TherapeuticeffectsofanovelPARP-1inhibitor,JPI-289,inmodelsofacuteischemicstroke

Abstract

ExcessiveactivationofPoly(ADP-ribose)polymerase-1(PARP-1)afterischemicstrokeisknowntodevelopneuronalapoptosis,necrosisandinflammation.ThepresentstudyinvestigatedinvitroandinvivoneuroprotectiveeffectsofanovelPARP-1inhibitor,JPI-289.TheinhibitorstronglyinhibitedPARP-1activity(IC50=18.5nM)andcellularPARlevel(IC50=10.7nM).Inratcorticalneuronalcells,JPI-289didnotaffectcellviabilityupto1mMasshownintrypanbluestaining(TBS)andlactatedehydrogenase(LDH)assays.Inoxygenglucosedeprived(OGD)ratcorticalneuron,treatmentofJPI-289attenuatedPARPactivityandrestoredATPandNAD+levels.JPI-289treatmentintheOGDmodelshoweddecrementofapoptosis-associatedmoleculesincludingapoptosis-inducingfactor(AIF),cytochrome-Candcleavedcaspase-3.AftertheevaluationofJPI-289invitromodel,weinvestigatedtheneuroprotectiveeffectsofJPI-289inratpermanentandtransientstrokemodels.Intransientmiddlecerebralarteryocclusion(MCAO)modelinrats,JPI-289treatmentshowedsignificantreductionofinfarctedareaofbrain,whichwasmaximalatthedoseof10mg/kgupto36%reduction.Thetherapeutictimewindowwas8hoursforreductionofischemicvolumeupto29%.Moreover,numberofapoptoticcellsdecreasedby56%comparedtocontrol.WhenmodelwastwitchedtopermanentMCAOmodelinrats,JPI-289treatmentsignificantlyreducedinfarctedvolumeupto20%atthedoseof40mg/kg,andimprovedbehavioralsocre.AlongwithstableandsafedataofnovelPARP-1inhibitor,JPI-289onpharmacokineticsandtoxicology,itseffectivenessonischemicstrokemodelsandmodesofactionmechanismssuggestthatJPI-289couldbeapotentialtherapeuticagentforthetreatmentofacuteischemicstroke.