative or nitrative damage playan important pathophysiological role The indoleamine melatonin is a hormone secreted or synthesized by pineal gland in thebrain which helps to regulate sleep and wake cycle Melatonin has been shown to be a versatile hormone having antioxidativeantiapoptotic neuroprotective and anti-inflammatory properties It has a special characteristic of crossing BBB Melatonin hasneuroprotective role in the injured part of the CNS after TBI and SCI A number of studies have successfully shown its therapeuticvalue as a neuroprotective agent in the treatment of neurodegenerative diseases Here in this review we have compiled the literaturesupporting consequences of CNS injuries TBI and SCI and the protective role of melatonin in it

1 Introduction

Central nervous system (CNS) is one of the complex systemsin the body which consists of brain and spinal cord Anydisease or traumatic assault may lead to the degenerationof CNS including loss of homeostasis [1] CNS injuries con-stitute a major cause of morbidity and mortality includethe life threatening injuries such as traumatic brain injury(TBI) and spinal cord injury (SCI) [2ndash4] TBI and SCI arecaused by both primary and secondary injuries influencingthe cascades of cellular andmolecular events whichwill causefurther damage in the system and loss of body functionsThe consequences of the secondary injury include mitochon-drial dysfunction neurotransmitter accumulation blood-brain barrier (BBB) and blood spinal cord barrier disruptionapoptosis excitotoxic damage initiation of inflammatoryand immune processes which is followed by initial primarymechanical trauma [5 6] Secondary injury involves theproduction of highly reactive species reactive oxygen species

(ROS) reactive nitrogen species (RNS) or free radicals whichwill cause damage to protein structure DNA and cell mem-brane and leads to oxidative stress which plays a major rolein the pathophysiology of CNS injuryThe progression of thedamage starts from the primary impact on brain or spinalcord and will continue for hours days and weeks after theinitial mechanical insult which will result in tissue damageThis review in which two models of CNS injury will becovered will explore the role of reactive oxygen species (ROS)and current research on therapeutic role of melatonin used inthe treatment of TBI and SCI

2 Oxidative Stress

Oxidative stress is a phenomenon which occurs when thereis an imbalance between prooxidants and antioxidants in theliving systemwhich plays amajor role in the pathophysiologyof many disorders or injury The cells of CNS have very lowcapacity to attenuate the effects of oxidative stress so CNS is

Hindawi Publishing Corporatione Scientific World JournalVolume 2014 Article ID 586270 13 pageshttpdxdoiorg1011552014586270

2 The Scientific World Journal

highly sensitive to oxidative stress and thus oxidative damageas the oxidative stress is associated with the pathogenesis ofCNS injury such as stroke TBI and SCI

There is a balance between the oxidants and antioxidantsactivities and when there is any disturbance caused by anyenvironmental or genetic factor excessive generation of freeradicals or ROS occurs which overwhelms the endogenousantioxidant systems Free radicals are highly reactive mole-cules having one or more unpaired electrons in their outer-most orbits which result in their instability and make themmore reactive as compared to their corresponding nonradi-cals They participate in a number of reactions and form veryreactive metabolites which includes hydroxyl radical (HO∙)hydrogen peroxide (H

2

O2

) singlet oxygen and peroxyni-trite Superoxide anion radicals (O

2

∙minus) which are derivedfrom oxygen are the most commonly occurring and one ofthe strongest ROS among the cellular free radicals generatedin living systems [7 8] The superoxide radical which is con-sidered as the ldquoprimaryrdquo ROS is capable of forming secondaryROS by reacting with other molecules Superoxide dismutase(SOD) is a superoxide scavenging enzyme which plays thecentral role in amelioration of the effects of superoxideanion radicals by dismutation reaction in which it convertsO2

∙minus into nonradical species singlet oxygen and hydrogenperoxide (H

2

O2

) H2

O2

forms highly reactive hydroxyl freeradical (OH∙) via Fenton reaction which causes damage tolipid proteins and DNA which is converted into H

2

O andoxygen by an antioxidant enzyme catalase [9 10] (Figure 3)Reactive by-products of oxygen such as superoxide anionradical (O

2

minus)H2

O2

and the highly reactive hydroxyl radicals(∙OH) are formed continuously as a by-product of oxidativemetabolism catalysed by several membrane-associated res-piratory chain enzymes and considered as the major sourceof oxidative injury in all aerobic organisms [11 12]

ROS plays an important role as secondary messengers inmany intracellular signalling pathways and also as mediatorsof oxidative damage and inflammation [13] CNS has highlevels of oxygen demand and unsaturated lipid content withwhich free radicals can easily react Lipids are susceptible tooxidative stress and one of the products of oxidative damageto lipids is 4-hydroxy-2-nonenal (4-HNE) and acrolein andfree radicals can attack directly polyunsaturated fatty acidsin membranes and initiate lipid peroxidation (LPO) Thesefeatures may make the CNS a target tissue for the onset andpathogenesis of a number ofCNSdisorders via oxygen radicalproduction and LPO [14 15] It has been well documentedthat in the CNS the transcription factor nuclear factorerythroid-2-related factor 2 (Nrf2) which is the principalregulator of phase-2 cellular antioxidant response plays thecentral role in astrocyte-mediated protection of neurons fromROS [16]

3 Traumatic Brain Injury

TBI is devastating and a leading cause of injury relatedmortality and morbidity and may result in permanent func-tional impairment due to both primary which is caused bythe initial mechanical injury and secondary injury mech-anisms [1] Primary injury is the initial traumatic brain

insult the consequences of which are immediate and irre-versible disruption of neuronal cell bodies contusion vascu-lar injury and axon shearing The primary injury also resultsin tissue deformation and compression leading to seizuresrespiratory depression apnoea ischemia hypoxia parenchy-mal inflammation LPO and nitric oxide production result-ing in cellular injury [4] The secondary injury which is adelayed nonmechanical insult to brain is caused by a complexcascade of metabolic physiologic and biochemical factorsinitiated by the primary insult continuing for hours to daysafter injury that results in progressive tissue damage [5]

Na+ K+-ATPase is a membrane transport protein inmammalian cell membrane which plays an important rolein maintaining ionic homeostasis It is documented that anyderegulation in the activity of the Na+ K+-ATPase pumpmight be a common feature in CNS pathologies related toischemic conditions and TBI since the pump is highly sensi-tive to reactive species and LPO and its decreased activity willincrease the intracellular concentration of Ca2+ thus playinga synergistic role in excitotoxicity The ischemic condition ofthe brain will lead to excitotoxicity which is induced by therelease of excitatory amino acid neurotransmitters partic-ularly glutamate from neurons injured by ischemia follow-ing which the subsequent activation of glutamate receptorsresulted in a consecutive influx of Ca2+ Na+ and K+ intoneuronal cells through these receptors Devastating effectsof increased intracellular Ca2+ concentrations lead to theproduction of free radicals such as super oxide (O

2

minus) andhydroxyl radical (∙OH) and synthesis of NO peroxidationof fatty acids which can induce xanthine pathway and ulti-mately to degeneration in the cellular system and cell deathby various mechanisms such as overactivation of phospholi-pases calpains protein kinases and endonucleases [17 18]

Brain has low level of antioxidant system and high oxida-tive utilization (20 of the total oxygen inspired) as well ashigh level of polyunsaturated fatty acids (PUFA) transitionmetals such as iron which is involved in the generationof the hydroxyl radical as compared to other organs whichmake it more susceptible to oxidative stress [19] PUFA isvery sensitive to free radicals which directly react with it andinitiate LPO during this process more radicals are formedwhich will disintegrate PUFA into a number of reactiveproducts which will cause cellular damage The deleteriouseffect of secondary injury to the brain revealed a numberof experimental studies and oxidative stress which generatesROS one of the main cause of pathophysiologic processesafter brain trauma including mitochondrial dysfunction lea-ding to energy failure production of a large number of toxicand proinflammatory molecules increase in intracranialpressure and a subsequent decrease in cerebral perfusionleading to ischemia astrocyte dysfunction ATP depletionproteolysis and vasogenic edema [20] Cerebral edema inTBI leads to exacerbating the severity of brain trauma byincreasing intercranial pressure (ICP) Increased ICP is animportant factor determining the outcomes of TBI patientsand therefore it is measured In an experimental study it wasconcluded that there was a significant rise in ICP in 4 and 24 hafter brain injury in TBI compared to sham [21] There are

The Scientific World Journal 3

a number of studies which have been underexplored researcharea to cure secondary injury after TBI

4 Spinal Cord Injury

SCI is a devastating event which initiates a series of complexcellular andmolecular cascade events which leads to physicaland social impact on individuals and society The series ofevents lead to initial tissue damage in CNS The patho-physiology of SCI is thought to include two stages primaryinjury and secondary injury which is mediated by multi-ple injury processes including inflammation autoimmuneresponse vascular events apoptosis free radical-inducedcell death and glutamate excitotoxicity [22] The primarydamage is restricted to the area of the mechanical insultand is characterized by ischemia Neuroinflammation playsan important role in the pathogenesis of neuropathic painA major contributor to neuropathic pain in spinal cordinjury ismicroglial activation and release of proinflammatorycytokines IL-1120573 and TNF-120572 that will enhance pain mech-anism In spite of many experimental studies done so faror still in the process of investigation there is no effectivetherapeutics which can eliminate the devastating effects ofsecondary damage after SCI The severity of SCI dependson the extent of secondary damage mediated by multipleseries of cellular molecular and biochemical reactions Thecascade of reactions includes calcium ion influx oxygen freeradical induced LPO inflammatory reaction autoimmuneresponse myelin degradation and vascular changes (includ-ing ischemia vasospasms haemorrhages and thrombosis) Italso includes activation of a variety of proteases including cas-pases phospholipases endonucleases metalloproteinasesand apoptosis which leads to the expansion of damage [23]

Inflammation acts as a key player in the pathogenesis ofSCI leading to glial scar formation neuronal loss and dem-yelination and upregulation of proinflammatory cytokineTNF-120572 immediately after SCI can enhance vascular perme-ability and may cause damage to multiple organ system andfinally in the neurological dysfunction or the most devas-tating result may come in the form of permanent loss ofmotor sensory and autonomic function due to inability of theadultmammalian nervous system to regenerate [32ndash34] ROSincluding O

