Thyroid hormones: Possible roles in epilepsy pathology

Thyroid

hormones:

Possible

roles

in

epilepsy

pathology

Seyedeh

Masoumeh

Seyedhoseini

Tamijani

a,1

,

Benyamin

Karimi

b,1

,

Elham

Amini

b,1

,

Mojtaba

Golpich

b

,

Leila

Dargahi

c

,

Raymond

Azman

Ali

b

,

Norlinah

Mohamed

Ibrahim

b

,

Zahurin

Mohamed

d

,

Rasoul

Ghasemi

e,f,

**

,

Abolhassan

Ahmadiani

a,

*

a_{NeuroscienceResearchCenter,ShahidBeheshtiUniversityofMedicalSciences,Tehran,Iran} b

DepartmentofMedicine,UniversitiKebangsaanMalaysiaMedicalCentre,Cheras,KualaLumpur,Malaysia c

NeuroBiologyResearchCenter,ShahidBeheshtiUniversityofMedicalSciences,Tehran,Iran d

DepartmentofPharmacology,FacultyofMedicine,UniversityofMalaya,50603KualaLumpur,Malaysia e

DepartmentofPhysiology,FacultyofMedicine,ShahidBeheshtiUniversityofMedicalSciences,Tehran,Iran f

NeurophysiologyResearchCenter,ShahidBeheshtiUniversityofMedicalSciences,Tehran,Iran

1. Introduction

The thyroid hormones (THs), triiodothyronine (T3) and its prohormonethyroxine (T4) are important regulators of gene expression.Throughinteractionwiththyroidhormonereceptors (TRs),THsregulatecelldevelopment,homeostasis,differentiation, growth and metabolism [1]. Thyroid hormones act in the brain wherethey play an essential role in fetal and post-natal brain development as well as the maintenance of adult brain function[2].TheimportanceofTHsinthecentralnervoussystem (CNS) function is well confirmed in both neonatal and adult

hypothyroidism[reviewedin[3]].Inaddition,THspromotesCNS repair, asit hasbeendemonstrated thatCNS re-myelination is dependent on these hormones [4]. In addition,THs have non-genomic and genomic effects on mitochondrial biogenesis and function[5]anddecreasedactivityofTHsinhumansislinkedto impairedmitochondrialbiogenesisandfunction[6].Furthermore, THsabnormalitiesincludingbothhypothyroidismand hyperthy-roidism,have beenshown toinducetheproduction ofreactive oxygen species (ROS) and affect the oxidative capacity of the adult brain by modulating antioxidant enzymes [7]. THs also specificallymodulatethedevelopmentandfunctionofGABAergic interneuronsinvitroandinvivo[8,9].

Epilepsy is one of the most common chronic neurological disorders affecting people of all ages [10]. It is a disorder of recurrent and spontaneous seizures resulting clinically into permanent alterations of normal function and morphology of neuronal cells and even cell death [11,12]. Though the actual pathogenesisofepilepsyremainsunclear,accumulatingevidences indicatethatmitochondrialdysfunction[13],oxidativestress[11] ARTICLE INFO

Articlehistory:

Received25March2015

Receivedinrevisedform26July2015 Accepted27July2015

Keywords: Seizures

Temporallobeepilepsy(TLE) Hyperthyroidism

Hypothyroidism Braindevelopment Epileptogenesis

ABSTRACT

Thyroidhormones(THs)L-thyroxineandL-triiodothyronine,primarilyknownasmetabolismregulators, aretyrosine-derivedhormonesproducedbythethyroidgland.Theyplayanessentialroleinnormal centralnervoussystemdevelopmentandphysiologicalfunction.Bybindingtonuclearreceptorsand modulatinggeneexpression,THsinfluenceneuronalmigration,differentiation,myelination, synapto-genesisandneurogenesisindevelopingandadultbrains.AnyuncorrectedTHssupplydeficiencyinearly life may result in irreversible neurological and motor deficits. The development and function of GABAergic neurons as well as glutamatergic transmission are also affected by THs. Though the underlyingmolecularmechanismsstillremainunknown,theeffectsofTHsoninhibitoryandexcitatory neuronsmayaffectbrainseizureactivity.Theenduringpredispositionofthebraintogenerateepileptic seizuresleadstoacomplexchronicbraindisorderknownasepilepsy.Pathologically,epilepsymaybe accompaniedbymitochondrialdysfunction,oxidativestressandeventuallydysregulationofexcitatory glutamatergic and inhibitory GABAergic neurotransmission. Based on the latest evidence on the associationbetweenTHsandepilepsy,wehypothesizethatTHsabnormalitiesmaycontributetothe pathogenesisofepilepsy.Wealsoreviewgenderdifferencesandthepresumedunderlyingmechanisms throughwhichTHabnormalitiesmayaffectepilepsyhere.

ß2015BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.

* Corresponding authorat: Neuroscience Research Center, Shahid Beheshti UniversityofMedicalSciences,Tehran,Iran.Tel.:+9822429765.

** Correspondingauthor.Tel.:+9822439971.

E-mailaddresses:[email protected](R.Ghasemi),

[email protected](A.Ahmadiani).

1_{Theseauthorscontributedequallytothisworkandshouldbeconsideredas} co-firstauthors.

