缺血神經(jīng)保護(hù)

缺血性卒中的腦保護(hù)治療內(nèi)容神經(jīng)保護(hù)治療的概念神經(jīng)保護(hù)劑的現(xiàn)狀從失敗到睿智自由基去除劑神經(jīng)保護(hù)劑的分層用藥神經(jīng)保護(hù)劑的聯(lián)合用藥內(nèi)容神經(jīng)保護(hù)治療的概念神經(jīng)保護(hù)劑的現(xiàn)狀從失敗到睿智自由基去除劑神經(jīng)保護(hù)劑的分層用藥神經(jīng)保護(hù)劑的聯(lián)合用藥急性缺血性卒中

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局部缺血BloodflowtobraininterruptedCentralregionoftissueinfarctsrapidly—coreInfarctextendstoischemicregionaroundcore—ischemicpenumbraProcessesofcellularinjury/deathverydifferentinthese2regionsTxobjectives—limitinfarctgrowth—protectagainstpenumbraldestruction“neuroprotection”急性缺血性卒中閉塞核心缺血半暗帶閉塞References:

1.LiptonP.Ischemiccelldeathinbrainneurons.PhysiologicalReviews.Oct1999;vol.79;

1431-1568.2.LoEH,DalkaraT,MoskowitzMA.Mechanisms,challengesandopportunitiesinstroke.

NatRevNeurosci.2003;4(5):399-415.正常組織半暗帶組織壞死組織腦血流正常腦血流的40%正常腦血流的150%缺血核心和半暗帶PenumbraInfarction缺血性卒中的病理生理生物化學(xué)級鏈反響氧和能量底物減少膜去極化鈣超載谷氨酸釋放鈣離子內(nèi)流NMDA/AMPA受體References:

1.DirnaglU,IadecolaC,MoskowitzMA.Pathobiologyofischaemicstroke:anintegratedview.

TrendsNeurosci.1999;22(9):391-7.2.LeeJM,GrabbMC,ZipfelGJ,ChoiDW.Braintissueresponses

toischemia.JClinInvest.2000;106(6):723-31.神經(jīng)保護(hù)可以改善臨床預(yù)后急性缺血性卒中神經(jīng)細(xì)胞死亡再灌注級鏈反響缺血級鏈反響一氧化氮自由基增加自由基增加其中一個途徑使減少自由基損害1,2References:

1.Bright,R,Mochly-RosenD.TheroleofproteinkinaseCincerebralischemicand

reperfusioninjury.Stroke.2005;36(12):2781-90.2.LiptonP.Ischemiccelldeathinbrainneurons.

PhysiolRev.1999;79(4):1431-568.去極化NMDA/AMPA受體活化谷氨酸釋放鈣離子增加神經(jīng)保護(hù)和神經(jīng)恢復(fù)神經(jīng)保護(hù)Neuroprotection神經(jīng)恢復(fù)Neurorestoration靶向缺血半暗帶全部有功能的組織時間窗0-24小時，或許更長24小時以后，數(shù)周？數(shù)月？目的控制分子事件調(diào)節(jié)功能組織的活動神經(jīng)保護(hù)劑的作用有神經(jīng)保護(hù)缺血損害減輕無神經(jīng)保護(hù)永久缺血性損害Reference:

1.FisherM.Theischemicpenumbra:identification,evolutionandtreatmentconcepts.

CerebrovascDis.2004;17(suppl1):1-6.神經(jīng)保護(hù)市場缺血細(xì)胞死亡的機(jī)制內(nèi)容神經(jīng)保護(hù)治療的概念神經(jīng)保護(hù)劑的現(xiàn)狀從失敗到睿智自由基去除劑神經(jīng)保護(hù)劑的分層用藥神經(jīng)保護(hù)劑的聯(lián)合用藥神經(jīng)保護(hù)應(yīng)用的范圍神經(jīng)外科心臟外科Beatingheart心臟驟停頸動脈治療創(chuàng)傷卒中〔缺血性和出血性〕潛在治療縮短缺血時間減少細(xì)胞內(nèi)鈣離子濃度減少細(xì)胞內(nèi)鈉離子濃度阻斷谷氨酸作用Blockeffectsofglutamate抑制自由基Trapfreeradicals抑制PARP活性阻斷caspase活性阻斷白細(xì)胞黏附改變細(xì)胞膜流動性降低組織溫度神經(jīng)保護(hù)劑:夭折的嬰兒動物實(shí)驗有效臨床試驗無效卒中神經(jīng)保護(hù)治療是否是根底科學(xué)工作者編織的夢？