2

minus H2

O2

OH∙ and peroxynitrite are believedto attack unsaturated fats lipids proteins DNA and alsoplay an important role to exacerbate the ill effects of thesecondary injury Like brain spinal cord is also susceptibleto oxidative damage because of having rich in PUFA acids[35] Oxidative stress is one of the well-defined consequenceswhich plays a significant role in the pathophysiology of SCIand is considered as a hallmark of secondary injury Afterthe mechanical insult caused to spinal cord generation of freeradical superoxide (O

2

∙minus) occurs within the first minutes andhours of injury [36]

5 Proposed Neuroprotective Therapies forTBI and SCI in Animal Model

Endogenously occurring hormones or other compoundssuch as progesterone [21 37] estrogen [1] and lipoic acid [38]

have been studied for their multifaceted role in neuroprotec-tion Among the endogenous compounds melatonin repre-sents one of the best promising candidates to be studied forits role in neuroprotection (Table 1)

6 Biology of Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) an amphiphilicmolecule was isolated by Lerner and his coworkers in 1956in the extract of bovine pineal tissue with skin lighteningproperties [39 40] Melatonin is a methoxyindole derivativeproduced by extra pineal tissues and organs such as retinaHarderian gland gut bonemarrow platelets astrocytes glialcells lymphocytes pancreas kidneys and skin but predomi-nantly by the pineal gland It is synthesized by pinealocyteswhich is the main source of melatonin in blood and CNSthat peaks during the night in mammals and considered asa powerful antioxidant [41] Melatonin occurrence has beenwell documented in animals but its occurrence in plants hasalso been mentioned [42]

The rate of endogenous melatonin synthesis depends onthe action of its precursors the amino acid as well as a neu-rotransmitter serotonin arylalkylamine N-acetyltransferase(AANAT) and tryptophan hydroxylase (TPH) in a circadianand seasonal manner [40] (Figure 1) There are a numberof studies where melatonin has been shown to regulatevarious physiological functions in the body such as immuneenhancing anti-inflammatory properties [43] radicals scav-enger [44] traumatic CNS injury [4] modulation of humanmood and behaviour [45] anticancer activity [46 47] in oralcavity [48] against angiogenesis in breast tumors [49] sleepregulation [50]

Melatonin activity is mediated by the specific receptors incellular membranes by two high affinity melatonin receptorsMT1 andMT2 which belong to the seven-transmembraneG-protein-coupled receptor (GPCR) superfamily and throughnuclear receptors RZRRORThesemelatonin receptorsMT1and MT2 are primarily found in the endogenous circadianmaster clock suprachiasmatic nuclei (SCN) in the hypotha-lamus of the mammalian cells being localized primarilyto neuronal elements and in many other organs as wellcoordinate the synthesis ofmelatonin in the pineal gland andalso participate in several neuroendocrine and physiologicalprocesses Melatonin receptors are widely distributed in CNSas well as in the peripheral organs which acts as a lipophilicand hydrophilic molecule and able to pass the morpho-physiological barriers such as the BBB Its neuroprotectivenature has also been described through the activation of thesereceptors but the actual mechanism is unknown

Metabolisation of melatonin occurs by cytP-450 enzymewhich metabolises it into 6-hydroxymelatonin which is fol-lowed by conjugation reaction resulting into the formationof 6-sulfatoxymelatonin [43] In a recent experimental studyit was shown that there were an increased number of MT1receptors patients as compared to MT2 receptors where noalteration has been shown in the SCN of depressed person[51] It also has an affinity for a third melatonin receptor con-sidered to represent a membrane-bound receptor (MT3)


Table1Prop

osed

neurop

rotectivetherapies

forT

BIandSC

Iinrodent

mod

els

Mod

elNutraceuticals

Dose

Resultseffects

TBI

(1)M

ice

Minocyclin

e90

mgkg

at5m

in45m

gkg

at3h

and9h

after

TBI

Minocyclin

ewas

ableto

attenu

atethe

mem

oryim

pairm

entinan

effectiv

eand

lastingmanner[24]

(2)M

ice

Minozac

5mgkg

Minozac

attenu

ates

acuteincreaseinproinfl

ammatorycytokine

andchem

okinelevels

andredu

ces

astro

cyteactiv

ationandthelon

gerterm

neurologicinjury

[25]

(3)R

at(minus)-Ep

igallocatechin-3-gallate

01

(wv)indrinking

water

EGCG

expo

sure

before

andaft

erTB

Idecreased

DNAdamagea

ndLP

Olevelsandneuron

alcell

andNSC

apop

tosis

arou

ndthed

amaged

area

follo

wingTB

Iat1

day4daysand

7days

[26]

(4)R

atAlpha

lipoica

cid

100m

gkgpo

Itredu

cedLP

Osup

pressin

gtheM

POenzymea

ctivity

increasedNa+K

+ -AT

Pase

activ

ityIt

redu

cese

demaformationandredu

cesB

BBperm

eabilityandtherebypreservesn

euronald

amage

[20]

(5)R

atCa

ffeicacid

phenethyleste

r10120583molkg

Decreased

thee

levatedMDAlevels

also

significantly

increasedther

educed

antio

xidant

enzyme

SODandGPx

activ

itiesreduced

theimmun

oreactivity

ofdegeneratin

gneuron

sandinhibited

apop

totic

celldeathby

downregulatingcaspase3

[27]

SCI

(1)M

ice

Green

teae

xtract

25mgkgip

Redu

cedup

regu

latio

nof

TNF-120572or

IL-1120573sup

pressesN

F-120581120573activ

ation

andattenu

ates

the

expressio

nof

iNOSnitro

tyrosin

eandpo

li(A

DP-rib

osio)synthetase(PA

RS)a

ndneutroph

ilic

infiltrationwas

markedlyredu

cedandam

elioratedther

ecoveryof

limbfunctio

n[28]

(2)R

atQuercetin

incombinatio

nwith

methylpredn

isolone

(MP)

andspecific

p38M

APK

inhibitorS

B203580

02m

gkg

perd

ayInhibitedincreasesinph

osph

orylated-p38MAPK

(p-p38MAPK

)and

iNOSexpressio

nand

redu

cedther

ateo

fiNOS-po

sitivec

ellsin

ratswith

SCIredu

cedMDAcontentandincreasedSO

Dactiv

ityin

SCIrats[29]

(3)R

atMela

toninwas

administered

incombinatio

nwith

exercise

10mgkg

Sign

ificant

increase

inhind

limbmovem

entredu

cing

NOprod

uctio

nandmotor

neuron

degeneratio

nredu

cedlevelofiNOSmRN

A[30]

(4)R

at17120573-Estr

adiol

100300or

600120583

gkg

Redu

cedoligod

endrocytec

elld

eath

viainh

ibition

ofRh

oAandJN

K3activ

ationandaxon

loss[31]


Aromatic amino acid decarboxylase (AAD)

Arylalkylamine N-acetyltransferase (AANAT)

Hydroxyindole O-methyltransferase (HIOMT)

Tryptophan

5-Hydroxytryptophan

Serotonin

N-Acetylserotonin

Melatonin

Figure 1 Biochemical synthesis of melatonin Tryptophan acts asa precursor for melatonin synthesis AAD is responsible for theconversion of 5-hydroxytryptophan into serotonin Melatonin isformed from serotonin through a phase of reaction with the help oftwo enzymes AANAT andHIOMT Acetylation of serotonin occurswith the action of AANAT which forms N-acetylserotonin andsubsequently HIOMT converts N-acetylserotonin into melatonin

identical to the cytosolic enzyme quinone reductase 2 (QR2)[52] Melatonin may be used for the treatment of sleep disor-ders such as insomnia as it is having hypnotic and chrono-biotic properties [53] ROS generation is a continuous phe-nomenon in cells and the cells have their own antioxidantsystem to combat this oxidative stress which is a consequenceof free radicals and one of the pathophysiological causes ofneurological disorders [54] It is well documented in previousliteratures that the melatonin regulates the enzymes involvedin redox cycle and is a potent free radical scavenger as itsadministration maintains the ratio of GSHGSSG and LPOduring aging seen in the brain mitochondria of male as wellas female mice [19]

It has also been demonstrated that melatonin regulatesboth the electron transport chain and oxidative phosphoryla-tion bymaintaining ATP level in normal cells and also duringaging It is lipophilic in nature so it gets accumulated inthe mitochondria at higher concentration and interacts withmitochondrial membrane so as to protect the brain mitoch-ondrial membranes andmtDNA as well as electron transportchain from the damage caused by ROSRNS by radical avoid-ance accomplished without the intervention of a receptor[55]Melatonin is a broad-spectrum antioxidant and versatileas compared to its naturally occurring molecular analogs

7 Melatonin As a Neuroprotectant

The research has been in process for more than 10ndash12 yearswhich has proved melatoninrsquos beneficial effects in exper-imental models of neurodegenerative disorders and CNSinjuriesTheneuroprotective effects ofmelatonin appear to bemediated by the antioxidant capacity of this pineal hormoneThe neuroprotective effects of melatonin may also be due tothe specific interactions of its indolemoietywith its receptorsActivated melatonin receptors of the brain take part in theregulation of the levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) which has an importantrole in the maintenance of neuronal cells and is widelydistributed in the central nervous system [56] Increasingmelatonin bioavailability decreased the severity of hemi-Par-kinson conditions caused by 6-OHDA

It has been reviewed that melatonin plays a great role inantiapoptotic activities via the inhibition of intrinsic apop-totic pathways and the activation of several signal pathways instroke Alzheimerrsquos disease Parkinsonrsquos disease (PD) Hunt-ingtonrsquos disease and amyotrophic lateral sclerosis [57] Inan experimental study it was concluded that post-treatmentprocess with melatonin individually or in combination withuridine can reduce posttraumatic edema in various brainregions in traumatic brain injury model [56] In an experi-mental study it was evaluated that the treatment with mela-tonin (5 and 10mgkg ip) improved the survival rate in astroke model of mice and restored the integrity of BBB bymitigating the effect of ROS production and gp91phox cellinfiltration [58] Melatonin has been evaluated to be effectivein TBIwhere it decreases brain edema BBB permeability andintercranial pressure and significantly increased superoxidedismutase (SOD) and glutathione peroxidase (GPx) activitieswhereas decreased malondialdehyde levels [59]

Melatonin has been shown to be protective in Parkin-sonrsquos disease (PD) as it is tested in an experimental studythat in combination with silymarin it provides neuropro-tection against manganese ethylenebisdithiocarbamate and111015840-dimethyl-441015840-bipyridinium (paraquat) induced PD [60]Melatonin plays a significant neuroprotective role in mitigat-ing the cognitive impairment induced by sleep deprivation(SD) and also restores the levels of oxidative stress markersincluding NO and MDA as well as SOD activity [23]

