缺血神经保护

缺血性卒中的脑保护治疗内容神经保护治疗的概念神经保护剂的现状从失败到睿智自由基去除剂神经保护剂的分层用药神经保护剂的联合用药内容神经保护治疗的概念神经保护剂的现状从失败到睿智自由基去除剂神经保护剂的分层用药神经保护剂的联合用药急性缺血性卒中

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局部缺血BloodflowtobraininterruptedCentralregionoftissueinfarctsrapidly—coreInfarctextendstoischemicregionaroundcore—ischemicpenumbraProcessesofcellularinjury/deathverydifferentinthese2regionsTxobjectives—limitinfarctgrowth—protectagainstpenumbraldestruction“neuroprotection”急性缺血性卒中闭塞核心缺血半暗带闭塞References:

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

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

NatRevNeurosci.2003;4(5):399-415.正常组织半暗带组织坏死组织脑血流正常脑血流的40%正常脑血流的150%缺血核心和半暗带PenumbraInfarction缺血性卒中的病理生理生物化学级链反响氧和能量底物减少膜去极化钙超载谷氨酸释放钙离子内流NMDA/AMPA受体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.神经保护可以改善临床预后急性缺血性卒中神经细胞死亡再灌注级链反响缺血级链反响一氧化氮自由基增加自由基增加其中一个途径使减少自由基损害1,2References:

1.Bright,R,Mochly-RosenD.TheroleofproteinkinaseCincerebralischemicand

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

PhysiolRev.1999;79(4):1431-568.去极化NMDA/AMPA受体活化谷氨酸释放钙离子增加神经保护和神经恢复神经保护Neuroprotection神经恢复Neurorestoration靶向缺血半暗带全部有功能的组织时间窗0-24小时，或许更长24小时以后，数周？数月？目的控制分子事件调节功能组织的活动神经保护剂的作用有神经保护缺血损害减轻无神经保护永久缺血性损害Reference:

1.FisherM.Theischemicpenumbra:identification,evolutionandtreatmentconcepts.

CerebrovascDis.2004;17(suppl1):1-6.神经保护市场缺血细胞死亡的机制内容神经保护治疗的概念神经保护剂的现状从失败到睿智自由基去除剂神经保护剂的分层用药神经保护剂的联合用药神经保护应用的范围神经外科心脏外科Beatingheart心脏骤停颈动脉治疗创伤卒中〔缺血性和出血性〕潜在治疗缩短缺血时间减少细胞内钙离子浓度减少细胞内钠离子浓度阻断谷氨酸作用Blockeffectsofglutamate抑制自由基Trapfreeradicals抑制PARP活性阻断caspase活性阻断白细胞黏附改变细胞膜流动性降低组织温度神经保护剂:夭折的婴儿动物实验有效临床试验无效卒中神经保护治疗是否是根底科学工作者编织的梦？

IsNeuroprotectiveStrokeTherapyJustaFanasyInventedbyBasicScientists?缺血神经保护剂：路在何方？NewPharmacologicalagents‘Cocktail’approachConsummatingtheMarriageBetweentheLaboratryandBedsideGrottaJC.UniversityofTexas-HustonMedicalSchool

Ubiquitin-ProteasomeComplexUbiquitin-ProteasomeComplexUbiquitin-ProteasomeComplexHuetal,J.Neurosci,2000,20(9):3191Following15minglobalcerebralischemia,proteinaggregatesareubiquitinlabeledCA1DG血管保护治疗SynthesisandScreening 10,000Pre-clinicaldevelopmentappraisal 6,000PhaseI 50Sub-acutetoxicity 20PhaseIIA(PoC) 15Chronictoxicity 10ClinicalPhaseII 5Carcinogenicity 3PLA 1Market 1PostMarket ? ProbabilityofSuccess=1in10,000COSTPERCOMPOUND$US1BNNewdiscoverycompounds内容神经保护治疗的概念神经保护剂的现状从失败到睿智自由基去除剂神经保护剂的分层用药神经保护剂的联合用药神经保护剂的误区(Pitfalls)临床前研究的时窗极短，而临床研究的时窗较长临床前治疗靶区是半暗带，而临床试验那么不是临床前治疗偏向对灰质的保护，而临床不针对特定的临床定位尚不清楚确切疗程临床前研究疗效判定主要依据梗死面积，而临床主要依据行为学临床前主要依据早期预后，而临床是远期评价卒中模型为同质性,而人类卒中为异质性预后测量方法比实际疗效更重要用小规模试验答复大规模试验要答复的问题

