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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.(依達(dá)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,
SteinbergGK2.Novel
Stroke
Therapeutics:
Unraveling
Stroke
Pathophysiology
andIts
Impact
on
Clinical
Treatments.Neuron.
2015Jul15;87(2):297-309.
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