8 Melatonin As an Antioxidant

Melatonin as well as several of its metabolites is proved to bean effective antioxidant as its antioxidative property is alsosynergised by its metabolites formed from the free radicalscavenging and also functions as an efficient radical scav-enger [42] Melatonin undergoes oxidation reaction resultingin the formation of cyclic 3-hydroxymelatonin (C3-OHM)which functions as a radical scavenger and scavenges two∙OH resulting into the formation of N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) [61] AFMK is also formeddirectly from the melatonin when melatonin reacts withH2

O2

AMK (N1-acetyl-5-methoxykynuramine)may even bea potent free radical scavenger of nitric oxide (NO) comparedto its precursor AFMK which is formed from AFMK via


2(hydroxyl radical)

2(hydroxyl radical)

Melatonin

Cyclic

3-hydroxymelatonin

(C3-OHM)

N1-Acetyl-N2-formyl-5-

(AFMK)

N(1)-Acetyl-5-

methoxykynuramine (AMK)

methoxykynuramine

Figure 2 Mechanism for the formation of metabolites by oxidativepyrrole ring cleavage of melatonin forming a primary metaboliteAFMKThe secondary metabolite AMK has potent radical scaveng-ing properties as compared to AFMK formed during the oxidationof melatonin by hydroxyl radicals (∙OH) as a result of pyrrole ringcleavage

pyrrole ring cleavage [43] (Figure 2) In a recent experimen-tal research it was concluded that oral administration ofmelatonin (10mgkg) induced a significant decrease in brainmalonaldehyde (MDA) level and raised brain glutathioneperoxidase activity against diazinon induced neurotoxicity[62] It is also documented that melatonin (5 and 20mgkgip) was effective against the increase in reactive species andprotein carbonyl levels as well as the inhibition of superoxidedismutase activity [63] Exposure of animals to melatonindecreased LPO restored GSH content and mitigated theactivities of CAT SOD and GPx in the brain from cholestaticanimals The neuroprotective effect of melatonin was shownto be more evident in the cortical and cerebral areas where itreduced the MDA content [64]

It is well documented in a number of studies that CNSis susceptible to oxidative stress or nitrosative stress causedby ROSRNS which may cause neuronal damage if the severeeffects of ROS are not suppressed or if they are not eliminatedMelatonin is an endogenously occurring hormone and isalso considered as a potent antioxidant which protects thevarious organs of the body via its antioxidative mechanismMelatonin is capable of scavenging a variety of ROS and RNSincluding hydroxyl radical (HO∙) superoxide anion radical(O2

∙minus) hydrogen peroxide (H2

O2

) nitric oxide (NO∙) andperoxynitrite anion (ONOOminus) and at the same time it alsoactivates several antioxidant enzymes including glutathioneperoxidase superoxide dismutase and catalase From this it

can be concluded that melatonin has been used as an antiox-idant from many years and several of its metabolites are alsoable to protect cells from oxidative damage caused by reactivespecies and it amplifies the antioxidant capacity of melatonin

9 Neuroprotective Mechanisms ofMelatonin in TBI

91 Reduced Inflammation Inflammation after the mechan-ical insult exacerbates the devastating effects of CNS injuryCNS injury such as SCI produces a marked neuroinflamma-tory response characterized by influx of monocytes such asmacrophages and neutrophils activation of microglial cellsand astrocytes which contribute to the secondary patho-logical and inflammatory response upregulation of proin-flammatory cytokines such as IL-1120572 IL-1120573 IL-6 TNF-120572interferon-Y and intracellular adhesion molecules (ICAM-1) and also contributed to neuroinflammation which havecontributed to facilitate CNS inflammatory responses byinducing expression of ROS such as superoxide radical andnitric oxide (NO) and chemokines which inhibit the processof neurogeneration and also exacerbate cerebral damage infl-ammation of which has a great role in the pathogenesis ofsecondary injury in TBI [65 66] It has been reported thatmelatonin has a potential role in deactivating the release ofproinflammatory cytokines in TBI [43]

92 Reduced Edema Cerebral edema is the critical factorinvolved in the pathogenesis of secondary injury in TBIDifferent reasons have been suggested for the occurrence ofedema in TBI such as swelling of damaged cells and injuryto blood vessels that forces fluid to enter the various regionsof brain and blood-brain barrier breakdown and increase ofendothelium permeability and vascular permeability Cere-bral edema can be classified into twomain categories namelycytotoxic edema (closed barrier) or vasogenic edema (openbarrier) Vasogenic brain edema is characterized by thestructural and functional disruption of the blood-brain bar-rier and involves accumulation of proteins due to increasedpermeability of endothelial cells to albumin dextran and soforth whereas cytotoxic edema is the result of cellular uptakeand cell swelling without interfering the integrity of blood-brain barrier Cerebral edema when left untreated results inan increase in intracranial pressure that may lead to limitingcerebral perfusion oxygenation of the tissue distortionherniation and even death [67] Previous studies have shownthat administration of melatonin after TBI in albino N-Maryrats model decreases brain edema BBB permeability andICP at 72 h after TBI at low as well as high dose [59] In ananother study administration ofmelatonin (200mgkg) bothindividually and in combination with uridine reduced post-traumatic edema in various brain regions of male Sprague-Dawley rat model of TBI [56]

93 Regulation of NF-120581120573 It has been well documented in aprevious study that transcription factor (NF-120581120573) has diversefunction in regulating synaptic transmission and plasticityspatial memory function and development and increased


Melatonin

CNS injury

TBI SCI

Oxidativestress

Antioxidants

ROS

Lipid peroxidationProtein oxidation

DNA damage

Receptors MT1MT2

RZRROR

Stimulating the expression of antioxidants (GPx GR and SOD)

Downregulation of iNOS

Peroxynitriteand

derivatives

Nitrosative stress

Mitochondria

Comp I Comp II Comp III Comp IV

Haber-Weiss Fenton reaction

Miochondrial dysfunction

Injury InflammationProduction of proinflammatory

cytokines and chemokines COX iNOS

to DNA and thus its translocation intonucleus

Neuroinflammation

eminus

NF-120581120573

Prevents the binding of NF-120581120573

O2

∙minus OH∙H2O2

O2

∙minus+ NO∙

NO∙

ONOO∙

Fe2+

Figure 3 Role of melatonin in several stress conditions CNS injury includes TBI and SCI which leads to oxidative stress which promotesROS at a very high level compared to that of antioxidants and plays an important role in the pathogenesis of disease ROS reacts with PUFAof lipid membranes which results in lipid peroxidation ROS can also damage DNA and protein which leads to protein oxidation and DNAdamage Melatonin acts as a radical scavenger as it reduces the level of ROS Fenton reaction leads to the production of hydroxyl radical OHassociated with mitochondrial complexes and melatonin has metal binding capacity which may form chelating compound and reduce OHgeneration Melatonin is a natural ligand for a nuclear retinoid related orphan nuclear hormone receptor superfamily RZRROR Melatonininvolves the regulation of expression antioxidant enzymes like GPx GR and SOD by involving MT1MT2 and ROR receptors Melatoninacts as an antinitrosative agent by reducing ONOO CNS injury triggers cerebral inflammation which involves NF-120581120573 which is a key playerin secondary injury Here melatonin acts as an antineuroinflammatory agent and inhibits the activation of NF-120581120573 and its binding to DNA

activation of which has been seen after different pathologicalconditions including traumatic brain injury ischemia [68]The mRNA expressions of NF-120581120573 were shown to be upregu-lated remarkably following TBI [35] Efficacy of melatonin isinvestigated in alteration of the molecular changes that occuras a result of closed head injury (CHI) Melatonin totallyblocks the late-phase activation of NF-120581120573 and decreases thatof AP-1 to half the basal level An effective dose of melatonin5mgkg has shown the significant effect bymitigating damage[69]

94 Regulation of BBB Integrity TBI can result in brain andBBB disruption resulting into increased BBB permeabilityDisruption of the BBB may lead to astrocytic dysfunctioninflammation-related mechanisms and permeability to end-ogenous proteins which may cause brain dysfunction [70

71] In a clinical study it was quantified that there was alasting focal increase in BBB permeability in up to 70 ofTBI patients [72] In a recent study it was documented thatmelatonin administration in both low and high doses can sig-nificantly decrease blood-brain barrier permeability at 72 hafter TBI [59]

95 Reduced Oxidative Damage Oxidative stress plays animportant role in the pathogenesis of secondary injury fol-lowing TBI It was evaluated in a study that the brain GSHcontent decreased significantly and TBARS level which isthe by-product of LPO increased significantly resulting intoenhanced LPO following TBI [20] LPO is the process inwhich free radicals steal electrons from the lipids and causedegradation of lipids and ultimately cell membrane Mela-tonin has been shown to be a good neuroprotectant in various


studies by suppressing oxidative stress markers and by upre-gulating endogenous antioxidants maybe due to its lipidsoluble characteristic due to which it easily crosses morpho-physiological barriers whichmakemelatonin an ideal antiox-idant and its antioxidative action is independent of receptors[52] Recently it has been found that daily administrationof melatonin after TBI increases SOD and GPX activity anddecreases the MDA level significantly within 72 h and thusprotected cerebral tissue against oxidative stress [59]

10 Neuroprotective Role of Melatonin in SCI

101 Reduced Inflammation In an experimental literatureit was demonstrated that proinflammatory cytokines suchas interleukin 1 (IL-1120572) and IL-1120573 are activated within thefew hours in SCI [73] It has been demonstrated that IL-6plays a great role in the pathogenesis of proinflammatorydamage after SCI and TNF-120572 which is having a significantrole in immune and vascular responses and is released earlyafter the inflammation plays a pivotal role in the process ofinflammation by increasing the number of inflammatory andimmune cells to the injured site [33] Activation of NF-120581120573signalling pathway has been shown to be important for theinduction of inflammation and a pathophysiologic cause ofspinal cord inflammatory response after injury and it alsotakes part in the generation of ROS and prostaglandins (COXand iNOS) which act to synergise the effects of inflammation[33] In an experimental literature it was concluded that thelevels of the p65 subunit protein in the nuclear fractions ofthe spinal cord tissue were significantly increased at 24 h afterSCI [28] In response to the inflammation proinflammatorycytokines the invasion of neutrophils and CNSmacrophagesis shown to be greater in spinal cord [74] Melatonin which isan endogenous hormone produced by tryptophan shows itspotency of neuroprotection suppresses the expression of NF-120581120573 regulated adhesionmolecules and reduces the productionof proinflammatory cytokines [75] If we consider the find-ings during the past few years then there are strong evidencesof this hormone that it could be a key player in preventingthe severity of secondary damage which could lead to theneuronal death by improving the recovery function in injur-ed neuronal cells [76] It has been well documented thatmelatonin is also protective against the devastating effectsof inflammation by reduction of the production of severalproinflammatory cytokines thus preventing neurons whichresults from the various neurological disorders [77] Inanother study it was concluded that melatonin treatment waseffective in reducing the activation of inflammation and tissueinjury in an animal model of spinal cord injury [78]