ContentslistsavailableatScienceDirect

Seizure

j o urn a lhom e pa g e :ww w . e l se v i e r. c om / l oca t e / y se i z

http://dx.doi.org/10.1016/j.seizure.2015.07.021

and failure in the regulation of excitatory (glutamate) and inhibitory (GABA) amino acids in the brain [14], are among important factors modulating its pathogenesis and seizure generation.

Knowingthatmitochondrialdysfunction,oxidativestressand GABAergic deregulation are among the main characteristic of epilepsyandthefactthattheseabnormalitiesareassociatedwith THsdeficits,allstrengthen theviewpointthat THsmightaffect epilepsypathogenesis.Thepresentreviewthereforeprovidesan overviewofrecentdevelopmentsinthefieldofTHsfunctionand its possible role in the pathogenesis of epilepsy, as a chronic neurologicaldisorder.

2. Thyroidhormones

The thyroid hormones, T3 and T4, are two tyrosine-based hormonesthataresynthesizedbythethyroidgland.Thereleaseof TH is controlled by the hypothalamic–pituitary–thyroid axis (HPTA). The hypothalamus releases thyrotropin-releasing hor-mone(TRH)whichstimulatesthepituitaryglandtoreleasethyroid stimulating hormone (TSH). TSH binds to its receptor on the thyroidglandandactivatesthesynthesisandreleaseofTHs.The majorityofTHsreleasedbythethyroidglandisT4whichisthen enzymatically deiodinated to a more potent from,T3 [15]. Al-though, THs exerts some non-genomic effects by binding to a numberofintracellulartargets,aswellasmembranereceptoron integrin

a

V

b

3[16],thesehormonesmediatetheirmainbiological functionsprimarilyatthegenomiclevel.Thegenomiceffectsof THsaremediatedbyasubgroupofthenuclearhormonereceptor (NR)familyoftheligandactivatedtranscriptionfactors.Inorderto interactwithTRs,THsmustenterthecellularnucleusandbindto TRs that are already bound toregulatory regions of thetarget genes.Toourknowledge,twomajorisoformsofTRsnamelyTR

a

andTR

b

,havebeencharacterizedwhichareencodedbyseparate genes(onhumanchromosomes17and3).Alternativesplicingof these genes, gives rise to additional heterogeneity for each memberoftheTRs (TR

a

-1and c-erbAa-2andTR

b

-1 andTR

b

-2)[reviewedin[17]].Incontrasttothenucleareffects,theextra nucleareffects,notdependent onnuclearreceptorscouldoccur withinashortperiod oftime andmaybefacilitated by signal-transducingpathwayssuchasproteinkinasesandcyclicadenosine monophosphate(cAMP)[18,19].

2.1. ThyroidhormoneinCNS

Aspreviouslymentioned,CNSisoneoftargettissuesforTHs where these hormones play an essential role in prenatal and postnatal braindevelopment as wellas themaintenance of its physiologicalfunction.Generally,theconcentrationofTHsinthe CNSismuchlessthanintheserum.Thisdifferenceiscausedbythe difficultyoftransportingTHsacrossthebloodbrainbarrier(BBB). TwomainpathwayshavebeenproposedbywhichTHscrossesthe BBBintotheCNS.Inthefirstpathway,THscrossestheBBBthrough OAT1P1CtransportersandenterastrocytesendfeetwhereT4is converted to T3, via the enzyme deiodinase 2. In the second pathway,MCT8transportershelpTHstoentertheCNS.THscan also directly enter the brain via gaps in the BBB, where the astrocytes end feet do not completely cover the capillaries [reviewedin [3]]. Like theperiphery,the centraleffects ofTHs areprimarilytriggeredbybindingtoTRsandthenrepressingor activatingthetargetgenes[20].

2.2. FunctionsofthyroidhormonesinCNS

The biological functionsofT4 and T3in theCNS havebeen widely reported. Some reports show that T4 exerts only

nongenomic effects in the brain while T3 serves as a unique agonistfornuclearTRs.However,othersshowthatTR-

a

1actsasa sensorforbothT3andT4whileTR-

b

1ismoreresponsivetoT3. Therefore, it seems that the transcription response mediated primarilybyTR-

a

1mightbetriggeredbybothT3andT4andmore pureT3effectsaremediatedbyTR-

b

1[3].

Oneofthebest-knownfunctionsofTHsintheCNSistheirrole inCNSdevelopment.Ithasbeenshownthatgestational/neonatal hypothyroidismchangescellmigrationpatternanddecreasescell number, synaptogenesis and dendritic arborization, as well as axonal myelination. These developmental defects induced by severe THs depletion are demonstrated in the cerebellum, neocortex and hippocampus, and in heavily myelinated white matter tracts, such as the corpus callosum [21]. It has been consistentlyshownthatTHsdeficiencyduringbraindevelopment (congenitalhypothyroidism)canleadtoirreversibleand progres-siveintellectualdeterioration(cretinism)andneurologicaldeficits. Mostofthesedefectscouldbepreventedbytimelydiagnosisand THsreplacementtherapy[22,23].Inadditiontotheearlystagesof life,appropriateTHssignalingalsoplaysanessentialroleinadult brainfunctions.TheimportanceofTHsin thefunction ofadult brainiswelldemonstratedinadulthypothyroidismwhichaffects thehippocampus andcortex andresultsin moodandbehavior abnormalitieslikeanxiety,anddepression-likesymptoms,aswell as memory impairment [24,25]. Adult-onset hypothyroidism reducesthenumberofnewbornneuroblastsinthedentategyrus. THs deficiency impairs adult neurogenesis particularly in the hippocampus, reduces hippocampus volumeand contributes to cognitiveproblemsinhypothyroidism[25,26].Inaddition,ithas beenrevealedthathypothyroidismisalsoassociatedwithother complicationssuchasimpairedmyelination,delayeddevelopment ofthedendritictree,reducedglialcellsandaxo-dendriticsynapses

