缺血性脑卒中机理以及新药研究进展课件

缺血性缺血性脑卒中机理以卒中机理以及新及新药研究研究进展展缺血性脑卒中机理以及新药研究进展缺血性脑卒中机理以及新药研究What is cerebral ischemic strokeWhat cause cerebral ischemic strokeWhat are the prominent mechanisms of strokeCurrent approaches for stroke therapeutics2WhatiscerebralischemicstroCerebral ischemic strokeCerebral ischemic isaconditioninwhichthereisinsufficientbloodflowtothebraintomeetmetabolicdemand.Thisleadstopooroxygensupplyorcerebralhypoxiaandthustothedeathofbraintissueorcerebralinfarction/ischemicstroke.Itisasub-typeofstrokealongwithsubarachnoidhemorrhageandintrace-rebralhemorrhage.3CerebralischemicstrokeCerebStrokeisresponsiblefor9%ofdeathsworldwide,makingitthesecondmostcommoncauseofmortality.Morethan25%ofstrokesurvivorsbecomepermanentlydisabledandloseindependenceinperformingday-to-dayactivities.Thesefigureswillcontinuetorisewiththepopulationlivinglongerthanpreviousgenerations.Assuch,effectivetreatmentsforstrokeareurgentlyneeded.4Strokeisresponsiblefor9%o55Stroke Risk Factors and Triggers6StrokeRiskFactorsandTrigge7788MechanismsofStrokeExcitotoxicityMitochondrialresponseReactiveoxygenspecies(ROS)EndoplasmicreticulumstressInflammatoryApoptosisInflammatoryRepairAcutePeriodSubacutePeriodChronicPeriod9MechanismsofStrokeExcitotoxDepolarizationNa+/K+pumpfailureCNSischemiaDeficiencyofglucoseandoxygen Unabletomaintaintheionic gradientsExcessiveglutamatereleaseExcitotoxicitExcitotoxicitExcitotoxicitExcitotoxicity y y yExcitotoxicitExcitotoxicity y10DepolarizationNa+/K+pumpfai11111212131314141515Mitochondrialresponse16Mitochondrialresponse16Reactiveoxygenspecies(ROS)17Reactiveoxygenspecies(ROS)1Endoplasmicreticulumstress18Endoplasmicreticulumstress1Inflammatory19Inflammatory19Currentapproachesforstroketherapeutics20CurrentapproachesforstrokeBlockingExcitotoxicEvents.NMDAreceptorantagonists01AMPAreceptorantagonists02GABAAreceptoragonists035-HT1Areceptoragonist 4potassiumchannelopeners05kappaopiatereceptorantagonists0621BlockingExcitotoxicEvents.NM2222TABLE 1:Examples of proposed neuroprotectants attempting to mitigate excitotoxicity,and the progression from preclinical experimental stroke models to clinical trials23TABLE1:ExamplesofproposedNoncompetitive NMDA AntagonistsMagnesiumThemechanismofneuroprotectionbymagnesiumremainsuncertain:increasingmagnesiumconcentrationreducespresynapticreleaseoftheneurotransmitterglutamate,blocksglutamatergicN-methyl-Daspartatereceptors,potentiatesadenosineaction,improvesmitochondrialcalciumbuffering,andblockscalciumentryviavoltage-gatedchannels.Furthermore,ithascardiovasculareffects,notablyenhancedcerebralperfusionafterMCAO9andraisedcardiacoutput.24NoncompetitiveNMDAAntagonist Preclinical Output Fig.1 the effects of MgSO4 pretreatment on infarct volumes MagnesiumhasdemonstrateditsneuroprotectiveeffectinanimalstudiesaswellasinaphaseIIstudyonstrokepatients.25PreclinicalOutputFig.1 Preclinical Output Fig.2 Representative tracings of(TTC)stained brain slices.Fig.3 slice infarction volumes in control and MgSO4-treated animals26PreclinicalOutputFig.2RePhaseIIICurrently,theFAST-MAG(FieldAdministrationofStrokeTherapyMagnesium)trialincludes1,700strokepatientsreceivingadoseof4g(intravenously)over15min,followedbyamaintenanceinfusionof16gover24hafterarrivalatthehospital;itwasstartedinJanuary2005andisstillinprogressClinical Output27PhaseIIICurrently,theFAST-MAClinical OutputFig 4:Kaplan-meier plot of cumulative mortality 28ClinicalOutputFig4:Kaplan-TABLE2:ExamplesofproposedneuroprotectiveattemptstoagainstoxidativestressFree-RadicalScavenging29TABLE2:ExamplesofproposedneMechanisms:Proposedinteractionofedaravonewithfreeradicals.Edaravone.