102 Regulation of iNOS Nitric oxide (NO)which is a neuro-transmitter as well as a free radical is able to form peroxyni-trite (ONOOminus) by reacting with superoxide forming a morepotent and devastating oxidant [79] NOS exists in threegenetically different isoforms neuronal NOS (nNOS NOSI)located within central and peripheral neurons and someother types of cell inducible NOS (iNOS NOS II) whichis Ca2+-calmodulin independent enzyme associated mainly

with macrophages and microglial cells and endothelial NOS(eNOS NOS III) expressed within vessel endothelia [30 8081] Nitric oxide is produced from L-arginine-NO pathwayby the NO synthase involving NADPH and O

2

and NO isinvolved in several cellular functions such as neurotrans-mission regulation of vascular tone apoptosis and immunesystem [82] In an experimental study it was investigated thatall SCI groups showed an upregulated iNOS mRNA expres-sion in damaged regions of the spinal cord compared withanimals with an intact spinal cord and highest expressionof iNOS mRNA was detected at 3 days after injury and itwas shown that administration of melatonin 10mgkg bodyweight significantly diminished iNOS expression and NOproduction [30]

103 Regulation ofMAPK Mitogen-activated protein kinases(MAPKs) which play important roles in cell signalling andgene expression consist of the extracellular signal-regulatedprotein kinase (ERK) c-Jun N-terminal kinase (JNK) andp38 pathways in which p38 MAPK is regarded as a stress-induced kinase [83 84] In a study a significant increase inphosphorylated-pERK12 levels was observed in mice modelof SCI [85] In an experimental study it was reported that 24 hpostspinal cord trauma a dose of 50mgkgmelatonin reducedactivation of MAPKs p38 JNK and ERK12 [86]

104 Reduced Oxidative Stress Oxidative stress by free rad-ical generation and LPO are the hallmarks of secondaryinjury caused by SCI In recent years much attention hasbeen focused on oxidative stress cascade leading to secondaryinjury after SCI because inhibition of the deleterious effects ofit is thought to be one of the mainmechanisms of therapeuticinterventions [87] ROS and RNS are the free radicals whichcause devastating effects in biological system [88] Recentlyit has been shown that MDA content significantly increasedat 1 day after injury and reached a peak value at 7 days inthe SCI group and SOD activity was significantly reducedin the SCI group at 1 day From 1 to 14 days SOD activitywas significantly reduced in the SCI group [29] Melatoninand its metabolic derivatives have been documented to be aneffective direct free radical scavenger and also stimulate theactivities of several endogenous antioxidative enzymes [89]In a SCI model of Wistar albino rats MDA level was foundto be increased in spinal cord in SCI group of animals whiletreatment with melatonin attenuated the elevated levels inMDA level in spinal cord tissue SCI has also been shownto cause a significant decline in GSH level whereas treatmentwith melatonin (10mgkg) was able to restore the decreasedlevel of GSH level in spinal cord tissue [90]

11 Adverse Effects of Melatonin

Melatonin is a hormone which is the main secretory productof pineal gland and has been shown to exhibit antioxidantproperties by increasing intracellular antioxidants activity oracting as a direct radical scavenger However recent evidencesindicate that melatonin is also able to generate intracellularROS [91 92] The deleterious effect of melatonin is not much


explored even though it can cross cell membranes due to itsamphilicity as it has been shown to decrease intracellular freethiols by melatonin [93] It has been explored that the activityof intracellular activity GSH reduced due to melatonintreatment in U937 cells which is correlated to its ability toproduce intracellular ROS after a certain time period [91]ROSmay be involved in inducing apoptosis as seen in variousstudies and thus act as a prooxidant as well as a proapoptoticfactor for causing apoptosis [94 95] Various studies on anti-apoptotic activity of melatonin are reported in which theadministration of exogenousmelatonin has been shown to beeffective in preventing normal cells from apoptosis in in vitro[96 97] as well as in vivo [98] But research reports also indi-cate melatonin has been reported to have proapoptotic andcytotoxic features in several cancer cells including the humanmyeloid cell line HL-60 [99ndash101] Its cytotoxicity in Caco-2cells in certain concentration range has been well proved in arecent study [102] In a study it was shown that melatonin inJurkat cells was responsible for prooxidant activity [103]

12 Protective Role of Melatonin in Human

Melatonin has been shown to be effective in neuroprotectionin various animal models [104ndash107] However a number ofscientific literatures have also investigated the neuroprotec-tive role of melatonin in human Melatonin which is themain secretory body of pineal gland is believed to be animportant part in sleepwake cycle regulation and also thesleep disorder in old age people [108] The biological clock inthe hypothalamic suprachiasmatic nucleus (SCN) regulatesmelatonin secretion by the pineal gland as well as circadianrhythm regulation [109] Endogenous melatonin as well asexogenous melatonin has been seen to be effective in com-bating oxidative stress in brain It has long been well reportedthat the level of endogenous CSF melatonin increases in TBIpatients to suppress the level of oxidants which has a directlink in the pathogenesis of brain injury [110] In a double blindstudy melatonin seemed to be effective in treating Alzheimertype dementia (ATD) which is a progressive fatal neurode-generative [109] Delirium is a common neuropsychiatriccondition which has shown to be decreased by exogenoussupplementation of melatonin in elderly patients [108]

In conclusion melatonin has been documented to be apotent neuroprotective agent in rodent models of traumaticbrain injury and spinal cord injuryMelatonin which is secre-ted by the pineal gland is a powerful scavenger of reactiveoxygen species Additionally melatonin is able to increase theactivity and expression of antioxidant enzyme activity underboth physiological conditions of elevated oxidative stress Itsinherent property of crossing the blood-brain barrier makesit more effective in mediating neuroprotection

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The Grant (no F 30-12013(SA-II)RA-2012-14-GE-WES-2400) received as ResearchAward (2012-14) from theUniver-sity Grants Commission (UGC) New Delhi Government ofIndia to Dr Suhel Parvez is thankfully acknowledged MeharNaseem is grateful to UGC for financial grant (MaulanaAzad National Fellowship sanction no MANF-2013-14-MUS-JHA-30114)

References

[1] S Samantaray N P Thakore D D Matzelle A Varma S KRay and N L Banik ldquoNeuroprotective drugs in traumatic CNSinjuryrdquoThe Open Drug Discovery Journal vol 2 no 3 pp 174ndash180 2010

[2] O G Bhalala M Srikanth and J A Kessler ldquoThe emergingroles ofmicroRNAs inCNS injuriesrdquoNature ReviewsNeurologyvol 9 no 6 pp 328ndash339 2013

[3] H Kim M J Cooke and M S Shoichet ldquoCreating permissivemicroenvironments for stem cell transplantation into the cen-tral nervous systemrdquo Trends in Biotechnology vol 30 no 1 pp55ndash63 2012

[4] S Samantaray A Das N P Thakore et al ldquoTherapeutic poten-tial of melatonin in traumatic central nervous system injuryrdquoJournal of Pineal Research vol 47 no 2 pp 134ndash142 2009

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

[6] A R khalatbary T TiraihiM B Boroujeni H AhmadvandMTavafi and A Tamjidipoor ldquoEffects of epigallocatechin gallateon tissue protection and functional recovery after contusivespinal cord injury in ratsrdquo Brain Research vol 1306 pp 168ndash1752010

[7] O A Aiyegoro and A I Okoh ldquoPreliminary phytochemicalscreening and in vitro antioxidant activities of the aqueousextract of Helichrysum longifolium DCrdquo BMC Complementaryand Alternative Medicine vol 10 article 21 2010

[8] K Dohi H Ohtaki T Nakamachi et al ldquoGp91119901ℎ119900119909 (NOX2)in classically activated microglia exacerbates traumatic braininjuryrdquo Journal of Neuroinflammation vol 7 article 41 2010

[9] Y Han S DeMorrow P Invernizzi et al ldquoMelatonin exertsby an autocrine loop antiproliferative effects in cholangiocar-cinoma its synthesis is reduced favoring cholangiocarcinomagrowthrdquo American Journal of Physiology Gastrointestinal andLiver Physiology vol 301 no 4 pp G623ndashG633 2011

[10] K Jomova D Vondrakova M Lawson and M Valko ldquoMetalsoxidative stress and neurodegenerative disordersrdquo Molecularand Cellular Biochemistry vol 345 no 1-2 pp 91ndash104 2010

[11] A Clausen S Doctrow and M Baudry ldquoPrevention of cogni-tive deficits and brain oxidative stress with superoxide dismu-tasecatalasemimetics in agedmicerdquoNeurobiology of Aging vol31 no 3 pp 425ndash433 2010

[12] T B Kryston A B Georgiev P Pissis and A G GeorgakilasldquoRole of oxidative stress and DNA damage in human car-cinogenesisrdquo Mutation ResearchFundamental and MolecularMechanisms of Mutagenesis vol 711 no 1-2 pp 193ndash201 2011

[13] S Waldbaum and M Patel ldquoMitochondrial dysfunction andoxidative stress a contributing link to acquired epilepsyrdquoJournal of Bioenergetics and Biomembranes vol 42 no 6 pp449ndash455 2010


[14] 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

[15] M-J Tsai J-F Liao D-Y Lin et al ldquoSilymarin protects spinalcord and cortical cells against oxidative stress and lipopolysac-charide stimulationrdquo Neurochemistry International vol 57 no8 pp 867ndash875 2010

[16] R H Scannevin S Chollate M-Y Jung et al ldquoFumaratespromote cytoprotection of central nervous system cells againstoxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathwayrdquo Journal of Pharmacology and ExperimentalTherapeutics vol 341 no 1 pp 274ndash284 2012

[17] T Itoh T Satou S Nishida et al ldquoEdaravone protects againstapoptotic neuronal cell death and improves cerebral functionafter traumatic brain injury in ratsrdquo Neurochemical Researchvol 35 no 2 pp 348ndash355 2010

