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Responses of CDKs and p53 in Delayed Ischemic Neuronal Death

By Antonio Stevens,2014-09-22 16:14
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Responses of CDKs and p53 in Delayed Ischemic Neuronal Deathof,in,In,CDKs,and,p53,Death,death

    Responses of CDKs and p53 in Delayed

    Ischemic Neuronal Death

;ofNanjg~gMedwalUniversity2002,l6(2):49

    ;ResponsesofCDKsandp53inDelayedIschemic

    ;NeuronalDeath

    ;WANGFuhhu(王伏虎)

    ;NeuroscienceResearchInstitute,UniversityofOttawa,OttawaOntario,CanadaK1H8M5

    ;[Abstract]Strokeis?

    debilitatingdiseasethataffectsmillionseachyear.Whileinmany ;Casescerebralisct~oraicinjurycar6e

    effectiveresuscitationthromboictrealraeal,thein

    ;juredneuronswitl~orinaprocessknownasdelayedneuronaldeath(DND).Mountingevidenceindicates

    ;thatDNDisnotsimplynecrosisplayedoutinslowmotionbutapoptosisis;triggered.Ofparticularinter

    ;estaretwogroupsofs~malproteinsttutlparticipateinapoptosis——cyclinde

    pendentkinases(CDKs)and

    ;53-amongamyriadofsignalingeventsafteranischemicinsult.Recentinvesti

gationshaveshownthat

    ;CDKs,afamilyofenz~jmesinitiallyknownjtheirroleincellcycleregulation,areactivatedinin

    ;juredReuronsinDND.As?p53,newreportssuggestthatitsup—regulationm

    ayrepresentafailed

    ;attempttoresoleinjuredneurons,althoughitsupregulationwaspreviously

    consideredanindicationof

    ;apoptos~s.77~eseobservationsthusrekindleanoldquesttoidentifyrtewneuroprotectivetargetstomin/-

    ;mizeZstrokedamage.Inthisreview.Zauthorwillexaminethecethatindicatesthepartieipa-

    ;tionofCDKsandp53inDNDandthenintroducegeeclinicaldatatoexplore

    CDKinh~ionasapolen-

    ;tlalneuroprotectivetarget.Finally.usingCDKinh~ion

    anexample,thispaperwilldisc~Lssthepert/-

    ;hentc~ilev/a?av/ableneuroprotectivestrategy?ischeraicinjury-

    ;[Keywords-~stroke;cerebralischemia;excitotoxicity;cyclindependentkinases;

    ;neuronaldeath;apoptosis;watermaze;retinoblastoma

    ;[JournalofNJMU,2002,l6(2):4964-]

    ;Introduction

    ;Strokeencompassesadiversegroupofbrain

    ;attacksthatresultfromacriticallOSSofblood ;flowtothecentralnervoustissuecerebralis

    ;chemia.Cardiacarrestandseverehypovolemic ;shockleadtoglobalischemia.Ontheother ;~Foundatlonitem]ThisworkwassupportedbyCanadian ;instituteofHealthResearchandtheHeartandStrokeFounda ;tionof0ntario

    ;hand,localcerebralhemorrhageandbloodclots ;restrictbloodflowtoaconfinedregionresulting ;infocalischemia.Sincestrokehasavasculareti

    ;ology,restorationofeffectivebloodflowisthe ;firstpriority.Forglobalischemia,earlyandef

    ;fectivecardiopulmonaryresuscitationisof ;essencetolimitdamagetothebrain.Forfocalis

    ;chemia,atpresent,themosteffectivetherapyis ;basedonrestorationofbloodflow.However,al

    ;thoughthetimelyuseofthrombolyticssuchas ;tissueplasminogenactivator(tPA)hasshown ;

    ;JourT~dU,-,#rigMedwalUnit,ers/ty2002,16(2):50 ;beneficialeffectsinnonhemorrhagicstroke,its

    ;confinedtimewindowofefficacyhaslimitedits

;clinicalapplicationL‟.

