缺血性腦卒中機(jī)理以及新藥研究進(jìn)展課件

1、缺血性腦卒中機(jī)理以及新藥研究進(jìn)展缺血性腦卒中機(jī)理以及新藥研究進(jìn)展缺血性腦卒中機(jī)理以及新藥研究進(jìn)展缺血性腦卒中機(jī)理以及新藥研究進(jìn)展缺血性腦卒中機(jī)理以及新藥研究What is cerebral ischemic strokeWhat cause cerebral ischemic strokeWhat are the prominent mechanisms of strokeCurrent approaches for stroke therapeutics2What is cerebral ischemic stroCerebral ischemic stroke Cerebral ische

2、mic is a condition in which there is insufficient blood flow to the brain to 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 int

3、race- rebral hemorrhage.3Cerebral ischemic stroke CerebStroke is responsible for 9% of deaths worldwide, making 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 c

4、ontinue to rise with the population living longer than previous generations. As such, effective treatments for stroke are urgently needed.4Stroke is responsible for 9% o55Stroke Risk Factors and Triggers6Stroke Risk Factors and Trigge7788Mechanisms of StrokeExcitotoxicityMitochondrial responseReacti

5、ve oxygen species (ROS) Endoplasmic reticulum stressInflammatory ApoptosisInflammatoryRepairAcute PeriodSubacute PeriodChronic Period9Mechanisms of StrokeExcitotoxDepolarizationNa+/ K+ pump failureCNS ischemiaDeficiency of glucose and oxygen Unable to maintain the ionic gradientsExcessiveglutamate r

6、eleaseExcitotoxicityExcitotoxicity10DepolarizationNa+/ K+ pump fai11111212131314141515Mitochondrial response16Mitochondrial response16Reactive oxygen species (ROS)17Reactive oxygen species (ROS)1 Endoplasmic reticulum stress18 Endoplasmic reticulum stress1Inflammatory 19Inflammatory 19Current approa

7、ches for stroke therapeutics20Current approaches for strokeBlocking Excitotoxic Events.NMDA receptor antagonists01 AMPA receptor antagonists02 GABAA receptor agonists035-HT1A receptor agonist 4 potassium channel openers05kappa opiate receptor antagonists0621Blocking Excitotoxic Events.NM2222TABLE 1:

8、 Examples of proposed neuroprotectants attempting to mitigate excitotoxicity, and the progression from preclinical experimental stroke models to clinical trials23TABLE 1: Examples of proposed Noncompetitive NMDA AntagonistsMagnesium The mechanism of neuroprotection by magnesium remains uncertain: in

9、creasing magnesium concentration reduces presynaptic release of the neurotransmitter glutamate,blocks glutamatergic N-methyl-Daspartate receptors,potentiates adenosine action,improves mitochondrial calcium buffering, and blocks calcium entry via voltage-gated channels. Furthermore, it has cardiovasc

10、ular effects, notably enhanced cerebral perfusion after MCAO9 and raised cardiac output.24Noncompetitive NMDA Antagonist Preclinical Output Fig.1 the effects of MgSO4 pretreatment on infarct volumes Magnesium has demonstrated its neuroprotective effect in animal studies as well as in a phase II stud

11、y on stroke patients.25 Preclinical Output Fig.1 Preclinical Output Fig.2 Representative tracings of (TTC)stained brain slices. Fig.3 slice infarction volumes in control and MgSO4-treated animals26 Preclinical Output Fig.2 RePhaseIIICurrently, the FAST-MAG (Field Administration of Stroke Therapy Mag

12、nesium) 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 Output27PhaseIIICurrently, the FAST-MAClinical OutputF

13、ig 4: Kaplan-meier plot of cumulative mortality 28Clinical OutputFig 4: Kaplan-TABLE2:Examples of proposed neuroprotective attempts to against oxidative stressFree-Radical Scavenging29TABLE2:Examples of proposed neMechanisms:Proposed interaction of edaravone with free radicals. Edaravone.(依達(dá)拉奉）30Mec

14、hanisms:Proposed interactio Preclinical OutputFigure1 B, Infarct volume was compared between the control and different edaravone groupsFigure 1. A, Coronal sections from ischemic mice brain stained with TTC31 Preclinical OutputFigure1 B, Preclinical OutputFigure 3. Edaravone protected HT22 cells aga

15、inst glutamate-induced oxidative stressFigure 2. Glutamate-induced oxidative damage in the HT22 neuronal cell line32Preclinical OutputFigure 3. EdPreclinical Output Figure 4. Hydrogen peroxide (H2O2)-induced cell damage in cultured rat astrocytesFigure 5 .Alteration of the lesion size33Preclinical O

16、utput Figure 4. H Clinical OutputEdaravone ameliorated the size of ischemic stroke lesions and neurological deficits in patients with small-vessel occlusion, i.e. lacunar infarction, within 1 year, while there were no significant differences in outcome after 1 year. In a study comparing edaravone an

17、d citicoline in acute ischemic stroke, edaravone wasmore effective with a better neurological outcome at 3 months than citicoline3434Clinical OutputFigure 6 . Alteration of the lesion size by different stroke subtypes. cardioembolism the large-arteryatherosclerosis the small-vessel occlusion35Clinic

18、al OutputFigure 6 . AlteTable3 Brif overview of ongoing phase III trials of neuroprotective agents36Table3 Brif overview of ongoiLOREM Preclinical Output Clinical OutputFailed?37LOREM Preclinical Output Clini Time windowshort time windowslonger time windows 1 Target ischemic penumbra NOT2Duration th

19、e 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 severe comorbidi

20、ties6 preclinical studies clinical trialsv38 Time windowshort time windowsFuture DirectionsEstablish animal models resembling the human diseaseFrom neuroprotection to full“cerebroprotectionFrom neuronal function to neurovascular unitUnderstanding Biphasic SignalingStroke treatments and “Precision Me

21、dicine” 39Future DirectionsEstablish ani1. Moskowitz 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 CellCalcium.2010 Feb;47(2):122-9. doi: 10.1016/j.ceca.2010.01.003. Epub 2010 Feb 18.3. George PM1,Steinberg GK2. NovelStrokeTherapeutics:UnravelingStrokePathophysiologyand ItsImpacton