[18] 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

[19] M Carretero G Escames L C Lopez et al ldquoLong-term mela-tonin administration protects brain mitochondria from agingrdquoJournal of Pineal Research vol 47 no 2 pp 192ndash200 2009

[20] H Z Toklu T Hakan N Biber S Solakoglu A V Oguncand G Sener ldquoThe protective effect of alpha lipoic acid againsttraumatic brain injury in ratsrdquo Free Radical Research vol 43 no7 pp 658ndash667 2009

[21] F Maghool M Khaksari and A Siahposht Khachki ldquoDif-ferences in brain edema and intracranial pressure followingtraumatic brain injury across the estrous cycle involvement offemale sex steroid hormonesrdquo Brain Research vol 1497 pp 61ndash72 2013

[22] A RKhalatbary andHAhmadvand ldquoAnti-inflammatory effectof the epigallocatechin gallate following spinal cord trauma inratrdquo Iranian Biomedical Journal vol 15 no 1-2 pp 31ndash37 2011

[23] L Zhang H-Q Zhang X-Y Liang H-F Zhang T Zhang andF-E Liu ldquoMelatonin ameliorates cognitive impairment inducedby sleep deprivation in rats role of oxidative stress BDNF andCaMKIIrdquo Behavioural Brain Research vol 256 pp 72ndash81 2013

[24] E Siopi G Llufriu-Daben F Fanucchi M Plotkine CMarchand-Leroux and M Jafarian-Tehrani ldquoEvaluation of latecognitive impairment and anxiety states following traumaticbrain injury in mice the effect of minocyclinerdquo NeuroscienceLetters vol 511 no 2 pp 110ndash115 2012

[25] E Lloyd K Somera-Molina L J van Eldik D M Wattersonand M S Wainwright ldquoSuppression of acute proinflammatorycytokine and chemokine upregulation by post-injury admin-istration of a novel small molecule improves long-term neu-rologic outcome in a mouse model of traumatic brain injuryrdquoJournal of Neuroinflammation vol 5 article 28 2008

[26] T Itoh M Imano S Nishida et al ldquoEpigallocatechin-3-gallate increases the number of neural stem cells around thedamaged area after rat traumatic brain injuryrdquo Journal of NeuralTransmission vol 119 no 8 pp 877ndash890 2012

[27] 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

[28] I Paterniti T Genovese C Crisafulli et al ldquoTreatment withgreen tea extract attenuates secondary inflammatory response

in an experimental model of spinal cord traumardquo Naunyn-Schmiedebergrsquos Archives of Pharmacology vol 380 no 2 pp179ndash192 2009

[29] Y Song J Liu F Zhang J Zhang T Shi and Z Zeng ldquoAntiox-idant effect of quercetin against acute spinal cord injury inrats and its correlation with the p38MAPKiNOS signalingpathwayrdquo Life Sciences vol 92 no 24ndash26 pp 1215ndash1221 2013

[30] K Park Y Lee S Park et al ldquoSynergistic effect of melatoninon exercise-induced neuronal reconstruction and functionalrecovery in a spinal cord injury animal modelrdquo Journal of PinealResearch vol 48 no 3 pp 270ndash281 2010

[31] J Y Lee S Y Choi T H Oh and T Y Yune ldquo17120573-estradiolinhibits apoptotic cell death of oligodendrocytes by inhibitingRhoa-JNK3 activation after spinal cord injuryrdquo Endocrinologyvol 153 no 8 pp 3815ndash3827 2012

[32] M B Leal-Filho ldquoSpinal cord injury from inflammation to glialscarrdquo Surgical Neurology International vol 2 article 112 2011

[33] L Mao H Wang L Qiao and X Wang ldquoDisruption of Nrf2enhances the upregulation of nuclear factor-kappaB activitytumor necrosis factor-120572 and matrix metalloproteinase-9 afterspinal cord injury inmicerdquoMediators of Inflammation vol 2010Article ID 238321 10 pages 2010

[34] R E White M Rao J C Gensel D M McTigue B K Kasparand L B Jakeman ldquoTransforming growth factor 120572 transformsastrocytes to a growth-supportive phenotype after spinal cordinjuryrdquo Journal of Neuroscience vol 31 no 42 pp 15173ndash151872011

[35] G Chen S Zhang J Shi J AiMQi andCHang ldquoSimvastatinreduces secondary brain injury caused by cortical contusionin rats possible involvement of TLR4NF-120581B pathwayrdquo Experi-mental Neurology vol 216 no 2 pp 398ndash406 2009

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

[37] C A OrsquoConnor I Cernak and R Vink ldquoBoth estrogenand progesterone attenuate edema formation following diffusetraumatic brain injury in ratsrdquo Brain Research vol 1062 no 1-2pp 171ndash174 2005

[38] N Tas B BakarMO Kasimcan et al ldquoEvaluation of protectiveeffects of the alpha lipoic acid after spinal cord injury an animalstudyrdquo Injury vol 41 no 10 pp 1068ndash1074 2010

[39] R J Reiter D-X Tan M P Terron L J Flores andZ Czarnocki ldquoMelatonin and its metabolites new find-ings regarding their production and their radical scavengingactionsrdquo Acta Biochimica Polonica vol 54 no 1 pp 1ndash9 2007

[40] J B Zawilska D J Skene and J Arendt ldquoPhysiology andpharmacology of melatonin in relation to biological rhythmsrdquoPharmacological Reports vol 61 no 3 pp 383ndash410 2009

[41] D-X Tan L CManchester E Sanchez-Barcelo M DMediav-illa and R J Reiter ldquoSignificance of high levels of endogenousmelatonin in mammalian cerebrospinal fluid and in the centralnervous systemrdquo Current Neuropharmacology vol 8 no 3 pp162ndash167 2010

[42] Y Zhao D-X Tan Q Lei et al ldquoMelatonin and its potentialbiological functions in the fruits of sweet cherryrdquo Journal ofPineal Research vol 55 no 1 pp 79ndash88 2013

[43] E Esposito and S Cuzzocrea ldquoAntiinflammatory activity ofmelatonin in central nervous systemrdquo Current Neuropharma-cology vol 8 no 3 pp 228ndash242 2010

[44] A Galano D X Tan and R J Reiter ldquoMelatonin as a naturalally against oxidative stress a physicochemical examinationrdquoJournal of Pineal Research vol 51 no 1 pp 1ndash16 2011


[45] G M Brown D P Cardinali and S R Pandi-PerumalldquoMelatonin and mental illnessrdquo in Sleep and Mental Illness SR Pandi-Perumal andM Kramer Eds pp 119ndash129 CambridgeUniversity Press Cambridge UK 2010

[46] M F McCarty ldquoMinimizing the cancer-promotional activityof cox-2 as a central strategy in cancer preventionrdquo MedicalHypotheses vol 78 no 1 pp 45ndash57 2012

[47] R Santoro M Marani G Blandino P Muti and S StranoldquoMelatonin triggers p53119878119890119903 phosphorylation and prevents DNAdamage accumulationrdquoOncogene vol 31 no 24 pp 2931ndash29422012

[48] A Mehta and G Kaur ldquoPotential role of melatonin in pre-vention and treatment of oral carcinomardquo Indian Journal ofDentistry vol 5 Supplement pp 56ndash61 2014

[49] B V Jardim L C Ferreira T F Borin et al ldquoEvaluation ofthe anti-angiogenic action of melatonin in breast cancerrdquo BMCProceedings vol 7 supplement 2 p P11 2013

[50] D P Cardinali V Srinivasan A Brzezinski and G M BrownldquoMelatonin and its analogs in insomnia and depressionrdquo Journalof Pineal Research vol 52 no 4 pp 365ndash375 2012

[51] Y-HWu J Ursinus J-N Zhou et al ldquoAlterations of melatoninreceptors MT1 and MT2 in the hypothalamic suprachiasmaticnucleus during depressionrdquo Journal of Affective Disorders vol148 no 2-3 pp 357ndash367 2013

[52] S R Pandi-Perumal A S Bahammam G M Brown et alldquoMelatonin antioxidative defense therapeutical implications foraging and neurodegenerative processesrdquo Neurotoxicity Resea-rch vol 23 no 3 pp 267ndash300 2013

[53] I Kostoglou-Athanassiou ldquoTherapeutic applications of mela-toninrdquoTherapeutic Advances in Endocrinology and Metabolismvol 4 no 1 pp 13ndash24 2013

[54] K Shinozuka M Staples and C V Borlongan ldquoMelatonin-based therapeutics for neuroprotection in strokerdquo InternationalJournal of Molecular Sciences vol 14 no 5 pp 8924ndash8947 2013

[55] P Sarti M C Magnifico F Altieri D Mastronicola and MArese ldquoNew evidence for cross talk between melatonin andmitochondria mediated by a circadian-compatible interactionwith nitric oxiderdquo International Journal of Molecular Sciencesvol 14 no 6 pp 11259ndash11276 2013

[56] S V Kabadi and T J Maher ldquoPosttreatment with uridine andmelatonin following traumatic brain injury reduces edema invarious brain regions in ratsrdquo Annals of the New York Academyof Sciences vol 1199 pp 105ndash113 2010

[57] X Wang ldquoThe antiapoptotic activity of melatonin in neurode-generative diseasesrdquo CNS Neuroscience amp Therapeutics vol 15no 4 pp 345ndash357 2009

[58] C-M Chern J-F Liao Y-HWang andY-C Shen ldquoMelatoninameliorates neural function by promoting endogenous neuro-genesis through theMT2melatonin receptor in ischemic-strokemicerdquo Free Radical Biology amp Medicine vol 52 no 9 pp 1634ndash1647 2012

[59] 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 no 4pp 251ndash258 2013

[60] N K Singhal G Srivastava D K Patel S K Jain and M PSingh ldquoMelatonin or silymarin reduces maneb- and paraquat-induced Parkinsons disease phenotype in themouserdquo Journal ofPineal Research vol 50 no 2 pp 97ndash109 2011

[61] R Hardeland D-X Tan and R J Reiter ldquoKynuraminesmetabolites of melatonin and other indoles the resurrection ofan almost forgotten class of biogenic aminesrdquo Journal of PinealResearch vol 47 no 2 pp 109ndash126 2009

[62] M A Ahmed H I Ahmed and E M El-Morsy ldquoMelatoninprotects against diazinon-induced neurobehavioral changes inratsrdquo Neurochemical Research vol 38 no 10 pp 2227ndash22362013

