缺血性脑卒中机理以及新药研究进展 PPT课件.pptx

Thescienceofischemicstroke:mechanisms and therapies What is cerebral ischemic strokeWhat cause cerebral ischemic strokeWhat are the prominent mechanisms of strokeCurrent approaches for stroke therapeuticsCerebral ischemic strokeCerebral ischemic isaconditioninwhichthereisinsufficientbloodflowtothebraintomeetmetabolicdemand.Thisleadstopooroxygensupplyorcerebralhypoxiaandthustothedeathofbraintissueorcerebralinfarction/ischemicstroke.Itisasub-typeofstrokealongwithsubarachnoidhemorrhageandintrace-rebralhemorrhage.Strokeisresponsiblefor9%ofdeathsworldwide,makingitthesecondmostcommoncauseofmortality.Morethan25%ofstrokesurvivorsbecomepermanentlydisabledandloseindependenceinperformingday-to-dayactivities.Thesefigureswillcontinuetorisewiththepopulationlivinglongerthanpreviousgenerations.Assuch,effectivetreatmentsforstrokeareurgentlyneeded.Stroke Risk Factors and TriggersMechanismsofStrokeExcitotoxicityMitochondrialresponseReactiveoxygenspecies(ROS)EndoplasmicreticulumstressInflammatoryApoptosisInflammatoryRepairAcutePeriodSubacutePeriodChronicPeriodDepolarizationNa+/K+pumpfailureCNSischemiaDeficiencyofglucoseandoxygen Unabletomaintaintheionic gradientsExcessiveglutamatereleaseExcitotoxicityExcitotoxicityExcitotoxicityMitochondrialresponseReactiveoxygenspecies(ROS)EndoplasmicreticulumstressInflammatoryCurrentapproachesforstroketherapeuticsBlockingExcitotoxicEvents.NMDAreceptorantagonists01AMPAreceptorantagonists02GABAAreceptoragonists035-HT1Areceptoragonist 4potassiumchannelopeners05kappaopiatereceptorantagonists06TABLE 1:Examples of proposed neuroprotectants attempting to mitigate excitotoxicity,and the progression from preclinical experimental stroke models to clinical trialsNoncompetitive NMDA AntagonistsMagnesiumThemechanismofneuroprotectionbymagnesiumremainsuncertain:increasingmagnesiumconcentrationreducespresynapticreleaseoftheneurotransmitterglutamate,blocksglutamatergicN-methyl-Daspartatereceptors,potentiatesadenosineaction,improvesmitochondrialcalciumbuffering,andblockscalciumentryviavoltage-gatedchannels.Furthermore,ithascardiovasculareffects,notablyenhancedcerebralperfusionafterMCAO9andraisedcardiacoutput.Fig.1 the effects of MgSO4 pretreatment on infarct volumes MagnesiumhasdemonstrateditsneuroprotectiveeffectinanimalstudiesaswellasinaphaseIIstudyonstrokepatients.Fig.2 Representative tracings of(TTC)stained brain slices.Fig.3 slice infarction volumes in control and MgSO4-treated animalsPhaseIIICurrently,theFAST-MAG(FieldAdministrationofStrokeTherapyMagnesium)trialincludes1,700strokepatientsreceivingadoseof4g(intravenously)over15min,followedbyamaintenanceinfusionof16gover24hafterarrivalatthehospital;itwasstartedinJanuary2005andisstillinprogressFig 4:Kaplan-meier plot of cumulative mortality TABLE2:ExamplesofproposedneuroprotectiveattemptstoagainstoxidativestressFree-RadicalScavengingMechanisms:Proposedinteractionofedaravonewithfreeradicals.Edaravone.(依达拉奉）Figure1 B,Infarct volume was compared between the control and different edaravone groupsFigure 1.A,Coronal sections from ischemic mice brain stained with TTCFigure 3.Edaravone protected HT22 cells against glutamate-induced oxidative stressFigure 2.Glutamate-induced oxidative damage in the HT22 neuronal cell line Figure 4.Hydrogen peroxide(H2O2)-induced cell damage in cultured rat astrocytesFigure 5.Alteration of the lesion sizeEdaravoneamelioratedthesizeofischemicstrokelesionsandneurologicaldeficitsinpatientswithsmall-vesselocclusion,i.e.lacunarinfarction,within1year,whiletherewerenosignificantdifferencesinoutcomeafter1year.Inastudycomparingedaravoneandciticolineinacuteischemicstroke,edaravonewasmoreeffectivewithabetterneurologicaloutcomeat3monthsthanciticolineFigure 6.Alteration of the lesion size by different stroke subtypes.cardioembolism the large-arteryatherosclerosis the small-vessel occlusionTable3 Brif overview of ongoing phase III trials of neuroprotective agentsLOREM Failed?Timewindowshorttimewindowslongertimewindows1TargetischemicpenumbraNOT2Durationtheoptimaldurationisunknown3Outcomeearlyoutcomes late assessments4Diversity of stroketypes middlecerebralarteryocclusionasamodelofischemicstrokepathophysiologicalheterogeneity5Differencesincomorbidities younghealthyrodentsstroke patients oftensuffer from several severecomorbidities6 preclinicalstudiesclinicaltrialsvFutureDirectionsEstablishanimalmodelsresemblingthehumandiseaseFromneuroprotectiontofull“cerebroprotectionFromneuronalfunctiontoneurovascularunitUnderstandingBiphasicSignalingStroketreatmentsand“PrecisionMedicine”1.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.References 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