[27,28].

3. Epilepsyanditspathologicalfeatures

Themostcharacteristicfeatureofepilepsyisacontinuousrise inneuronalexcitabilitywhichleadstoanundulysustainedand synchronous discharge of a group of neurons. In about half of epilepticpatients,nocausativefactorshavebeenfoundyetwhile in the other half, different causative factors such as oxygen deprivation,trauma,infection,tumorsandmetabolicimbalances are suggested to be involved in abnormal cellular discharges

[29].Malfunctionsofcerebralcortexdevelopmentalsoparticipate in the pathogenesis of epilepsy [30]. It has consistently been proposed thatmacro ormicroscopic corticalabnormalitiesthat mayoccurinthefirstorsecondtrimesterofpregnancycouldlead toepilepticseizures[31].Non-neuronalcellsoftheCNSsuchas microgliaandastrocytesplayapivotalroleinthemaintenanceof tissuehomeostasisandneuronalactivity.Therefore,itisbelieved that dysfunction of these cells may also participate in the pathogenesisofepilepsy[32].

Considering the essential role of THs in early fetal brain development and theprofoundeffects of THsabnormalities on brain neuronal cytoarchitecture, neurotransmitters and pro/ antioxidantsystems[33],itwouldbeconceivabletohypothesize that THs dysregulation might play a determining role in the pathogenesisofepilepsy.Intheothersectionsofthisreview,THs andtheirdysregulation,aswellashowtheymayparticipateinthe pathophysiologyofepilepsyhavebeendiscussed.

4. Thyroidhormones,adultCNSandepilepsy

Headinjuryisoneofthecausativefactorsofadultepilepsyand ontheotherhand,patientswithbraininjurieshavebeenshownto havelowerlevelsofTHs.Inpatientswithtraumaticbraininjury

(TBI), THsmetabolism is defected,and conversionof T4 tothe activeformT3catalyzedbydeiodinaseenzymebecomesimpaired. Furthermore, in the early phases of brain injury, TSH level is decreased and this might be another causative factor for THs decreased levels [reviewed in [34]]. In this regard, Crupiet al. investigatedtheeffectofT3onamurinemodelofTBIandreported thattreatmentofmicewithT3(1.2

m

g/100gbodyweight,i.p)one hourafterTBIcansignificantlyprotectagainstbraintraumaand improve motor and cognitivefunction [35]. Though the repair capabilities of thespinal cord and brain are limited,THs exert regenerativeeffectsonnervescells.Themyelinationprocesswas alsoshowntobedependentonTHsfunctioninbothperipheraland central nervous systems [4]. THs are able to induce oligoden-drocytesformationfrommultipotentneuralstemcellsand also play a role in regulating different developmental stages of oligodendrocytes[36,37].However,thepotentialprotectiveeffects ofTHsinpost-TBIseizureeventsstillremainunknown.

Inaddition,ithasbeenshownthatthyroiddeficiencyduring pregnancy and lactation make offsprings more susceptible to audiogenicconvulsion[38].Persistently,ithasalsobeenreported thatmicelackingTR

b

aremoresusceptibletoaudiogenicseizures

[39].AmongthegenesaffectedbyTHs,neurotrophicfactorsareof specialsignificance,astheyplayakeyroleinpathophysiological conditions such as seizures [40]. Neurotrophic factors exert a varietyofeffectson neuraldifferentiation,survivalandgrowth, andalsoinfluenceneurotransmittersynthesis,synapticplasticity andneuralexcitability[41].Neurotrophicfactorsthatareshownto influence epileptic conditions and seizures include fibroblast growthfactor-2(FGF-2),brainderivedneurotrophicfactor(BDNF), neurotrophin-3(NT-3),nervegrowthfactor(NGF),glialcellline derivedneurotrophicfactor(GDNF),andthevascularendothelial

growth factor (VEGF) [42]. While some studies imply that increased expression of many neurotrophic factors after brain injuryoracuteseizurescontributetotheneuroprotectionofthe injured brain [43], some others proposed that some of these neurotrophic factors such as BDNF and NGF, actually promote epileptogenic changes [44]. Itis wellknown that epileptogenic insults increase the synthesis of BDNF and activation of trkB receptors[45].Subsequently,studiesinanimalmodelsofepilepsy showanincreaseofBDNFlevelsin survivinghippocampalcells after glutamate receptor activation, at earlypost seizure delay

[46,47]. Though theprecise role of neurotropic factors in post seizurephaseisnotwelldefined,thepotentialprotectiveeffectsof THsthrough modulationof neurotrophicfactorsorothergenes expressiononseizure-inducedneuraldamageneedstobestudied.