[63] E A Wilhelm C R Jesse C F Bortolatto and C W NogueiraldquoCorrelations between behavioural and oxidative parameters ina rat quinolinic acid model of Huntingtonrsquos disease protectiveeffect ofmelatoninrdquoEuropean Journal of Pharmacology vol 701no 1ndash3 pp 65ndash72 2013

[64] A Cruz I Tunez R Martınez et al ldquoMelatonin prevents brainoxidative stress induced by obstructive jaundice in ratsrdquo Journalof Neuroscience Research vol 85 no 16 pp 3652ndash3656 2007

[65] J J Breunig M-V Guillot-Sestier and T Town ldquoBrain injuryneuroinflammation and Alzheimerrsquos diseaserdquo Frontiers in AgingNeuroscience vol 5 article 26 2013

[66] V R Feeser and R M Loria ldquoModulation of traumatic braininjury using progesterone and the role of glial cells on itsneuroprotective actionsrdquo Journal of Neuroimmunology vol 237no 1-2 pp 4ndash12 2011

[67] E Kenne A Erlandsson L Lindbom L Hillered and FClausen ldquoNeutrophil depletion reduces edema formation andtissue loss following traumatic brain injury in micerdquo Journal ofNeuroinflammation vol 9 article 17 2012

[68] O Sanz L Acarin B Gonzalez and B Castellano ldquoNF-120581Band I120581b120572 expression following traumatic brain injury to theimmature rat brainrdquo Journal of Neuroscience Research vol 67no 6 pp 772ndash780 2002

[69] 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-120581B and AP-1rdquo The FASEB Journalvol 18 no 1 pp 149ndash151 2004

[70] 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

[71] D Shlosberg M Benifla D Kaufer and A Friedman ldquoBlood-brain barrier breakdown as a therapeutic target in traumaticbrain injuryrdquo Nature Reviews Neurology vol 6 no 7 pp 393ndash403 2010

[72] O Tomkins A Feintuch M Benifla A Cohen A Friedmanand I Shelef ldquoBlood-brain barrier breakdown following trau-matic brain injury a possible role in posttraumatic epilepsyrdquoCardiovascular Psychiatry and Neurology vol 2011 Article ID765923 11 pages 2011

[73] M-F Ritz and O N Hausmann ldquoEffect of 17120573-estradiol onfunctional outcome release of cytokines astrocyte reactivityand inflammatory spreading after spinal cord injury in maleratsrdquo Brain Research vol 1203 pp 177ndash188 2008

[74] D J Donnelly and P G Popovich ldquoInflammation and its role inneuroprotection axonal regeneration and functional recoveryafter spinal cord injuryrdquo Experimental Neurology vol 209 no2 pp 378ndash388 2008

[75] M Szczepanik ldquoMelatonin and its influence on immune sys-temrdquo Journal of Physiology and Pharmacology vol 58 no 6 pp115ndash124 2007


[76] A Schiaveto-de-Souza C A da-Silva H L A Defino andE A del Bel ldquoEffect of melatonin on the functional recoveryfrom experimental traumatic compression of the spinal cordrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 348ndash358 2013

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

[78] T Genovese E Mazzon C Muia P Bramanti A de Sarroand S Cuzzocrea ldquoAttenuation in the evolution of experimentalspinal cord trauma by treatment with melatoninrdquo Journal ofPineal Research vol 38 no 3 pp 198ndash208 2005

[79] D A Drechsel A G Estevez L Barbeito and J S BeckmanldquoNitric oxide-mediated oxidative damage and the progressivedemise of motor neurons in ALSrdquo Neurotoxicity Research vol22 no 4 pp 251ndash264 2012

[80] V Calabrese C Cornelius E Rizzarelli J B Owen A TDinkova-Kostova and D A Butterfield ldquoNitric oxide in cellsurvival a JanusmoleculerdquoAntioxidants amp Redox Signaling vol11 no 11 pp 2717ndash2739 2009

[81] K Kuboyama M Tsuda M Tsutsui et al ldquoReduced spinalmicroglial activation and neuropathic pain after nerve injuryin mice lacking all three nitric oxide synthasesrdquoMolecular Painvol 7 article 50 2011

[82] P Tripathi ldquoNitric oxide and immune responserdquo Indian Journalof Biochemistry and Biophysics vol 44 no 5 pp 310ndash319 2007

[83] R-R Ji R W Gereau IV M Malcangio and G R StrichartzldquoMAP kinase and painrdquo Brain Research Reviews vol 60 no 1pp 135ndash148 2009

[84] S W Scheff M A Ansari and K N Roberts ldquoNeuroprotectiveeffect of Pycnogenol following traumatic brain injuryrdquo Experi-mental Neurology vol 239 no 1 pp 183ndash191 2013

[85] T Genovese E Esposito EMazzon et al ldquoEvidence for the roleof mitogen-activated protein kinase signaling pathways in thedevelopment of spinal cord injuryrdquo Journal of Pharmacology andExperimental Therapeutics vol 325 no 1 pp 100ndash114 2008

[86] E Esposito T Genovese R Caminiti P Bramanti R Meli andS Cuzzocrea ldquoMelatonin reduces stress-activatedmitogen-activated protein kinases in spinal cord injuryrdquo Journal of PinealResearch vol 46 no 1 pp 79ndash86 2009

[87] A F Cristante T E P de Barros Filho R M Marcon O BLetaif and I D da Rocha ldquoTherapeutic approaches for spinalcord injuryrdquo Clinics vol 67 no 10 pp 1219ndash1224 2012

[88] T Lam Z Chen M M Sayed-Ahmed A Krassioukov and AA Al-Yahya ldquoPotential role of oxidative stress on the prescrip-tion of rehabilitation interventions in spinal cord injuryrdquo SpinalCord vol 51 no 9 pp 656ndash662 2013

[89] R J Reiter L C Manchester and D-X Tan ldquoNeurotoxinsfree radical mechanisms and melatonin protectionrdquo CurrentNeuropharmacology vol 8 no 3 pp 194ndash210 2010

[90] M Ersahin Z Ozdemir D Ozsavcı et al ldquoMelatonin treatmentprotects against spinal cord injury induced functional andbiochemical changes in rat urinary bladderrdquo Journal of PinealResearch vol 52 no 3 pp 340ndash348 2012

[91] M C Albertini F Radogna A Accorsi et al ldquoIntracellular pro-oxidant activity of melatonin deprives U937 cells of reducedglutathione without affecting glutathione peroxidase activityrdquoAnnals of the New York Academy of Sciences vol 1091 pp 10ndash16 2006

[92] M Buyukavci O Ozdemir S Buck M Stout Y Ravindranathand S Savasan ldquoMelatonin cytotoxicity in human leukemiacells relation with its pro-oxidant effectrdquo Fundamental andClinical Pharmacology vol 20 no 1 pp 73ndash79 2006

[93] S Eskiocak F Tutunculer U N Basaran A Taskiran and ECakir ldquoThe effect of melatonin on protein oxidation and nitricoxide in the brain tissue of hypoxic neonatal ratsrdquo Brain andDevelopment vol 29 no 1 pp 19ndash24 2007

[94] D Gonzalez J Espino I Bejarano A B Rodriguez and JA Pariente ldquoH

2

O2

-induced caspase activation is dependentof calcium signal in HL-60 cellsrdquo Current Signal TransductionTherapy vol 25 pp 181ndash186 2010

[95] I Bejarano J Espino D Gonzalez-Flores et al ldquoRole of calciumsignals on hydrogen peroxide-induced apoptosis in humanmyeloid HL-60 cellsrdquo International Journal of Biomedical Sci-ence vol 5 no 3 pp 246ndash256 2009

[96] J I Chuang T Y Chang and H S Liu ldquoGlutathione depletion-induced apoptosis of Ha-ras-transformed NIH3T3 cells can beprevented bymelatoninrdquoOncogene vol 22 no 9 pp 1349ndash13572003

[97] F Luchetti B Canonico R Curci et al ldquoMelatonin preventsapoptosis induced by UV-B treatment in U937 cell linerdquo Journalof Pineal Research vol 40 no 2 pp 158ndash167 2006

[98] F C Munoz-Casares F J Padillo J Briceno et al ldquoMelatoninreduces apoptosis and necrosis induced by ischemiareperfu-sion injury of the pancreasrdquo Journal of Pineal Research vol 40no 3 pp 195ndash203 2006

[99] I Bejarano P C Redondo J Espino et al ldquoMelatonin inducesmitochondrial-mediated apoptosis in human myeloid HL-60cellsrdquo Journal of Pineal Research vol 46 no 4 pp 392ndash4002009

[100] S Rubio F Estevez J Cabrera R J Reiter J Loro and J Quin-tana ldquoInhibition of proliferation and induction of apoptosis bymelatonin in human myeloid HL-60 cellsrdquo Journal of PinealResearch vol 42 no 2 pp 131ndash138 2007

[101] I Bejarano J Espino C Barriga R J Reiter J A Pariente andA B Rodrıguez ldquoPro-oxidant effect of melatonin in tumourleucocytes relationwith its cytotoxic and pro-apoptotic effectsrdquoBasic and Clinical Pharmacology and Toxicology vol 108 no 1pp 14ndash20 2011

[102] A P C Batista T G da Silva A A C Teixeira et al ldquoUltra-structural aspects of melatonin cytotoxicity on Caco-2 cells invitrordquoMicron vol 59 pp 17ndash23 2014

[103] AWolfler H C Caluba PM Abuja G Dohr K Schauensteinand P M Liebmann ldquoProoxidant activity of melatonin pro-motes fas-induced cell death in human leukemic Jurkat cellsrdquoFEBS Letters vol 502 no 3 pp 127ndash131 2001

[104] E-J Lee M-Y Lee H-Y Chen et al ldquoMelatonin attenuatesgray and white matter damage in a mouse model of transientfocal cerebral ischemiardquo Journal of Pineal Research vol 38 no1 pp 42ndash52 2005

[105] P-O Koh ldquoMelatonin regulates the calcium-buffering proteinsparvalbumin and hippocalcin in ischemic brain injuryrdquo Journalof Pineal Research vol 53 no 4 pp 358ndash365 2012

[106] P-O Koh ldquoMelatonin prevents down-regulation of astrocyticphosphoprotein PEA-15 in ischemic brain injuryrdquo Journal ofPineal Research vol 51 no 4 pp 381ndash386 2011

[107] M Kerman B Cirak M F Ozguner et al ldquoDoes melatoninprotect or treat brain damage from traumatic oxidative stressrdquoExperimental Brain Research vol 163 no 3 pp 406ndash410 2005


