Cellular and Molecular Pathways of Ischemic Neuron

JournalofBiochemistryandMolecularBiology,Vol.35,No.1,January2002,pp.67-86©BSRK&Springer-Verlag2002ReviewCellularandMolecularPathwaysofIschemicNeuronalDeathSeokJoonWon,DooYeonKim†andByoungJooGwag*CenterfortheInterventionalTherapyofStrokeandAlzheimersDisease,DepartmentofPharmacology,AjouUniversitySchoolofMedicine,San5,Wonchondong,Paldalgu,Suwon,Kyungkido442-749,SouthKorea†GeneticsandAgingResearchUnit,MassachusettsGeneralHospitalEast,Building114,Room3012,11416thStreet,Charlestown,MA02129Received28December2001Threerouteshavebeenidentifiedtriggeringneuronaldeathunderphysiologicalandpathologicalconditions.ExcessactivationofionotropicglutamatereceptorscauseinfluxandaccumulationofCa2+andNa+thatresultinrapidswellingandsubsequentneuronaldeathwithinafewhours.Thesecondrouteiscausedbyoxidativestressduetoaccumulationofreactiveoxygenandnitrogenspecies.Apoptosisorprogrammedcelldeaththatoftenoccursduringdevelopmentalprocesshasbeencoinedasadditionalroutetopathologicalneuronaldeathinthematurenervoussystem.Evidenceisbeingaccumulatedthatexcitotoxicity,oxidativestress,andapoptosispropagatethroughdistinctiveandmutuallyexclusivesignaltransductionpathwayandcontributetoneuronallossfollowinghypoxic-ischemicbraininjury.Thus,thetherapeuticinterventionofhypoxic-ischemicneuronalinjuryshouldbeaimedtopreventexcitotoxicity,oxidativestress,andapoptosisinaconcertedway.Keywords:Glutamate,Oxidativestress,Apoptosis,Ischemia,NecrosisIntroductionStrokeoccurswhenlocalthrombosis,embolicparticles,ortheruptureofbloodvesselsinterruptsthebloodflowtothebrain.Whilestrokeisthethirdmostcommoncauseofdeathinmostdevelopedcountries,itisrankedasthefirstleadingcauseofdeathandseveredisabilityinKorea.Brainfunctionisimpairedimmediatelyafterthebloodflowdropsbelowonefourthofnormalvalues.Iftheischemicconditionpersistsforaprolongedperiodoftime,primaryneuronaldeathappearsrapidlyinthecoreareas,andisaccompaniedbysecondarydeathintheischemicpenumbrathatslowlyevolvessubsequenttotheactivationofmultipledeathpathways;therefore,ithasbeentargetedfortherapeuticintervention.Thefirstlineofinterventionaltherapystemsfromfindingsthatexcitotoxicityunderliesoneoftheleadingcausesofneuronaldeathfollowinghypoxic-ischemicinsults.Accordingly,antagonistsofionotropicglutamatereceptorshavebeendeveloped.Thesereducehypoxic-ischemicbraininjuryinvariousanimalmodels,andhavebeenappliedforclinicaltrialofischemicstroke,butwithlittletherapeuticefficacytodate.Freeradicalsareprimarilyproducedduringaperiodofreperfusion,andarebelievedtocontributetodelayedneuronaldeath.Finally,severallinesofevidencesuggestthatapoptosis,orprogrammedcelldeath,comprisesaportionofischemicneuronaldeath.Itisconceivabletopostulatethatthetherapeuticinterventionofischemicneuronaldeathlikelyinvolvesanappropriatecombinationofneuroprotectivedrugsthataredesignedtopreventexcitotoxicity,oxidativestress,andapoptosis.ExcitotoxicityGlutamatemediatesexcitatorysynaptictransmissionthroughtheactivationofionotropicglutamatereceptorsthataresensitivetoNMDA(N-methyl-D-aspartate),AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid),orkainate.Thisexcitatorytransmissionmediatesnormalinformationprocessingandneuronalplasticity.Aninterruptedbloodsupplytothebraincausesdeprivationofoxygenandglucosethatareutilizedtoproduceenergy.Impairedenergyincreasespresynapticglutamatereleasethroughmembranedepolarizationandthesubsequentactivationofthevoltage-gatedCa2+channel.Italsointerfereswiththere-uptakeofglutamate(primarilyintoastrocytes),whichresultsintheabnormalaccumulationofsynapticglutamate.Excessandsustainedactivationoftheionotropicglutamatereceptorscausesfulminantneuronaldeath,namelyglutamateneurotoxicityorexcitotoxicity.*Towhomcorrespondenceshouldbeaddressed.Tel:[phone];Fax:[phone]E-mail:[e-mail]2+-mediatedfastexcitotoxicityThepentamericNMDAreceptorsconsistofthefundamentalsubunitNMDAR1andmodulatorysubunitsofNMDAR2A-2D(HollmannandHeinemann,1994;Sucheretal.,1996).TheheteromericNMDAreceptorsarehighlypermeabletoCa2+,aswellasNa+andK+.TheNMDAreceptorsmediateslowly,evolvinganddesensitizingcomponentsofexcitatorypostsynapticcurrents.NMDAreceptorscanbefullyactivatedunderthedepolarizationofplasmamembranethatabolishestheinhibitionofNMDAreceptorsbyMg2+.Sinceabrief(3min)activationofNMDAreceptorsissufficienttotriggerneuronaldeath,thentheactivationofNMDAreceptorshasbeenproposedasaprimarycauseofneuronaldeathafterthefocalcerebralischemiathatisaccompaniedbythetransient(~30-60min)elevationofextracellularglutamate(Benvenisteetal.,1984;Takagietal.,1993).TheCa2+influxthroughNMDAreceptorsmediatestherapidly-triggeredNMDAneurotoxicity,whileNa+influxcontributestotheswellingoftheneuronalcellbody(Choi,1987)(Fig.1).AMPAreceptorsconsistofacombinationofGluR1-GluR4subunits(HollmannandHeinemann,1994;Pellegrini-Giampietroetal.,1997).MostoftheAMPAreceptorsarehighlypermeabletoNa+andK+,andmediaterapidly,evolvinganddesensitizingcomponentsofexcitatorypostsynapticcurrents.IncontrasttoNMDA,aprolonged(60min)activationofAMPAreceptorsisrequiredtotrigge