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1、TheJournalofNeuroscience,November19,2003•23(33):10681–10690•10681Cellular/MolecularHypoglycemicNeuronalDeathandCognitiveImpairmentArePreventedbyPoly(ADP-Ribose)PolymeraseInhibitorsAdministeredafterHypoglycemiaSangWonSuh,1,3KojiAoyama,1,3YongmeiChen,1,3PhilippeGarnier,1,
2、3YasuhikoMatsumori,2,3ElizabethGum,1,3JialingLiu,2,3andRaymondA.Swanson1,3Departmentsof1Neurologyand2Neurosurgery,UniversityofCalifornia,SanFrancisco,California94143,and3VeteransAffairsMedicalCenter,SanFrancisco,California94121Severehypoglycemiacausesneuronaldeathandcog
3、nitiveimpairment.EvidencesuggeststhathypoglycemicneuronaldeathinvolvesexcitotoxicityandDNAdamage.Poly(ADP-ribose)polymerase-1(PARP-1)normallyfunctionsinDNArepair,butpromotescelldeathwhenextensivelyactivatedbyDNAdamage.Corticalneuronculturesweresubjectedtoglucosedeprivat
4、iontoassesstheroleofPARP-1//inhypoglycemicneuronaldeath.PARP-1neuronsandwild-type,PARP-1neuronstreatedwiththePARPinhibitor3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinonebothshowedincreasedresistancetoglucosedeprivation.Aratmodelofinsulin-inducedhypoglyc
5、emiawasusedtoassessthetherapeuticpotentialofPARPinhibitorsafterhypoglycemia.Ratssubjectedtoseverehypoglycemia(30minEEGisoelectricity)accumulatedbothnitrotyrosineandthePARP-1product,poly(ADP-ribose),invulnerableneurons.TreatmentwithPARPinhibitorsimmediatelyafterhypoglyce
6、miablockedproductionofpoly(ADP-ribose)andreducedneu-ronaldeathby80%inmostbrainregionsexamined.IncreasedneuronalsurvivalwasalsoachievedwhenPARPinhibitorswereadministeredupto2hrafterbloodglucosecorrection.Behavioralandhistologicalassessmentsperformed6weeksafterhypoglycem
7、iaconfirmedasustainedsalutaryeffectofPARPinhibition.TheseresultssuggestthatPARP-1activationisamajorfactormediatinghypoglycemicneuronaldeathandthatPARP-1inhibitorscanrescueneuronsthatwouldotherwisedieafterseverehypoglycemia.Keywords:diabetes;glucose;glutamate;neuron;nitr
8、otyrosine;watermaze;7-nitroindazole;3-aminobenzamideIntroductioncemicneuronaldeath(Wielochetal.,1985;Butcheret