[108] T Al-Aama C Brymer I Gutmanis S M Woolmore-Goodwin J Esbaugh and M Dasgupta ldquoMelatonin decreasesdelirium in elderly patients a randomized placebo-controlledtrialrdquo International Journal of Geriatric Psychiatry vol 26 no 7pp 687ndash694 2011

[109] K Asayama H Yamadera T Ito H Suzuki Y Kudo andS Endo ldquoDouble blind study of melatonin effects on thesleep-wake rhythm cognitive and non-cognitive functions inAlzheimer type dementiardquo Journal of Nippon Medical Schoolvol 70 no 4 pp 334ndash341 2003

[110] M A Seifman A A Adamides P N Nguyen et al ldquoEndoge-nous melatonin increases in cerebrospinal fluid of patients aftersevere traumatic brain injury and correlates with oxidativestress and metabolic disarrayrdquo Journal of Cerebral Blood Flowand Metabolism vol 28 no 4 pp 684ndash696 2008

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


BioMed Research International


Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


Neural Plasticity


Parkinsonrsquos Disease


Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Psychiatry Journal


Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases


Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


highly sensitive to oxidative stress and thus oxidative damageas the oxidative stress is associated with the pathogenesis ofCNS injury such as stroke TBI and SCI

There is a balance between the oxidants and antioxidantsactivities and when there is any disturbance caused by anyenvironmental or genetic factor excessive generation of freeradicals or ROS occurs which overwhelms the endogenousantioxidant systems Free radicals are highly reactive mole-cules having one or more unpaired electrons in their outer-most orbits which result in their instability and make themmore reactive as compared to their corresponding nonradi-cals They participate in a number of reactions and form veryreactive metabolites which includes hydroxyl radical (HO∙)hydrogen peroxide (H

2

O2

) singlet oxygen and peroxyni-trite Superoxide anion radicals (O

2

∙minus) which are derivedfrom oxygen are the most commonly occurring and one ofthe strongest ROS among the cellular free radicals generatedin living systems [7 8] The superoxide radical which is con-sidered as the ldquoprimaryrdquo ROS is capable of forming secondaryROS by reacting with other molecules Superoxide dismutase(SOD) is a superoxide scavenging enzyme which plays thecentral role in amelioration of the effects of superoxideanion radicals by dismutation reaction in which it convertsO2

∙minus into nonradical species singlet oxygen and hydrogenperoxide (H

2

O2

) H2

O2

forms highly reactive hydroxyl freeradical (OH∙) via Fenton reaction which causes damage tolipid proteins and DNA which is converted into H

2

O andoxygen by an antioxidant enzyme catalase [9 10] (Figure 3)Reactive by-products of oxygen such as superoxide anionradical (O

2

minus)H2

O2

and the highly reactive hydroxyl radicals(∙OH) are formed continuously as a by-product of oxidativemetabolism catalysed by several membrane-associated res-piratory chain enzymes and considered as the major sourceof oxidative injury in all aerobic organisms [11 12]

ROS plays an important role as secondary messengers inmany intracellular signalling pathways and also as mediatorsof oxidative damage and inflammation [13] CNS has highlevels of oxygen demand and unsaturated lipid content withwhich free radicals can easily react Lipids are susceptible tooxidative stress and one of the products of oxidative damageto lipids is 4-hydroxy-2-nonenal (4-HNE) and acrolein andfree radicals can attack directly polyunsaturated fatty acidsin membranes and initiate lipid peroxidation (LPO) Thesefeatures may make the CNS a target tissue for the onset andpathogenesis of a number ofCNSdisorders via oxygen radicalproduction and LPO [14 15] It has been well documentedthat in the CNS the transcription factor nuclear factorerythroid-2-related factor 2 (Nrf2) which is the principalregulator of phase-2 cellular antioxidant response plays thecentral role in astrocyte-mediated protection of neurons fromROS [16]

3 Traumatic Brain Injury

TBI is devastating and a leading cause of injury relatedmortality and morbidity and may result in permanent func-tional impairment due to both primary which is caused bythe initial mechanical injury and secondary injury mech-anisms [1] Primary injury is the initial traumatic brain

insult the consequences of which are immediate and irre-versible disruption of neuronal cell bodies contusion vascu-lar injury and axon shearing The primary injury also resultsin tissue deformation and compression leading to seizuresrespiratory depression apnoea ischemia hypoxia parenchy-mal inflammation LPO and nitric oxide production result-ing in cellular injury [4] The secondary injury which is adelayed nonmechanical insult to brain is caused by a complexcascade of metabolic physiologic and biochemical factorsinitiated by the primary insult continuing for hours to daysafter injury that results in progressive tissue damage [5]

Na+ K+-ATPase is a membrane transport protein inmammalian cell membrane which plays an important rolein maintaining ionic homeostasis It is documented that anyderegulation in the activity of the Na+ K+-ATPase pumpmight be a common feature in CNS pathologies related toischemic conditions and TBI since the pump is highly sensi-tive to reactive species and LPO and its decreased activity willincrease the intracellular concentration of Ca2+ thus playinga synergistic role in excitotoxicity The ischemic condition ofthe brain will lead to excitotoxicity which is induced by therelease of excitatory amino acid neurotransmitters partic-ularly glutamate from neurons injured by ischemia follow-ing which the subsequent activation of glutamate receptorsresulted in a consecutive influx of Ca2+ Na+ and K+ intoneuronal cells through these receptors Devastating effectsof increased intracellular Ca2+ concentrations lead to theproduction of free radicals such as super oxide (O

2

minus) andhydroxyl radical (∙OH) and synthesis of NO peroxidationof fatty acids which can induce xanthine pathway and ulti-mately to degeneration in the cellular system and cell deathby various mechanisms such as overactivation of phospholi-pases calpains protein kinases and endonucleases [17 18]

Brain has low level of antioxidant system and high oxida-tive utilization (20 of the total oxygen inspired) as well ashigh level of polyunsaturated fatty acids (PUFA) transitionmetals such as iron which is involved in the generationof the hydroxyl radical as compared to other organs whichmake it more susceptible to oxidative stress [19] PUFA isvery sensitive to free radicals which directly react with it andinitiate LPO during this process more radicals are formedwhich will disintegrate PUFA into a number of reactiveproducts which will cause cellular damage The deleteriouseffect of secondary injury to the brain revealed a numberof experimental studies and oxidative stress which generatesROS one of the main cause of pathophysiologic processesafter brain trauma including mitochondrial dysfunction lea-ding to energy failure production of a large number of toxicand proinflammatory molecules increase in intracranialpressure and a subsequent decrease in cerebral perfusionleading to ischemia astrocyte dysfunction ATP depletionproteolysis and vasogenic edema [20] Cerebral edema inTBI leads to exacerbating the severity of brain trauma byincreasing intercranial pressure (ICP) Increased ICP is animportant factor determining the outcomes of TBI patientsand therefore it is measured In an experimental study it wasconcluded that there was a significant rise in ICP in 4 and 24 hafter brain injury in TBI compared to sham [21] There are






2

minus H2

O2


2











Table1Prop

osed

neurop

rotectivetherapies

forT

BIandSC

Iinrodent

mod

els

Mod

elNutraceuticals

Dose

Resultseffects

TBI

(1)M

ice

Minocyclin

e90

mgkg

at5m

in45m

gkg

at3h

and9h

after

TBI

Minocyclin

ewas

ableto

attenu

atethe

mem

oryim

pairm

entinan

effectiv

eand

lastingmanner[24]

(2)M

ice

Minozac

5mgkg

Minozac

attenu

ates


ammatorycytokine

andchem

okinelevels

andredu

ces

astro

cyteactiv

ationandthelon

gerterm

neurologicinjury

[25]

(3)R

at(minus)-Ep


01

(wv)indrinking

water

EGCG

expo

sure

before

andaft

erTB

Idecreased

DNAdamagea

ndLP

Olevelsandneuron

alcell

andNSC

apop

tosis

arou

ndthed

amaged

area

follo

wingTB

Iat1

day4daysand

7days

[26]

(4)R

atAlpha

lipoica

cid

100m

gkgpo

Itredu

cedLP

Osup

pressin

gtheM

POenzymea

ctivity

increasedNa+K

+ -AT

Pase

activ

ityIt

redu

cese


cesB

BBperm


euronald

amage

[20]

(5)R

atCa

ffeicacid

phenethyleste

r10120583molkg

Decreased

thee

levatedMDAlevels

also

significantly

increasedther

educed

antio

xidant

enzyme

SODandGPx

activ

itiesreduced

theimmun

oreactivity

ofdegeneratin

gneuron

sandinhibited

apop

totic

celldeathby


[27]

SCI

(1)M

ice

Green

teae

xtract

25mgkgip

Redu

cedup

regu

latio

nof

TNF-120572or

IL-1120573sup

pressesN

F-120581120573activ

ation

andattenu

ates

the

expressio

nof

iNOSnitro

tyrosin

eandpo

li(A

DP-rib

osio)synthetase(PA

RS)a

ndneutroph

ilic

infiltrationwas

markedlyredu

cedandam

elioratedther

ecoveryof

limbfunctio

n[28]

(2)R

atQuercetin

incombinatio

nwith

methylpredn

isolone

(MP)

andspecific

p38M

APK

inhibitorS

B203580

02m

gkg

perd


osph

orylated-p38MAPK

(p-p38MAPK

)and

iNOSexpressio

nand

redu

cedther

ateo

fiNOS-po

sitivec

ellsin

ratswith

SCIredu


Dactiv

ityin

SCIrats[29]

(3)R

atMela

toninwas

administered

incombinatio

nwith

exercise

10mgkg

Sign

ificant

increase

inhind

limbmovem

entredu

cing

NOprod

uctio

nandmotor

neuron

degeneratio

nredu

cedlevelofiNOSmRN

A[30]

(4)R

at17120573-Estr

adiol

100300or

600120583

gkg

Redu

cedoligod

endrocytec

elld

eath

viainh

ibition

ofRh

oAandJN

K3activ

ationandaxon

loss[31]





Tryptophan

5-Hydroxytryptophan

Serotonin

N-Acetylserotonin

Melatonin










O2



2(hydroxyl radical)

2(hydroxyl radical)

Melatonin

Cyclic

3-hydroxymelatonin

(C3-OHM)


(AFMK)