    ;Afteranischemicinsultthehopetocontain

     ;ischemicinjuryrestsonlimitingdelayedneu

    ;ronaldeath(DND)themainmechanismre

    ;sponsibleforcontinualneuronalinjuryevenaf

    ;terrestorationofbloodflow,asinthecaseof ;successfulcardiopulmonaryresuscitationorreso

    ;lutionofbloodclotsfollowingtPAtreatment. ;Duetothisdelayednatureofischemicinjuryone ;hopestoexploitthiswindowofopportunityto ;rescueviablebutdyingneurons[.,.Advances ;inourunderstandingofthesignalingprocesses ;thatmediateneurona1deathinthelastdecade ;sparkedanenduringoptimismthatneuroprotec

    ;tivestrategieswouldeventuallyleadtoareduc

    ;tioninischemicinjury.However,ourunder

    ;standingofunderlyingmechanismsofthispro

    ;gressiveneuronallossremainsincomplete[,. ;Failureofnumerousexperimentaldrugsinpre

    ;clinica1studiesandclinica1trialsillustratesthe ;complexityofischemicinjuryandservesasare

    ;minderthatfurtherunderstandingofsignaling

    ;pathwaysinDNDmustbeachievedbeforea ;comprehensiveapproachtostroketherapycanbe ;formulated.

    ;Toachievethisgoal,therehavebeenre

    ;newedeffortstoidentifynovelmechanismsthat ;mediateneuronaldeath.Thediscoverythatthe ;apoptoticpathwayisactivatedduringDNDhas ;leadtotheidentificationofmultipleenzymatic ;cascadesthatcanbepotentiallytargetedtogain ;therapeuticbenefits.Ofamultitudeofsignals, ;twohaveattractedparticularattention:thecy(

    ;clindependentkinases(CDKs)andp53both ;ofthemhavebecomeexperimentaltargetsforre

    ;ducingDND.CDKs,bestknownfortheregula

    ;tionofcellcycleprogression,haverecentlybeen ;identifiedtoserveadualfunctionfororchestrat

    ;ingthecellcycleprogressionandactivatingthe ;apoptoticpathwayifallisnotwell[.Similar

    ;ly,p53iswellcharacterizedtobethe”guardian

    ;ofthegenome”inthatitsensessignalsproduced

    ;bydamagedDNA.Oncethedamagereachesa ;certainthreshold,p53commitsthecelltoapopto

    ;sisviaboththemitochondrionanddeathligand ;pathways[.

    ;Toprovideahistoricperspective,1will ;brieflyreviewtheclassicalmechanismsofstroke ;injury,1willnextdescribeprincipalupstream, ;anddownstreammechanismsthatparticipatein ;CDKandp53apoptoticsignalinganddiscussthe ;neuroprotectivepotentialoftargetingCDKsand ;p53inreducingDND.Then1willintroduceour ;latestdatagatheredfromstudiesinrodentis

    ;chemicmodelstodemonstratetheroleforCDKs ;inDND.Likewise.1willsummarizethestudies ;onp53signalingandeffectsofitsinhibitionon ;ischemicneuronaldeath.Finally,usingCDKin

    ;hibitionasanexample,1willdiscusssomeof ;theknowncriterianecessaryforaneffectiveneu

    ;roprotectivetreatment.

    ;AcuteStrokeInjuryMechanisms

    ;Excellentreviewshavebeenpublishedin ;theareaofcerebralischemicresearch.Someof ;topicsincludepathophysiologyofcerebralis

    ;chemicinjury[9-113,excitotoxicity,cytoplasmic

    ;Caoverload[12-14].strokeinjurydynamics[, ;apoptoticneuronaldeath[]andwhitematterin

    ;jury[.However.toprovideahistoricback

    ;groundtothisdiscussion,theclassicalmecha

    ;nismsofizchemicinjurywillbebrieflyoutlined. ;Ischemicneuronaldeathcanbegenerallydi

    ;videdintotwocategories:acuteneuronaldeath ;anddelayedneuronaldeath[](Figure1). ;Acuteneuronaldeath,aresponsetodepletionof ;

    ;oxygenandglucose,istheresultofacomplete ;collapseinionicandpHhomeostasis,suchas ;seeninthecoreofafocalstroke[9-11,1. ;Initial