内容神经保护治疗的概念神经保护剂的现状从失败到睿智自由基去除剂神经保护剂的分层用药神经保护剂的联合用药OxygenMetabolismO2RBCHb-O2CellsMitochondriae-transportH2O2H2OO2O2.-SERP-450PHSAAPGsLTsH2OO2O2.-PeroxisomeOxidasesO2MembraneMPxNOSNO.H2O2O2.-NO.HOCl-PSO21O2hn缺血半暗带超氧化物(自由基)增加(n=18)6005004003002001000100200分钟缺血1小时后再灌注脑中动脉缺血对照超氧化物化学发光计数PetersO.etal.,1996钙超载导致自由基产生促氧化酶1:一氧化氮合成酶

环氧化酶,腺嘌呤脱氢酶，腺嘌呤氧化酶，NADPH氧化酶

髓过氧化酶和单氨氧化酶自由基形成线粒体破坏MMP活化钙离子超载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.自由基可以损害细胞和DNAMMP活化细胞处理过程失调内皮细胞DNA氧化损伤自由基线粒体破坏细胞膜破坏References:

1.LiptonP.Ischemiccelldeathinbrainneurons.PhysiologicalReviews.Oct1999;

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

anintegratedview.TrendsNeurosci.1999;22(9):391-7.自由基损伤线粒体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/再灌注使自由基产生增加神经细胞胶质细胞内皮细胞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结论TheadministrationofNXY-059withinsixhoursaftertheonsetofacuteischemicstrokesignificantlyimprovedtheprimaryoutcome(reduceddisabilityat90days),butitdidnotsignificantlyimproveotheroutcomemeasures,includingneurologicfunctioningasmeasuredbytheNIHSSscore.AdditionalresearchisneededtoconfirmwhetherNXY-059isbeneficialinischemicstroke.TreatmentInteractionswithImportantCovariatesPrimaryOutcomeat90DaysAccordingto

theScoreontheModifiedRankinScaleSAINT-IINXY-059isineffectiveforthetreatmentofacuteischemicstrokewithin6hoursaftertheonsetofsymptoms.国内II期临床结果入组病例229例，实际完成病例213例ESS评分：神经功能缺损评分、有效率在第7天、14天、21天均有显著性差异，且随着时间延长差异逐步明显；ADL评分：日常生活活动量表评分、有效率在第7天、14天、21天、90天均有显著性差异，且随着时间延长差异逐步明显*复旦大学附属华山医院,第二军医大学长征医院,浙江大学医学院第二附属医院,江苏省人民医院南京医科大学附属脑科医院，必存®治疗急性脑堵塞____随机、双盲、叠加、对照、多中心临床试验依达拉奉组对照组<24hr最终综合改善率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最终综合改善率64.8％(81例/125例)32.0％(40例/125例)日本III期临床CerebrovascularDiseases2003;15(3):222-9Effectofanovelfreeradicalscavenger,edaravone(MCI-186),onacutebraininfarction.Randomized,placebo-controlled,double-blindstudyatmulticenters.三期临床有效!EdaravoneAcuteInfarctionStudyGroup,CerebrovascularDiseases2003;15(3):222-9神经保护治疗的概念神经保护剂的现状从失败到睿智自由基去除剂神经保护剂的分层用药神经保护剂的联合用药KidwellCSetal,AnnNeurol52:698-703,2002Reperfusioninjury?再灌注增加自由基的产生MMP

活化再灌注DNA氧化损伤自由基炎性细胞活化细胞因子(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