5. Thyroidhormonesandpathogenesisofepilepsy/ epileptogenesis

5.1. Thyroidhormonesandmitochondria

Several lines of evidenceshowing that oxidativestress, free radicals and mitochondrial dysfunctionplay important roles in seizuregenerationandepileptogenesisareavailable[13,48,49].On theotherhand,THs havenon-genomic andgenomic effectson mitochondrial biogenesisandfunction[5].Accordingly,THsare showntoregulatetheexpressionoftargetgenesandeventually mitochondrial biogenesis through three different pathways (Fig.1).Inthefirstpathway,T3directlyaffectsthemitochondria throughthebindingofamitochondriallocalizedreceptor[50].A truncatedproductoftheTR

a

genenamedP43,locatedinsidethe mitochondriaprovidesbindingsitesforT3inthemitochondrial

Fig.1.SchematicrepresentationofhowTHsregulatemitochondrialfunction(biogenesis,oxygenconsumption,andgeneexpression)affectingnuclearand/ormitochondrion genome(directandindirectpathways).

inner membrane. P43 attaches to numerous thyroid hormone response element (TRE)-like sequences on the mitochondrial genomeandtriggerstranscriptioninaligand-dependentwayin thepresenceofTH[51].Consequently,ithasbeenreportedthatthe over-expression of P43 in vivo and in cell culture contexts increases protein synthesis and mitochondrial transcription

[51]. In the second pathway, T3 attaches to nuclear-localized TRs and TREs to control gene expression of nuclear-encoded proteinsthat aredestined tothemitochondriaand inthis way affect mitochondrial biogenesis [50]. In the third pathway, intermediaryfactorssuchastheperoxisomeproliferator-activated receptor gamma(PPAR

g

), nuclear respiratory factor 1 (NRF-1), NRF-2transcriptionfactors,aswellastheperoxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1

a

) and peroxisome proliferator-activated receptor gamma, coactivator 1 beta(PGC-1

b

) maybe generated byTHs and then these co-activators enter the mitochondrion where they could regulate anothergroupofTHstargetgenes[52].Therefore,itseemsthatT3 canregulatemitochondrialgenetranscriptioneitherviaadirect pathwaythroughTHsreceptoractionsorviaanindirectpathway whichincludesco-activatorsandintermediatefactors.

Asearliermentioned,besidesregulationofdevelopmentand growth, THsacts as a regulatorof energy metabolism [53]. T3 strongly increases oxygen consumption and the rate of ATP hydrolysis.Hyperthyroidismisassociatedwithanincreasedrateof oxygenconsumptioninmosttissuesexceptthosefromthetestis, spleenandadultbrain[54,55].Itisbelievedthattheprotonleak throughthemitochondrialinnermembraneisakeytargetfor THs-induced oxygen consumption. This THs mediated increase in protonpermeabilitythroughtheinnermembraneisthoughttobe achievedviadifferentmechanisms.Firstly,THsalterthe phospho-lipid composition and fluidityof themitochondrial membrane

[56].IthasbeenreportedthatwhilereductioninratTHsdecreases respiratoryrates,alpha-glycerophosphatedehydrogenaseactivity andprotonpermeability,T3replacementtherapyrestoresthese parametersafter9–12h[57].Mitochondrialuncouplingproteins (UCPs) are anion carrier proteins in the mitochondria which dissociateoxidativephosphorylationfromATPsynthesis;theyare therefore,alsoreferredtoasmitochondrialprotonleak[58]. Sev-eral lines of evidence are available showing that UCPs gene expression is increased by T3 [59–61]. Therefore, T3-induced elevationofUCPsexpressionisanothermechanismbywhichT3 increasesprotonleak[62].

Inaddition,thedecreasedactivityofTHshasbeenshowntobe associatedwithdiminishedmitochondrialfunctionandbiogenesis

[6] and interestingly, in cell lines with mitochondrial DNA (mtDNA) deficiencies, THs treatment restores mitochondrial functions [63]. These hormonal effects on mitochondria have beenexaminedindifferentbrainstructuresandhasbeenreported that mitochondria in the striatum and the cerebral cortex are sensitivetothyroidhormoneaction[64].Therefore,itseemsthat by controlling mitochondrial gene expression, THs modulates mitochondrialbiogenesisandoxidativephosphorylationcapacity incertain areasof thebrain suchas thestriatum and cerebral cortex[65].Consistently,ithasbeenevidencedthat hypothyroid-ismduringprimarymammalianbraindevelopmentisassociated withreducedexpressionofdifferentmitochondrialgenes,aswell asmitochondrialimpairment.However,thereceptortype(nuclear ormitochondrial)andtheexactmechanismsbywhichTHsexerts mitochondrialeffectsduringdevelopmentarestillunclear[66].

