缺血性脑卒中机理以及新药研究进展

Thescienceofischemicstroke:mechanismsandtherapies

WhatiscerebralischemicstrokeWhatcausecerebralischemicstrokeWhataretheprominentmechanismsofstrokeCurrentapproachesforstroketherapeuticsCerebralischemicstroke

Cerebralischemicisaconditioninwhichthereisinsufficientbloodflowtothebraintomeetmetabolicdemand.Thisleadstopooroxygensupplyorcerebralhypoxiaandthustothedeathofbraintissueorcerebralinfarction/ischemicstroke.Itisasub-typeofstrokealongwithsubarachnoidhemorrhageandintrace-rebralhemorrhage.Strokeisresponsiblefor9%ofdeathsworldwide,makingitthesecondmostcommoncauseofmortality.Morethan25%ofstrokesurvivorsbecomepermanentlydisabledandloseindependenceinperformingday-to-dayactivities.Thesefigureswillcontinuetorisewiththepopulationlivinglongerthanpreviousgenerations.Assuch,effectivetreatmentsforstrokeareurgentlyneeded.StrokeRiskFactorsandTriggers

MechanismsofStrokeExcitotoxicityMitochondrialresponseReactiveoxygenspecies(ROS)EndoplasmicreticulumstressInflammatoryApoptosisInflammatoryRepairAcutePeriodSubacutePeriodChronicPeriodDepolarizationNa+/K+pumpfailureCNSischemiaDeficiencyofglucoseandoxygen

Unabletomaintaintheionic

gradientsExcessiveglutamatereleaseExcitotoxicityExcitotoxicityMitochondrialresponseReactiveoxygenspecies(ROS)EndoplasmicreticulumstressInflammatory

CurrentapproachesforstroketherapeuticsBlockingExcitotoxicEvents.NMDAreceptorantagonists01

AMPAreceptorantagonists02GABAAreceptoragonists035-HT1Areceptoragonist

4

potassiumchannelopeners05kappaopiatereceptorantagonists06TABLE1:Examplesofproposedneuroprotectantsattemptingtomitigateexcitotoxicity,andtheprogressionfrompreclinicalexperimentalstrokemodelstoclinicaltrialsNoncompetitiveNMDAAntagonistsMagnesiumThemechanismofneuroprotectionbymagnesiumremainsuncertain:increasingmagnesiumconcentrationreducespresynapticreleaseoftheneurotransmitterglutamate,blocksglutamatergicN-methyl-Daspartatereceptors,potentiatesadenosineaction,improvesmitochondrialcalciumbuffering,andblockscalciumentryviavoltage-gatedchannels.Furthermore,ithascardiovasculareffects,notablyenhancedcerebralperfusionafterMCAO9andraisedcardiacoutput.

PreclinicalOutput

Fig.1theeffectsofMgSO4pretreatmentoninfarctvolumesMagnesiumhasdemonstrateditsneuroprotectiveeffectinanimalstudiesaswellasinaphaseIIstudyonstrokepatients.

PreclinicalOutput

Fig.2Representativetracingsof(TTC)–stainedbrainslices.

Fig.3sliceinfarctionvolumesincontrolandMgSO4-treatedanimalsPhaseIIICurrently,theFAST-MAG(FieldAdministrationofStrokeTherapy–Magnesium)trialincludes1,700strokepatientsreceivingadoseof4g(intravenously)over15min,followedbyamaintenanceinfusionof16gover24hafterarrivalatthehospital;itwasstartedinJanuary2005andisstillinprogressClinicalOutputClinicalOutputFig4:Kaplan-meierplotofcumulativemortalityTABLE2:ExamplesofproposedneuroprotectiveattemptstoagainstoxidativestressFree-RadicalScavengingMechanisms:Proposedinteractionofedaravonewithfreeradicals.Edaravone.(依达拉奉）

PreclinicalOutputFigure1B,InfarctvolumewascomparedbetweenthecontrolanddifferentedaravonegroupsFigure1.A,CoronalsectionsfromischemicmicebrainstainedwithTTCPreclinicalOutputFigure3.EdaravoneprotectedHT22cellsagainstglutamate-inducedoxidativestressFigure2.Glutamate-inducedoxidativedamageintheHT22neuronalcelllinePreclinicalOutputFigure4.Hydrogenperoxide(H2O2)-inducedcelldamageinculturedratastrocytesFigure5

.AlterationofthelesionsizeClinicalOutputEdaravoneamelioratedthesizeofischemicstrokelesionsandneurologicaldeficitsinpatientswithsmall-vesselocclusion,i.e.lacunarinfarction,within1year,whiletherewerenosignificantdifferencesinoutcomeafter1year.Inastudycomparingedaravoneandciticolineinacuteischemicstroke,edaravonewasmoreeffectivewithabetterneurologicaloutcomeat3monthsthanciticolineClinicalOutputFigure6

.Alterationofthelesionsizebydifferentstrokesubtypes.cardioembolismthelarge-arteryatherosclerosisthesmall-vesselocclusionTable3BrifoverviewofongoingphaseIIItrialsofneuroprotectiveagentsLOREM

PreclinicalOutput

ClinicalOutputFailed???Timewindowshorttimewindowslongertimewindows1Targetischemicpenumbra

NOT2Durationtheoptimaldurationisunknown3Outcomeearlyoutcomes

lateassessments4Diversityofstroketypes

middlecerebralarteryocclusionasamodelofischemicstrokepathophysiologicalheterogeneity5Differencesincomorbidities

younghealthyrodentsstrokepatientsoftensufferfromseveralseverecomorbidities6

preclinicalstudies

clinicaltrialsvFutureDirectionsEstablishanimalmodelsresemblingthehumandiseaseFromneuroprotectiontofull“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,ischemiaandexcitotoxicityCell

Calcium.

2010Feb;47(2):122-9.doi:10.1016/j.ceca.2010.01.003.Epub2010Feb18.3.GeorgePM1,

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Stroke

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Stroke

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2015Jul15;87(2):297-309.