(依达拉奉）30Mechanisms:Proposedinteractio Preclinical OutputFigure1B,InfarctvolumewascomparedbetweenthecontrolanddifferentedaravonegroupsFigure 1.A,Coronal sections from ischemic mice brain stained with TTC31PreclinicalOutputFigure1B,Preclinical OutputFigure 3.Edaravone protected HT22 cells against glutamate-induced oxidative stressFigure 2.Glutamate-induced oxidative damage in the HT22 neuronal cell line32PreclinicalOutputFigure3.EdPreclinical Output Figure 4.Hydrogen peroxide(H2O2)-induced cell damage in cultured rat astrocytesFigure 5.Alteration of the lesion size33PreclinicalOutputFigure4.HClinicalOutputEdaravoneamelioratedthesizeofischemicstrokelesionsandneurologicaldeficitsinpatientswithsmall-vesselocclusion,i.e.lacunarinfarction,within1year,whiletherewerenosignificantdifferencesinoutcomeafter1year.Inastudycomparingedaravoneandciticolineinacuteischemicstroke,edaravonewasmoreeffectivewithabetterneurologicaloutcomeat3monthsthanciticoline3434Clinical OutputFigure 6.Alteration of the lesion size by different stroke subtypes.cardioembolism the large-arteryatherosclerosis the small-vessel occlusion35ClinicalOutputFigure6.AlteTable3 Brif overview of ongoing phase III trials of neuroprotective agents36Table3BrifoverviewofongoiLOREM Preclinical Output Clinical OutputFailed?37LOREMPreclinicalOutputCliniTimewindowshorttimewindowslongertimewindows1TargetischemicpenumbraNOT2Durationtheoptimaldurationisunknown3Outcomeearlyoutcomes late assessments4Diversity of stroketypes middlecerebralarteryocclusionasamodelofischemicstrokepathophysiologicalheterogeneity5Differencesincomorbidities younghealthyrodentsstroke patients oftensuffer from several severecomorbidities6 preclinicalstudiesclinicaltrialsv38TimewindowshorttimewindowsFutureDirectionsEstablishanimalmodelsresemblingthehumandiseaseFromneuroprotectiontofull“cerebroprotectionFromneuronalfunctiontoneurovascularunitUnderstandingBiphasicSignalingStroketreatmentsand“PrecisionMedicine”39FutureDirectionsEstablishani1.MoskowitzMA1,LoEH,IadecolaC.Thescienceofstroke:mechanismsinsearchoftreatments.Neuron.2010Jul29;67(2):181-98.doi:10.1016/j.neuron.2010.07.0022.KingaSzydlowskaa,b,MichaelTymianski.Calcium,ischemiaandexcitotoxicityCellCalcium.2010Feb;47(2):122-9.doi:10.1016/j.ceca.2010.01.003.Epub2010Feb18.3.GeorgePM1,SteinbergGK2.NovelStrokeTherapeutics:UnravelingStrokePathophysiologyandItsImpactonClinicalTreatments.Neuron.2015Jul15;87(2):297-309.doi:10.1016/j.neuron.2015.05.041.4.KaurH,PrakashA,MedhiB.Drugtherapyinstroke:frompreclinicaltoclinicalstudies.Pharmacology.2013;92(5-6):324-34.Epub2013Dec12.5.TurnerRC1,DodsonSC,RosenCL.Thescienceofcerebralischemiaandthequestforneuroprotection:navigatingpastfailuretofuturesuccess.JNeurosurg.2013May;118(5):1072-85.doi:10.3171/2012.11.JNS12408.Epub2013Jan18.6.BaeON1,SerfozoK,BaekSHetal.Safetyandefficacyevaluationofcarnosine,anendogenousneuroprotectiveagentforischemicstroke.Stroke.2013Jan;44(1):205-12.doi:10.1161/STROKEAHA.112.673954.Epub2012Dec18.References401.MoskowitzMA1,LoEH,IadecTHANKYOU41THANKYOU41谢谢！谢谢！