Compelling proofs obtained from humans and experimental seizure models show that mitochondrial dysfunction and the resulting oxidative stress contributes to the pathogenesis of chronicepilepsy[67,68].Ithasbeendemonstratedthat mitochon-drial Complex I in the brain seizure foci decreases in patients sufferingfromtemporal-lobe epilepsy(TLE) [69,70]. Ithasalso

beenshownthathippocampalcomplexIactivitydecreasedinan experimental model of status epilepticus [69]. Impaired mito-chondrial metabolism accompanied by deregulated glutamate– glutamine–GABA cycling was also observed in neurons and astrocytesofepileptogenichippocampalformations[71,72]. Col-lectively,consideringtheroleofTHs,particularlyT3,innormal mitochondrialfunctionsandtheroleofmitochondrialdysfunction inepilepticprocesses,itcanbeconcludedthatabnormalitiesin THs function may participate in the pathogenesis of epilepsy, however,moredirectstudiesareneededtoprovethishypothesis. 5.2. Thyroidhormonesandoxidativestress

Oxidativestressisanimbalance betweentheproductionof oxidant agents and antioxidant activity of defense systems

[73].Whiletheadultbraincomprisesonlyabout2%oftheentire bodymass,ituses20–35%ofthetotalabsorbedoxygeninthelung andconsumesabout25%ofthebody’sglucose[74].Mitochondria arethecorecellorganellethatusesoxygentoproduceenergy

[75].However,1–2%oftheoxygenusedbythemitochondriais incompleteandleadstotheproductionofsuperoxideradicalsin cells.InthepresenceoffreeironandthroughclassicalFenton reaction,superoxideradicalshaveahighpropensitytoreactwith hydrogenperoxideandgeneratehydroxylradicalsunlessthese superoxideradicalsaredeactivatedimmediately.Thesehydroxyl andsuperoxide radicals togetherwith thenon-radical oxygen and hydrogen peroxide species are known as reactiveoxygen species (ROS), which attack different biomolecules such as proteins, DNA and lipids and mediate the process known as oxidativestress[76].

Previous studies have suggested that ROS might play an essentialroleinthegenerationofepilepticseizures[77].Unlike nuclearDNAwhichhasahistonemediatedprotection,mtDNAhas nosuchprotection.Ontheotherhand,mtDNAislocatedadjacent totheelectrontransportchainasthemainsourceofsuperoxide radicalproduction.Therefore,mtDNAisreportedlyconsideredas an assailable target for oxidative stress [78]. As mammalian mtDNAistheencodingsourceforsomepivotalpolypeptidesofthe oxidativephosphorylationsystem,anydamagetomtDNAmight hamper the expression of these important polypeptides and eventually cause mitochondrial oxidative phosphorylation defi-ciency[79].

IthasbeenshownthatTHsdysregulation,either hyperthyroid-ismor hypothyroidism,affects antioxidant/oxidantbalanceand promoteROSgeneration[80].Inthisregard,DasandChainyhave comparedoxidativestressandantioxidantdefenseparametersof mitochondrial and post-mitochondrial fractions of rat cerebral cortex in hypothyroid, euthyroid, and hyperthyroid states and reported that the body’s thyroid state significantly affects the brain’s antioxidant defense status [7]. While hypothyroidism increases protein carbonyl and lipid peroxidation products as oxidativestressindicesinthemitochondrialfractionofthebrain, replacementofT3restorestheseparameters[76]. Hyperthyroid-ismisalsoassociatedwithincreasedoxidativestressandaffects mitochondriaastheprimarytargetofoxidativestress[81].

Thebrain’spoorantioxidantdefensesystemandhighamount of poly-unsaturated fatty acids makes it more susceptible to oxidativeattackscomparedtoothertissueslikethelungsandliver

[7].Oxidativestresshasbeenshowntobeimplicatedinavarietyof acuteconditionslikecerebralischemiaandchronicneurological conditionsincludingepilepsy[14].Evidencesaboundshowingthat oxidative impairmentof mtDNA and subsequentmitochondrial dysfunctionparticipatesin epilepticseizures[13,82,83]. Collec-tively, as both hypothyroidism and hyperthyroidism promote oxidativestressandoxidativestressplaysanessentialroleinthe pathogenesisofepilepsy,itwouldbeconceivabletohypothesize

thattheproperfunctionofTHsinthebrainmightpreventorslow downthedevelopmentofepilepticseizures.

5.3. ThyroidhormonesandGABAergicneurons

Several lines of evidence show that THs modulate the developmentandfunctionofGABAergicneurons[8,9].Aninvitro studyonfatalratbrainreportsthatdevelopmentalincreaseinthe activityofglutamicaciddecarboxylase(GAD)asthemainenzyme intheconversionofglutamicacidtoGABAcouldbeincreasedby T3 administration [84]. Experimental neonatal hypothyroidism hasalsobeenshowntodecreasetheactivityofthisenzymeinrat brain[85–87].Besidethisenzyme,activitiesofotherenzymesthat participate in GABA metabolism such as GABA-transaminase (GABA-T) and succinate semialdehyde dehydrogenase (SSDH) are alsoaffected by THs,and consequently disturbancein THs affects GABA life cycle. While induction of hypothyroidism in developingbraindecreasestheactivityofGABAgeneratingand destroyingenzymes,replacementofTHisshowntorestorethese changes.IthasbeenproposedthatimpairmentinGABAergic inter-neuronsdevelopmentmaycontributetolocomotor dysfunction and anxiety induced by THs deficits [88–91]. Effects of TH deficiencyon GABAshowcomplexityin neonatalandadultlife as induction of neonatal hypothyroidism by 131_{I injection} decreases GABAergic function in neonatal developing rat brain

