1、缺血性脑卒中机理以缺血性脑卒中机理以及新药研究进展及新药研究进展What is cerebral ischemic strokeWhat cause cerebral ischemic strokeWhat are the prominent mechanisms of strokeCurrent approaches for stroke therapeutics2Cerebral ischemic stroke Cerebral ischemic is a condition in which there is insufficient blood flow to the brain to
2、 meet metabolic demand.This leads to poor oxygen supply or cerebral hypoxia and thus to the death of brain tissue or cerebral infarction/ischemic stroke.It is a sub-type of stroke along with subarachnoid hemorrhage and intrace-rebral hemorrhage.3Stroke is responsible for 9%of deaths worldwide,making
3、 it the second most common cause of mortality.More than 25%of stroke survivors become permanently disabled and lose independence in performing day-to-day activities.These figures will continue to rise with the population living longer than previous generations.As such,effective treatments for stroke
4、 are urgently needed.45Stroke Risk Factors and Triggers678Mechanisms of Stroke Excitotoxicity Mitochondrial response Reactive oxygen species(ROS)Endoplasmic reticulum stress Inflammatory Apoptosis Inflammatory RepairAcute PeriodSubacute PeriodChronic Period9DepolarizationNa+/K+pump failureCNS ischem
5、iaDeficiency of glucose and oxygen Unable to maintain the ionic gradientsExcessiveglutamate release101112131415Mitochondrial response16Reactive oxygen species(ROS)17 Endoplasmic reticulum stress18Inflammatory 19Current approaches for stroke therapeutics20Blocking Excitotoxic Events.NMDA receptor ant
6、agonists01 AMPA receptor antagonists02 GABAA receptor agonists035-HT1A receptor agonist 4 potassium channel openers05kappa opiate receptor antagonists062122TABLE 1:Examples of proposed neuroprotectants attempting to mitigate excitotoxicity,and the progression from preclinical experimental stroke mod
7、els to clinical trials23Noncompetitive NMDA Antagonists Magnesium The mechanism of neuroprotection by magnesium remains uncertain:increasing magnesium concentration reduces presynaptic release of the neurotransmitter glutamate,blocks glutamatergic N-methyl-Daspartate receptors,potentiates adenosine
8、action,improves mitochondrial calcium buffering,and blocks calcium entry via voltage-gated channels.Furthermore,it has cardiovascular effects,notably enhanced cerebral perfusion after MCAO9 and raised cardiac output.24 Preclinical Output Fig.1 the effects of MgSO4 pretreatment on infarct volumes Mag
9、nesium has demonstrated its neuroprotective effect in animal studies as well as in a phase II study on stroke patients.25 Preclinical Output Fig.2 Representative tracings of(TTC)stained brain slices.Fig.3 slice infarction volumes in control and MgSO4-treated animals26PhaseIII Currently,the FAST-MAG(
10、Field Administration of Stroke Therapy Magnesium)trial includes 1,700 stroke patients receiving a dose of 4 g(intravenously)over 15 min,followed by a maintenance infusion of 16 g over 24 h after arrival at the hospital;it was started in January 2005 and is still in progressClinical Output27Clinical
11、OutputFig 4:Kaplan-meier plot of cumulative mortality 28TABLE2:Examples of proposed neuroprotective attempts to against oxidative stressFree-Radical Scavenging29Mechanisms:Proposed interaction of edaravone with free radicals.Edaravone.(依达拉奉）30 Preclinical OutputFigure1 B,Infarct volume was compared
12、between the control and different edaravone groupsFigure 1.A,Coronal sections from ischemic mice brain stained with TTC31Preclinical OutputFigure 3.Edaravone protected HT22 cells against glutamate-induced oxidative stressFigure 2.Glutamate-induced oxidative damage in the HT22 neuronal cell line32Pre
13、clinical Output Figure 4.Hydrogen peroxide(H2O2)-induced cell damage in cultured rat astrocytesFigure 5.Alteration of the lesion size33 Clinical OutputEdaravone ameliorated the size of ischemic stroke lesions and neurological deficits in patients with small-vessel occlusion,i.e.lacunar infarction,wi
14、thin 1 year,while there were no significant differences in outcome after 1 year.In a study comparing edaravone and citicoline in acute ischemic stroke,edaravone wasmore effective with a better neurological outcome at 3 months than citicoline34Clinical OutputFigure 6.Alteration of the lesion size by
15、different stroke subtypes.cardioembolism the large-arteryatherosclerosis the small-vessel occlusion35Table3 Brif overview of ongoing phase III trials of neuroprotective agents36LOREM Preclinical Output Clinical Output37 Time windowshort time windowslonger time windows 1 Target ischemic penumbra NOT2
16、Duration the optimal durationis unknown3Outcome early outcomes late assessments4Diversity of stroke types middle cerebral artery occlusion as a model of ischemic stroke pathophysiological heterogeneity5Differences in comorbidities young healthy rodents stroke patients often suffer from several sever
17、e comorbidities6 preclinical studies clinical trialsv38Future Directions Establish animal models resembling the human disease From neuroprotection to full“cerebroprotection From neuronal function to neurovascular unit Understanding Biphasic Signaling Stroke treatments and“Precision Medicine”391.Mosk
18、owitz MA1,Lo EH,Iadecola C.The science of stroke:mechanisms in search of treatments.Neuron.2010 Jul 29;67(2):181-98.doi:10.1016/j.neuron.2010.07.0022.Kinga Szydlowska a,b,Michael Tymianski.Calcium,ischemia and excitotoxicity Cell Calcium.2010 Feb;47(2):122-9.doi:10.1016/j.ceca.2010.01.003.Epub 2010
19、Feb 18.3.George PM1,Steinberg GK2.Novel Stroke Therapeutics:Unraveling Stroke Pathophysiology and Its Impact on Clinical Treatments.Neuron.2015 Jul 15;87(2):297-309.doi:10.1016/j.neuron.2015.05.041.4.Kaur H,Prakash A,Medhi B.Drug therapy in stroke:from preclinical to clinicalstudies.Pharmacology.201
20、3;92(5-6):324-34.Epub 2013 Dec 12.5.Turner RC1,Dodson SC,Rosen CL.The science of cerebral ischemia and the quest for neuroprotection:navigating past failure to future success.J Neurosurg.2013 May;118(5):1072-85.doi:10.3171/2012.11.JNS12408.Epub 2013 Jan 18.6.Bae ON1,Serfozo K,Baek SH et al.Safety and efficacy evaluation of carnosine,an endogenous neuroprotective agent for ischemic stroke.Stroke.2013 Jan;44(1):205-12.doi:10.1161/STROKEAHA.112.673954.Epub 2012 Dec 18.References40THANKYOU41谢谢！
