EpigeneticInterventionsforEpileptogenesis:ANewFrontierforCuringEpilepsyIyanYounusandDoodipalaSambaReddy*DepartmentofNeuroscienceandExperimentalTherapeutics,CollegeofMedicine,TexasA&MHealthScienceCenter,Bryan,TX77807,USAAbstractThisarticlehighlightstheemergingtherapeuticpotentialofspecificepigeneticmodulatorsaspromisingantiepileptogenicordisease-modifyingagentsforcuringepilepsy.Currently,thereisanunmetneedforantiepileptogenicagentsthattrulypreventthedevelopmentofepilepsyinpeopleatrisk.Thereisstrongevidencethatepigeneticsignaling,whichexertshighfidelityregulationofgeneexpression,playsacrucialroleinthepathophysiologyofepileptogenesisandchronicepilepsy.Thesemodificationsarenothard-wiredintothegenomeandareconstantlyreprogrammedbyenvironmentalinfluences.Thepotentialepigeneticmechanisms,includinghistonemodifications,DNAmethylation,microRNA-basedtranscriptionalcontrol,andbromodomainreadingactivity,candrasticallyaltertheneuronalgeneexpressionprofilebyexertingtheirsummativeeffectsinacoordinatedfashion.Suchanepigeneticinterventionappearsmorerationalstrategyforpreventingepilepsybecauseittargetstheprimarypathwaythatinitiallytriggersthenumerousdownstreamcellularandmoleculareventsmediatingepileptogenesis.Amongcurrentlyapprovedepigeneticdrugs,themajorityareanticancerdrugswithwell-establishedprofilesinclinicaltrialsandpractice.Evidencefrompreclinicalstudiessupportsthepremisethatthesedrugsmaybeappliedtoawiderangeofbraindisorders.Targetinghistonedeacetylationbyinhibitinghistonedeacetylaseenzymesappearstobeonepromisingepigenetictherapysincecertaininhibitorshavebeenshowntopreventepileptogenesisinanimalmodels.However,developingneuronalspecificepigeneticmodulatorsrequiresrational,pathophysiology-basedoptimizationtoefficientlyintercepttheupstreampathwaysinepileptogenesis.Overall,epigeneticagentshavebeenwellpositionedasnewfrontiertoolstowardsthenationalgoalofcuringepilepsy.KeywordsEpigenetics;epileptogenesis;histonemodification;DNAmethylation;miRNA;epilepsy*Correspondenceauthor:D.SambaRe...