[92],butincontrast,131_{Iinjectiontoadultratstoinduce} adult-onsethypothyroidismimpairstheexchangeofglutamate, gluta-mineand GABAbetweenneuronal andglial compartmentsand

increase GABA concentration [93]. Results similar to those reported in adult rats were also observed when adult-onset hypothyroidism was induced by intraperitoneal carbimazole

[94].ThisincreaseinGABAfollowingadult-onsethypothyroidism isconsistentwithreportsshowingthatGADactivityincreasesin the visual cortex following hypothyroidism [95]. Induction of hyperthyroidism by intraperitoneal T4 injection is shown to decreaseGABAandincreaseglutamatelevelsinthethalamusand hypothalamus [94]. In addition, an in vitro study on brain synaptosomesrevealedthatlownanomolarconcentrationsofT3 could increase depolarization-induced GABA release through a direct, non-genomicmechanism [96].Itis thoughtthat this T3 inducedGABAreleaseisachievedviaadirectnon-genomiceffect ofT3whichincreasesCa2+_{uptakebythesynaptosomes[97].Based} on the presented evidences, it can be summarized that THs differentially regulate the GABAergic system. THs induce or increase GABA function in developing brain, but oppose it in matured brain.Thislinkagepresentsanewfield ofresearchto elucidateiftheeffectsofTHsonGABAergicsystemscontributeto thepathogenesisofepilepsy.

Interestingly,researcheshaveprovedthatGABAalsomodulates thyroid system function [91]. Generally, GABA inhibits thyroid function at all three levels of the hypothalamus, pituitary, and thyroidaxes(Fig.2)[91].Besidethisbidirectionalinterplaybetween GABA and THs, GABA also plays an important role in seizure suppressionasaninhibitoryneurotransmitter.Thus,incontrastto adult brain, it can be presumed that THs inhibits seizures by increasingGABAergicsystemduringbraindevelopment.

Fig.2.SchematicrepresentationofthepossibleinteractionsbetweenthethyroidandGABAsystemsinvertebrates.The+andsymbolsindicatestimulationandinhibition, respectively.GABA,g-aminobutyricacid;TRH,thyrotropinreleasinghormone;TSH,thyroidstimulatinghormone;T3,triiodothyronine;T4,thyroxine.

6. Thyroidhormones,epilepsyandparticipantgenes

Different studies have founda set ofgenes whose products mightbeaffectedbyTHsorinfluenceitsfunction.Thesesetof genesisalsofoundtobeaffectedinavarietyofothersituations suchasepilepticseizures.Here,anattemptwasmadetoprovide abriefreviewonlatestevidencesaboutthegenesassociatedwith THswhicharealsoimplicatedinepilepticsituations.

A group of factors that are influenced by THs and their dysregulationcouldparticipateinepilepticconditionsis neuro-trophinsandnervegrowthfactors.Ithasbeendemonstratedthat inseizuresinducedbyamygdalakindling,expressionof neuro-trophinscouldbechanged;ontheotherhand,THshasalsobeen showntomodulatetheexpressionofthesefactors.Investigating theexpressionofneurotrophinsfollowing thedepletion ofTHs has shown that while the expression of BDNF mRNA in the hypothalamus and pituitary gland increased, theexpression of NGF andNT-3 mRNAdidnot change.In this study, amygdala-kindledseizuresdecreasedtheexpressionlevelsofNT-3mRNAin granulecelllayerofthedentategyrus,which interestinglywas reversedbyTHsreplacement[98].

Inaddition,anumberofstudieshavebeenpublishedshowing thatgeneexpressionofthyrotropin-releasinghormone(TRH)and itsreceptorareaffectedbyseizuressuggestingthatTRHmightplay arole inthepathogenesisof epilepsy[99,100]. NeuropeptideY (NPY)isanotherfactorthatiscloselyassociatedwithTHs.Onone hand,NPYisshowntonegativelymodulateTSH/T4concentration

[101] and on the other hand, it has been shown that seizure inductionalterstheexpressionofNPYanddifferentNPYreceptor subtypes[102,103].

Proteomic studieson cerebrospinalfluid(CSF)obtainedfrom TLEpatientshaveshownanincreaseinvitaminD-bindingprotein (DBP), indicating that this protein might be involved in the pathologyofepilepsy[104].Thisbindingproteinanditspartner vitamin-D are also shown tocontribute to thyroid pathologies like thyroid autoimmune diseases and thyroid tumorigenesis

[105,106].Anothersetofgenesthatparticipateintheprocessof epileptogenesis and are also affected by THs are some of the immediateearlygenes(IEGs)likeHomer1,earlygrowthresponse 1 (egr1) and activity-regulated cytoskeleton-associated protein (Arc). Prenatal propylthiouracil (PTU)-induced hypothyroidism decreasesthehippocampalandcorticalexpressionofimmediate earlygenesandindicatestheirinvolvementinbraindefectscaused by developmental hypothyroidism [107]. The immediate early genes on the other hand are shown to be over-expressed in different regions of the hippocampus and cortex of epileptic animals and therefore may play a significant role in seizure-inducedsynapticreorganization[108,109].