IsNeuroprotectiveStrokeTherapyJustaFanasyInventedbyBasicScientists?缺血神經(jīng)保護(hù)劑：路在何方？NewPharmacologicalagents‘Cocktail’approachConsummatingtheMarriageBetweentheLaboratryandBedsideGrottaJC.UniversityofTexas-HustonMedicalSchool

Ubiquitin-ProteasomeComplexUbiquitin-ProteasomeComplexUbiquitin-ProteasomeComplexHuetal,J.Neurosci,2000,20(9):3191Following15minglobalcerebralischemia,proteinaggregatesareubiquitinlabeledCA1DG血管保護(hù)治療SynthesisandScreening 10,000Pre-clinicaldevelopmentappraisal 6,000PhaseI 50Sub-acutetoxicity 20PhaseIIA(PoC) 15Chronictoxicity 10ClinicalPhaseII 5Carcinogenicity 3PLA 1Market 1PostMarket ? ProbabilityofSuccess=1in10,000COSTPERCOMPOUND$US1BNNewdiscoverycompounds內(nèi)容神經(jīng)保護(hù)治療的概念神經(jīng)保護(hù)劑的現(xiàn)狀從失敗到睿智自由基去除劑神經(jīng)保護(hù)劑的分層用藥神經(jīng)保護(hù)劑的聯(lián)合用藥神經(jīng)保護(hù)劑的誤區(qū)(Pitfalls)臨床前研究的時窗極短，而臨床研究的時窗較長臨床前治療靶區(qū)是半暗帶，而臨床試驗?zāi)敲床皇桥R床前治療偏向?qū)屹|(zhì)的保護(hù)，而臨床不針對特定的臨床定位尚不清楚確切療程臨床前研究療效判定主要依據(jù)梗死面積，而臨床主要依據(jù)行為學(xué)臨床前主要依據(jù)早期預(yù)后，而臨床是遠(yuǎn)期評價卒中模型為同質(zhì)性,而人類卒中為異質(zhì)性預(yù)后測量方法比實(shí)際療效更重要用小規(guī)模試驗答復(fù)大規(guī)模試驗要答復(fù)的問題

內(nèi)容神經(jīng)保護(hù)治療的概念神經(jīng)保護(hù)劑的現(xiàn)狀從失敗到睿智自由基去除劑神經(jīng)保護(hù)劑的分層用藥神經(jīng)保護(hù)劑的聯(lián)合用藥OxygenMetabolismO2RBCHb-O2CellsMitochondriae-transportH2O2H2OO2O2.-SERP-450PHSAAPGsLTsH2OO2O2.-PeroxisomeOxidasesO2MembraneMPxNOSNO.H2O2O2.-NO.HOCl-PSO21O2hn缺血半暗帶超氧化物(自由基)增加(n=18)6005004003002001000100200分鐘缺血1小時后再灌注腦中動脈缺血對照超氧化物化學(xué)發(fā)光計數(shù)PetersO.etal.,1996鈣超載導(dǎo)致自由基產(chǎn)生促氧化酶1:一氧化氮合成酶

環(huán)氧化酶,腺嘌呤脫氫酶，腺嘌呤氧化酶，NADPH氧化酶

髓過氧化酶和單氨氧化酶自由基形成線粒體破壞MMP活化鈣離子超載磷酸化酶活化蛋白酶活化一氧化氮References:

1.ChanPH.Reactiveoxygenradicalsinsignalinganddamageintheischemicbrain.JCerebBloodFlowMetab.

2001;21(1):2-14.2.SchildL,ReiserG.Oxidativestressisinvolvedinthepermeabilizationofthe

innermembraneofbrainmitochondriaexposedtohypoxia/reoxygenationandlowmicromolarCa2+.

FEBSJ.2005;272(14):3593-601.自由基可以損害細(xì)胞和DNAMMP活化細(xì)胞處理過程失調(diào)內(nèi)皮細(xì)胞DNA氧化損傷自由基線粒體破壞細(xì)胞膜破壞References:

1.LiptonP.Ischemiccelldeathinbrainneurons.PhysiologicalReviews.Oct1999;

vol.79;1431-1568.2.DirnaglU,IadecolaC,MoskowitzMA.Pathobiologyofischaemicstroke:

anintegratedview.TrendsNeurosci.1999;22(9):391-7.自由基損傷線粒體References:

1.DirnaglU,IadecolaC,MoskowitzMA.Pathobiologyofischaemicstroke:anintegratedview.TrendsNeurosci.