N(1)-Acetyl-5-


methoxykynuramine





O2








Melatonin

CNS injury

TBI SCI

Oxidativestress

Antioxidants

ROS


DNA damage

Receptors MT1MT2

RZRROR



Peroxynitriteand

derivatives

Nitrosative stress

Mitochondria







Neuroinflammation

eminus

NF-120581120573


O2

∙minus OH∙H2O2

O2

∙minus+ NO∙

NO∙

ONOO∙

Fe2+












2













Acknowledgments


References



































































































2

O2































Neural Plasticity










Psychiatry Journal









Journal of







2

minus H2

O2


2











Table1Prop

osed

neurop

rotectivetherapies

forT

BIandSC

Iinrodent

mod

els

Mod

elNutraceuticals

Dose

Resultseffects

TBI

(1)M

ice

Minocyclin

e90

mgkg

at5m

in45m

gkg

at3h

and9h

after

TBI

Minocyclin

ewas

ableto

attenu

atethe

mem

oryim

pairm

entinan

effectiv

eand

lastingmanner[24]

(2)M

ice

Minozac

5mgkg

Minozac

attenu

ates


ammatorycytokine

andchem

okinelevels

andredu

ces

astro

cyteactiv

ationandthelon

gerterm

neurologicinjury

[25]

(3)R

at(minus)-Ep


01

(wv)indrinking

water

EGCG

expo

sure

before

andaft

erTB

Idecreased

DNAdamagea

ndLP

Olevelsandneuron

alcell

andNSC

apop

tosis

arou

ndthed

amaged

area

follo

wingTB

Iat1

day4daysand

7days

[26]

(4)R

atAlpha

lipoica

cid

100m

gkgpo

Itredu

cedLP

Osup

pressin

gtheM

POenzymea

ctivity

increasedNa+K

+ -AT

Pase

activ

ityIt

redu

cese


cesB

BBperm


euronald

amage

[20]

(5)R

atCa

ffeicacid

phenethyleste

r10120583molkg

Decreased

thee

levatedMDAlevels

also

significantly

increasedther

educed

antio

xidant

enzyme

SODandGPx

activ

itiesreduced

theimmun

oreactivity

ofdegeneratin

gneuron

sandinhibited

apop

totic

celldeathby


[27]

SCI

(1)M

ice

Green

teae

xtract

25mgkgip

Redu

cedup

regu

latio

nof

TNF-120572or

IL-1120573sup

pressesN

F-120581120573activ

ation

andattenu

ates

the

expressio

nof

iNOSnitro

tyrosin

eandpo

li(A

DP-rib

osio)synthetase(PA

RS)a

ndneutroph

ilic

infiltrationwas

markedlyredu

cedandam

elioratedther

ecoveryof

limbfunctio

n[28]

(2)R

atQuercetin

incombinatio

nwith

methylpredn

isolone

(MP)

andspecific

p38M

APK

inhibitorS

B203580

02m

gkg

perd


osph

orylated-p38MAPK

(p-p38MAPK

)and

iNOSexpressio

nand

redu

cedther

ateo

fiNOS-po

sitivec

ellsin

ratswith

SCIredu


Dactiv

ityin

SCIrats[29]

(3)R

atMela

toninwas

administered

incombinatio

nwith

exercise

10mgkg

Sign

ificant

increase

inhind

limbmovem

entredu

cing

NOprod

uctio

nandmotor

neuron

degeneratio

nredu

cedlevelofiNOSmRN

A[30]

(4)R

at17120573-Estr

adiol

100300or

600120583

gkg

Redu

cedoligod

endrocytec

elld

eath

viainh

ibition

ofRh

oAandJN

K3activ

ationandaxon

loss[31]





Tryptophan

5-Hydroxytryptophan

Serotonin

N-Acetylserotonin

Melatonin










O2



2(hydroxyl radical)

2(hydroxyl radical)

Melatonin

Cyclic

3-hydroxymelatonin

(C3-OHM)


(AFMK)

N(1)-Acetyl-5-


methoxykynuramine





O2








Melatonin

CNS injury

TBI SCI

Oxidativestress

Antioxidants

ROS


DNA damage

Receptors MT1MT2

RZRROR



Peroxynitriteand

derivatives

Nitrosative stress

Mitochondria







Neuroinflammation

eminus

NF-120581120573


O2

∙minus OH∙H2O2

O2

∙minus+ NO∙

NO∙

ONOO∙

Fe2+












2













Acknowledgments


References



































































































2

O2































Neural Plasticity










Psychiatry Journal









Journal of



Table1Prop

osed

neurop

rotectivetherapies

forT

BIandSC

Iinrodent

mod

els

Mod

elNutraceuticals

Dose

Resultseffects

TBI

(1)M

ice

Minocyclin

e90

mgkg

at5m

in45m

gkg

at3h

and9h

after

TBI

Minocyclin

ewas

ableto

attenu

atethe

mem

oryim

pairm

entinan

effectiv

eand

lastingmanner[24]

(2)M

ice

Minozac

5mgkg

Minozac

attenu

ates


ammatorycytokine

andchem

okinelevels

andredu

ces

astro

cyteactiv

ationandthelon

gerterm

neurologicinjury

[25]

(3)R

at(minus)-Ep


01

(wv)indrinking

water

EGCG

expo

sure

before

andaft

erTB

Idecreased

DNAdamagea

ndLP

Olevelsandneuron

alcell

andNSC

apop

tosis

arou

ndthed

amaged

area

follo

wingTB

Iat1

day4daysand

7days

[26]

(4)R

atAlpha

lipoica

cid

100m

gkgpo

Itredu

cedLP

Osup

pressin

gtheM

POenzymea

ctivity

increasedNa+K

+ -AT

Pase

activ

ityIt

redu

cese


cesB

BBperm


euronald

amage

[20]

(5)R

atCa

ffeicacid

phenethyleste

r10120583molkg

Decreased

thee

levatedMDAlevels

also

significantly

increasedther

educed

antio

xidant

enzyme

SODandGPx

activ

itiesreduced

theimmun

oreactivity

ofdegeneratin

gneuron

sandinhibited

apop

totic

celldeathby


[27]

SCI

(1)M

ice

Green

teae

xtract

25mgkgip

Redu

cedup

regu

latio

nof

TNF-120572or

IL-1120573sup

pressesN

F-120581120573activ

ation

andattenu

ates

the

expressio

nof

iNOSnitro

tyrosin

eandpo

li(A

DP-rib

osio)synthetase(PA

RS)a

ndneutroph

ilic

infiltrationwas

markedlyredu

cedandam

elioratedther

ecoveryof

limbfunctio

n[28]

(2)R

atQuercetin

incombinatio

nwith

methylpredn

isolone

(MP)

andspecific

p38M

APK

inhibitorS

B203580

02m

gkg

perd


osph

orylated-p38MAPK

(p-p38MAPK

)and

iNOSexpressio

nand

redu

cedther

ateo

fiNOS-po

sitivec

ellsin

ratswith

SCIredu


Dactiv

ityin

SCIrats[29]

(3)R

atMela

toninwas

administered

incombinatio

nwith

exercise

10mgkg

Sign

ificant

increase

inhind

limbmovem

entredu

cing

NOprod

uctio

nandmotor

neuron

degeneratio

nredu

cedlevelofiNOSmRN

A[30]

(4)R

at17120573-Estr

adiol

100300or

600120583

gkg

Redu

cedoligod

endrocytec

elld

eath

viainh

ibition

ofRh

oAandJN

K3activ

ationandaxon

loss[31]





Tryptophan

5-Hydroxytryptophan

Serotonin

N-Acetylserotonin

Melatonin










O2



2(hydroxyl radical)

2(hydroxyl radical)

Melatonin

Cyclic

3-hydroxymelatonin

(C3-OHM)


(AFMK)

N(1)-Acetyl-5-


methoxykynuramine





O2








Melatonin

CNS injury

TBI SCI

Oxidativestress

Antioxidants

ROS


DNA damage

Receptors MT1MT2

RZRROR



Peroxynitriteand

derivatives

Nitrosative stress

Mitochondria







Neuroinflammation

eminus

NF-120581120573


O2

∙minus OH∙H2O2

O2

∙minus+ NO∙

NO∙

ONOO∙

Fe2+












2













Acknowledgments


References



































































































2

O2































Neural Plasticity










Psychiatry Journal









Journal of






Tryptophan

5-Hydroxytryptophan

Serotonin

N-Acetylserotonin

Melatonin










O2



2(hydroxyl radical)

2(hydroxyl radical)

Melatonin

Cyclic

3-hydroxymelatonin

(C3-OHM)


(AFMK)

N(1)-Acetyl-5-


methoxykynuramine





O2








Melatonin

CNS injury

TBI SCI

Oxidativestress

Antioxidants

ROS


DNA damage

Receptors MT1MT2

RZRROR



Peroxynitriteand

derivatives

Nitrosative stress

Mitochondria







Neuroinflammation

eminus

NF-120581120573


O2

∙minus OH∙H2O2

O2

∙minus+ NO∙

NO∙

ONOO∙

Fe2+












2













Acknowledgments


References



































































































2

O2































Neural Plasticity










Psychiatry Journal









Journal of



2(hydroxyl radical)

2(hydroxyl radical)

Melatonin

Cyclic

3-hydroxymelatonin

(C3-OHM)


(AFMK)

N(1)-Acetyl-5-


methoxykynuramine





O2








Melatonin

CNS injury

TBI SCI

Oxidativestress

Antioxidants

ROS


DNA damage

Receptors MT1MT2

RZRROR



Peroxynitriteand

derivatives

Nitrosative stress

Mitochondria







Neuroinflammation

eminus

NF-120581120573


O2

∙minus OH∙H2O2

O2

∙minus+ NO∙

NO∙

ONOO∙

Fe2+












2













Acknowledgments


References



































































































2

O2































Neural Plasticity










Psychiatry Journal









Journal of



Melatonin

CNS injury

TBI SCI

Oxidativestress

Antioxidants

ROS


DNA damage

Receptors MT1MT2

RZRROR



Peroxynitriteand

derivatives

Nitrosative stress

Mitochondria







Neuroinflammation

eminus

NF-120581120573


O2

∙minus OH∙H2O2

O2

∙minus+ NO∙

NO∙

ONOO∙

Fe2+












2













Acknowledgments


References



































































































2

O2































Neural Plasticity










Psychiatry Journal









Journal of








2













Acknowledgments


References



































































































2

O2































Neural Plasticity










Psychiatry Journal









Journal of









Acknowledgments


References



































































































2

O2































Neural Plasticity










Psychiatry Journal









Journal of























































































2

O2































Neural Plasticity










Psychiatry Journal









Journal of


















Neural Plasticity










Psychiatry Journal









Journal of


review article role of melatonin in traumatic brain...

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