7. Thyroidhormones,genderdifferences,sexsteroids,and epilepsy

Theroleofsexhormonesinthedevelopmentofanimalscannot beoverlooked,especially whenitcomes todevelopmentof the brainandthecentralnervoussystem.Itiswellevidentthatsexual differentiationofthebrainleadstolastingchangesinitsstructure andfunction.Thisprocesstoagreatextentisundertheinfluenceof sexandothercirculatinghormones,aswellastheinteractionof theenvironmentandthedevelopingneurons;nutrients, medica-tionandotherchemicalsubstancesarealsoabletoinfluencethe process[110].

Epidemiological studies have suggested that males have a slightly higher incidence of epilepsy and unprovoked seizures comparedtofemales.Thoughitseemsthatmalesareatgreater riskthanfemalesforseizuresandepilepsy,thisisnotappealable for all types of epilepsies. For instance, idiopathic generalized

epilepsies(IGEs)haveahigherprevalenceinfemales[111].Several linesofevidenceshowthatsexhormones, besidetheirrolesin braindevelopmentarealsoinvolvedintheregulationofneuronal excitabilityandsurvival.Fluctuationsinsexhormonescouldaffect thepathogenesisofepilepsyandfurthermore,seizuresaffectthe function of thesexualendocrine system(reviewedin [10]). As mentionedearlier,THsareofspecialimportanceintheprocessof braindevelopmentandtherefore,itisconceivabletoassumethat sex hormones and THs interact with each other during brain development. Accordingly, it is reported that hypothyroidism prolongsthecriticalperiodforthedefeminizationprocessinduced by testosterone; on the other hand, hyperthyroidism leads to prematureterminationoftestosteronesensitivity[112].

Like steroid hormones, THs, steroids interact with their receptorstoalter genomic activityand affect proteinsynthesis duringdevelopmentandotherstagesoflife.AsisthecasewithT4, themetabolictransformationoftestosteroneandprogesteroneis criticalfortheiractions.Inaddition,THsandsexsteroidhormones differentiallyalterbrainfunctionsinadultswhencomparedtothe developmentalstages [113–115]. Anotherimportant factorthat demonstratestherelationand interactionbetweensteroidsand THs is the thyroid hormone receptor-associated protein (TRAP220).TRAP220isacoactivatorfornuclearreceptors,recruits TRAP mediator complex to the hormone responsive promoter regions and stimulates gene transcription. In other words, TRAP220enhancesthefunctionofTRs,steroidhormonereceptors, retinoic acidreceptor

a

and vitamin D receptor[116,117]. De-creased TRAP220 mRNA levels in epileptic tissue can be an indicatoroftherolethatTRAP220playsintheneuropathologyof epilepticseizures[118].Inotherstudies,boththegeneandprotein expressionlevelsofTRAP220inbrainsofepilepticpatientswere measured.Thefocuswasonthetemporallobesofpatientswith chronicpharmaco-resistantepilepsywhounderwentsurgery.The resultsshowedthatexpressionofTRAP220mRNAinthetemporal cortex was significantly reduced in epileptic patients both in mRNA and protein levels. This decrease might affect the pathophysiology of epilepsyand maybe related tosubsequent braindamageafterfrequentseizures[119,120].

Anotherimportantfactorinvolvedintheinteractionbetween THsandsteroidsisthetype3deiodinaseorD3,whichisnecessary forthematurationandfunctionofthebrain.D3hasdistinctively highexpressioninthebrainofnewbornratsandusuallyoccursin those areas of the rat brain which are involved in sexual differentiation [113,121]. D3 Deficiency profoundly alters THs availability before and afterbirth and increases its availability duringtheperinatalperiod[122–124].D3protectsthebrainfrom highdosesofT3byreducingitseffects.D3itselfisalsoregulated bytheeffectofthyroidhormonesontheTR

a

1receptorsubtype

[125,126].

Ithasalsobeenindicated thatdevelopment of CNSand sex hormonesareimportantfactorsinthesusceptibilityofthebrainto seizures.Seizuresingeneralandepilepticseizuresinparticularare morelikelytodevelopintheimmaturebrain.Maleinfantsand newborns are more likely to experience epileptic seizures or developanunprovokedseizurethanfemales.Sexualdifferences whichareexpressed inthedevelopmentofseizure-suppressing neuronalnetworkscanbeconsideredasoneofthereasonsbehind this susceptibility [127]. These observeddifferences aremostly linked to the type of epileptic disorder. For instance, gender differencewasidentifiedinidiopathicgeneralizedseizureintwo population-basedstudies;inanoutpatientstudy,thedifferences wereattributedtogenderdifferencesinjuvenileabsenceepilepsy and juvenile myoclonic epilepsy[128,129]. Aspreviously men-tioned,females ingeneralareatagreaterriskofIGEs,whichis probablybecauseoftheeffectsofsexhormones.Thisassumption issupportedbytheobservationthatIGEismorelikelytooccurin

females betweentheages of 15and 50 and before menopause

[111,130,131]. Among patients with cryptogenic localization-relatedepilepsy,womenweremorefrequent.Therefore,itseems thatnon-symptomatic epilepsymore oftenoccursin womenin contrasttosymptomaticlocalization-relatedepilepsy,whichhas preponderanceinmen.