    ;membranedepolarization,resultingfromATP ;depletion,leadstotheactivationofthevoltage ;gatedchannelsandreleaseofglutamate.Extra

    ;cellularglutamatelevelsincreasebynon——func——

    ;tionalreleasesfromthesynapticterminalsand ;malfunctionoftheglialglutamatetranspor

    ;ters[.,.Increasesinextracellularglutamate ;levelsresultinover——stimulationofbothionotrop——

;icandmetabotropicglutamatereceptors.There

    ;sultispathologicalincreasesincytoplasmicCa ;fromtheextracellularspaceandinternalsequest ;edCa一一stores.Theinfluxfromtheextracel ;lularspaceismediatedviathevoltagegated

    ;Cachannelsandtheionotropicglutamatechan

    ;nelsoftheAMPA(aamino3hydroxy5-me

    ;thyl4-isoxazolepropionate)andNMDA(N

    aspartate)subtypesEJ33.Therelease ;methylD

    ;fromtheinternalstoresislargelymediatedby ;theryanodineandinositoltriphosphate(IP3) ;gatedCa.channelsontheendoplasmicreticu

    ;lumE?](Figure11.

    ;Convergenceofthesemechanismsresultsin ;cytoplasmicCa.overloadthefinalcommo13m

    ;echanisminneuronalinjury(Figure1).Subse

    ;quently,however,Caoverloaddivergeto ;wreckhavoconmultipledownstreamenzyme ;systems”?.Over—activationofphospholipase ;Aandcyclooxygenase,alsoresultingfromthe ;over——activationofmetabotropicglutamaterecep——

    ;tors.generatesfreeradicalspecies[.Calpains

    ;andotherproteolyticenzymes,whichaffecta ;varietyofintracellularsignalsandcytoskeletal ;structure,areactivated[.?..].Abnormalaccu

    ;mulationofCa+inthemitochondriabreaks ;downthemitochondrionpotentialandcauses ;leakageoftheapoptoticproteins[..Inaddi

    ;J~trrTa/ofNan.~tgMedi~‟alUniz,er,s-/ty2002,l6(2):51

    ;tion,increasedCamediatestheactivationof

    ;nitricoxidesynthase(NOS):-.Nitricox ;ide.ifnotutilizedandclearedbyviabletissueto ;increasecGMPproductionandtoenhancevessel ;dilation,inturnreactswithsuperoxideand ;formsperoxynitrite.Ahighlyreactiveoxidative ;species,peroxynitritecompoundstheeffectsof ;otherfreeradicalspeciesfurther.?.Unfortu ;nately,inthemostseverelyischemicregions, ;neuronslooseviabilityinamatterofminutes, ;leavinglittlechanceforneuroprotectiVeinterven

    ;tion.

    ;Inspiteoftheshortwindowofopportu

    ;nity,manyneuroprotectiVeagentshavebeen ;testedtocurbtheischemicinjurylargelybased

;ontheunderstandingoftheacuteischemicmech

    ;anisms.Somewerehighlysuccessfulinanimal ;modelsandintroducedintoclinicaltrials.Forex

    ;ample,toreduceCa”influxthroughtheL—type

    ;Cachannels.voltagegatedcalciumblockers

    ;havebeenextensivelystudiedwithsomesuccess ;inreducingcerebralischemicinjury[26-~a3.Nu

    ;meroustherapeuticapproacheshavealsobeen ;testedtoreduceglutamateexcitotoxicitybycurb ;ingitsreleasefromthepresynapticterminalor ;over——stimulationofitssynapticreceptors(presy——

    ;napticandpostsynaptic).Forexample,wcono

    ;toxinGVIAextractedfromacarnivorouscone ;snail,Conusgeographus,wasusedtoblockthe ;NtypeCachannelstoreducereleaseofgluta

    ;matefromthesynapticterminal[..,..Ionic ;glutamatereceptorantagonists,suchasthenon

    ;competitiveNMDAblockerdizocilpine(MK

    ;801)andthefastglutamatereceptorblocker ;NBQX[2,3dihydroxy6nitro7sulfamoyl

    ;benzo(F)quinoxaline],havebeenextensively ;examined[.?..Whilesomecompoundshave

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