缺血性脑卒中机理以及新药研究进展

The science of ischemic stroke:,mechanisms and therapies,What is cerebral ischemic strokeWhat cause cerebral ischemic strokeWhat are the prominent mechanisms of strokeCurrent approaches for stroke therapeutics,Cerebral ischemic stroke,Cerebral ischemic 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 intrace- rebral hemorrhage.,Stroke 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 continue to rise with the population living longer than previous generations. As such, effective treatments for stroke are urgently needed.,Stroke Risk Factors and Triggers,Mechanisms of Stroke,ExcitotoxicityMitochondrial responseReactive oxygen species (ROS) Endoplasmic reticulum stressInflammatory ApoptosisInflammatoryRepair,Acute Period,Subacute Period,Chronic Period,Depolarization,Na+/ K+ pump failure,CNS ischemia,Deficiency of glucose and oxygen,Unable to maintain the ionic gradients,Excessiveglutamate release,Excitotoxicity,Excitotoxicity,Mitochondrial response,Reactive oxygen species (ROS),Endoplasmic reticulum stress,Inflammatory,Current approaches for stroke therapeutics,Blocking Excitotoxic Events.,TABLE 1: Examples of proposed neuroprotectants attempting to mitigate excitotoxicity, and the progression from preclinical experimental stroke models to clinical trials,Noncompetitive 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 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.,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 study on stroke patients.,Preclinical Output,Fig.2 Representative tracings of (TTC)stained brain slices.,Fig.3 slice infarction volumes in control and MgSO4-treated animals,PhaseIII,Currently, the FAST-MAG (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 progress,Clinical Output,Clinical Output,Fig 4: Kaplan-meier plot of cumulative mortality,TABLE2:Examples of proposed neuroprotective attempts to against oxidative stress,Free-Radical Scavenging,Mechanisms:Proposed interaction of edaravone with free radicals.,Edaravone.(依达拉奉）,Preclinical Output,Figure1 B, Infarct volume was compared between the control and different edaravone groups,Figure 1. A, Coronal sections from ischemic mice brain stained with TTC,Preclinical Output,Figure 3. Edaravone protected HT22 cells against glutamate-induced oxidative stress,Figure 2. Glutamate-induced oxidative damage in the HT22 neuronal cell line,Preclinical Output,Figure 4. Hydrogen peroxide (H2O2)-induced cell damage in cultured rat astrocytes,Figure 5 .Alteration of the lesion size,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 and citicoline in acute ischemic stroke, edaravone wasmore effective with a better neurological outcome at 3 months than citicoline,Clinical Output,Figure 6 . Alteration of the lesion size by different stroke subtypes.,cardioembolism,the large-arteryatherosclerosis,the small-vessel occlusion,Table3 Brif overview of ongoing phase III trials of neuroprotective agents,LOREM,Preclinical Output,Clinical Output,Failed?,Time window,short time windowslonger time windows,1,Target,ischemic penumbra NOT,2,Duration,the optimal durationis unknown,3,Outcome,early outcomes late assessments,4,Diversity of stroke types,middle cerebral artery occlusion as a model of ischemic stroke pathophysiological heterogeneity,5,Differences in comorbidities,young healthy rodents stroke patients often suffer from several severe comorbidities,6,preclinical studies clinical trials,v,Future Directions,Establish animal models resembling the human diseaseFrom neuroprotection to full“cerebroprotectionFrom neuronal function to neurovascular unitUnderstanding Biphasic SignalingStroke treatments and “Precision Medicine”,1. 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 ItsImpactonClinicalTreatments. Neuron.2015 Jul 15;87(2):297-309. doi: 10.1