On theotherhand, malesmay bemore vulnerabletobrain damageinducedseizure [132], anddevelopment ofgeneralized tonic–clonic seizures [133]. They are also more susceptible to developsymptomaticlocalization-relatedepilepsywhichcanbe attributedtohigherriskofphysicaldamagetothebrainandthe consequentseizures[128,134].Thedifferencesbetweengenders aremostlyexpressedinages30–59;whichistheagerangefor higherTBIrisks.Malesarealsomoreprobabletoexperiencebrain damagesaccompaniedwithseizures[135,136].Agender depen-dent difference has also been reported in childhood absence epilepsy[137,138].Aquantitativeanalysisshowedthatthereisa sexdifferenceinthenumberofspinesandprimarydendriteson theapicalCA3pyramidalcellsofthehippocampus.Inthisstudy, femalespossessedmoreprimarydendriteswhilemalesshowed moreapical excrescences and interestingly,neonatal treatment with thyroid hormone resulted in long-lasting and dramatic changesintheentireCA3pyramidalcells[139].

8. Antiepilepticdrugsandthyroidhormones

Severallinesofevidenceshowthatantiepilepticdrugs(AEDs) affectdifferentaspectsof THshemostasis suchasbiosynthesis, releaseandtransportaswellasmetabolisminbothchildrenand adults[reviewedin[140]].Inthisregard,in1981Strandjordetal. reportedforthefirsttimethattreatmentwithsomeAEDscould affectthyroid function [141].In accordance,Yilmaz et al. have evaluatedtheeffectsofwidelyusedAEDsonthyroidfunctionin childrenwithnewonsetandcontrolled epilepsy.Theyreported that during a 12-months period of therapy, all AEDs except levetiracetamincreasedTSHlevelanddecreasedfT4concentration

[142]. In another study, it was reported that carbamazepine monotherapy in epileptic children and adultpatients impaired thyroidfunction[143].Evidencesarealsoavailableshowingthat AEDsaffectthecellularmechanismofTHfunctions.Forinstance,a singleinjectionofdiazepam(abenzodiazepine)after24haffects nuclearT3bindingandrelativeexpressionofTHreceptorTR

a

2but notTR

a

1andTR

b

1andsynaptosomalTHavailability[144]. Alter-natively, THs also modulate in vivo and in vitro binding of benzodiazepines on their specific membrane receptors

[145,146].TheseresultsraisetheriskofusingAEDsinpatients withTH deregulation[147]. Itmust beemphasizedthat AEDs-inducedalterationinthyroidfunctionisnotpermanentandcould bereversedby termination oftheir intake.For instance,it was reported that the serum level of fT4 increased 4 months after withdrawalofcarbamazepineinepilepticmenandwomen[148]. Interestingly,thyroidfunctionisalsosensitivetodrugsusedto induceseizureinexperimentalmodels.Inthisregard,Bolarisetal. investigatedifcentralresponsestoTHsareaffectedbya single convulsiondoseofpentylenetetrazole(PTZ).Theirresultsshowed that 4h after PTZ-induced seizures, the density of specific T3 nuclearreceptorsincreasedinthecerebralhemisphereswhilethe non T3 binding receptor (TR

a

2) decreased. These effects were associated with an increased synaptosomal T3 level during epilepticseizures[149].

9. Conclusion

Althoughthecompletepathogenesisofepilepsystillremains to be elucidated, it is well demonstrated that mitochondrial dysfunction, oxidative stress and deregulation of GABAergic

systemplaypivotalrolesinthisprocess.Inspiteofthefactthat BBB impedes the access of THs to the CNS and limits the concentration of these hormones compared to that of serum, researches have now shown that THs play essential roles in differentphysiologicalaspectsoftheCNSsuchasdevelopment, normal brain function and repairing machinery. Molecular evidenceshaveshownthatTHsparticipateinnormal mitochon-drial biogenesisandlackoftheir functioncausesmitochondrial dysfunctionandoxidativestress.Inaddition,itiswellevidenced thatthedevelopmentandfunctionofGABAergicneuronsdepends onnormalTHsfunction.Amassivebodyofknowledgehasbeen gatheredoverthepastdecadestosupportthepositiveeffectsof THsonneuralcellsregeneration.However,BDNF,oneofthemost importantneurotrophicfactorsinfluencedbyTHs,seemstocause detrimental effects on the development and aftermaths of epilepsy. Nevertheless,most collected evidenceand knowledge areinfavorofthepositiveeffectofTHsandthereisnodoubtthat THs plays a significantly influential role in various aspects of epilepsy,fromdevelopmenttohealingand recreation.However, differenttheoreticalwaysbywhichTHsisbelievedtocontribute tothepathologiesofepilepsyshouldbefurtherclarified.

Conflictofinterest

Theauthorsdeclarethattheyhavenoconflictofinterests.

Acknowledgment

ThisworkwassupportedbytheFundamentalResearchGrant Scheme(FRGS)Grant(Number;FP011-2013B).

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