1999;22(9):391-7.2.SasakiC,KitagawaH,ZhangWR,WaritaH,SakaiK,AbeK.Temporalprofile

ofcytochromecandcaspase-3immunoreactivitiesandTUNELstainingafterpermanent

middlecerebralarteryocclusioninrats.NeurolRes.2000;22(2):223-8.缺血/再灌注使自由基產(chǎn)生增加神經(jīng)細(xì)胞膠質(zhì)細(xì)胞內(nèi)皮細(xì)胞Stroke.2004;35:1449-1453NXY-059

Disodium4-[(tert-butylimino)methyl]benzene-1,3-disulfonateN-oxideTrapsfreeradicalsMeetsSTAIRcriteriaforneuroprotectantefficacyinrodentandprimateinbothtransientandpermanentmodesofacuteischaemicstrokereducesinfarctsizeandpreservesbrainfunctionWelltoleratedinhumanstargetplasmaconcentrationof260μMexceedseffectivelevelsinanimalmodelsSAINTIoutcomes1.20(1.01-1.42)mRSSubgroupinteractionswithprimaryendpointnotsignificantTreatment-time p=0.92Treatment-age p=0.62Treatment-severity p=0.72Treatment-alteplase p=0.93Treatment-diabetes p=0.98Treatment-glucose p=0.27etcSafety:ICHafterthrombolysisAsymptICHSymptICH20.9%P<0.005SAINT-I結(jié)論TheadministrationofNXY-059withinsixhoursaftertheonsetofacuteischemicstrokesignificantlyimprovedtheprimaryoutcome(reduceddisabilityat90days),butitdidnotsignificantlyimproveotheroutcomemeasures,includingneurologicfunctioningasmeasuredbytheNIHSSscore.AdditionalresearchisneededtoconfirmwhetherNXY-059isbeneficialinischemicstroke.TreatmentInteractionswithImportantCovariatesPrimaryOutcomeat90DaysAccordingto

theScoreontheModifiedRankinScaleSAINT-IINXY-059isineffectiveforthetreatmentofacuteischemicstrokewithin6hoursaftertheonsetofsymptoms.國內(nèi)II期臨床結(jié)果入組病例229例，實(shí)際完成病例213例ESS評分：神經(jīng)功能缺損評分、有效率在第7天、14天、21天均有顯著性差異，且隨著時間延長差異逐步明顯；ADL評分：日常生活活動量表評分、有效率在第7天、14天、21天、90天均有顯著性差異，且隨著時間延長差異逐步明顯*復(fù)旦大學(xué)附屬華山醫(yī)院,第二軍醫(yī)大學(xué)長征醫(yī)院,浙江大學(xué)醫(yī)學(xué)院第二附屬醫(yī)院,江蘇省人民醫(yī)院南京醫(yī)科大學(xué)附屬腦科醫(yī)院，必存?治療急性腦堵塞____隨機(jī)、雙盲、疊加、對照、多中心臨床試驗依達(dá)拉奉組對照組<24hr最終綜合改善率73.8％(31/42例)25.6%(10/39例)安全性85.7%(36/42例)76.9%(30/39例)有效率69%(29/42例)20.5%(8/39例)<72hr最終綜合改善率64.8％(81例/125例)32.0％(40例/125例)日本III期臨床CerebrovascularDiseases2003;15(3):222-9Effectofanovelfreeradicalscavenger,edaravone(MCI-186),onacutebraininfarction.Randomized,placebo-controlled,double-blindstudyatmulticenters.三期臨床有效!EdaravoneAcuteInfarctionStudyGroup,CerebrovascularDiseases2003;15(3):222-9神經(jīng)保護(hù)治療的概念神經(jīng)保護(hù)劑的現(xiàn)狀從失敗到睿智自由基去除劑神經(jīng)保護(hù)劑的分層用藥神經(jīng)保護(hù)劑的聯(lián)合用藥KidwellCSetal,AnnNeurol52:698-703,2002Reperfusioninjury?再灌注增加自由基的產(chǎn)生MMP

活化再灌注DNA氧化損傷自由基炎性細(xì)胞活化細(xì)胞因子(TNF,IL-1)References:

1.SchildL,ReiserG.Oxidativestressisinvolvedinthe

permeabilizationoftheinnermembraneofbrainmitochondriaexposedtohypoxia/reoxygenationandlow

micromolarCa2+.FEBSJ.2005;272(14):3593-601.2.DirnaglU,IadecolaC,MoskowitzMA.Pathobiology

ofischaemicstroke:anintegratedview.TrendsNeurosci.1999;22(9):391-7.3.LoEH,Dal