DELAYED REPERFUSION WITH TPA IN THROMBOEMBOLIC STROKE

随着纤维蛋白特异性溶栓剂的出现， 对脑卒中溶栓治疗感兴趣。 目前了解的 中风的病理生理学表明再通的安全性 阻塞的脑血管，因为它涉及神经元的挽救， 再灌注损伤，是强度、持续时间和体积的函数 缺血性损伤 此外，越来越多的证据表明， 中性粒细胞可能在再灌注损伤中起重要作用。 这 建议旨在严格确定安全时限， 在血栓栓塞性中风模型中用tPA建立再灌注，和 随后审查，单独和组合， 阴离子通道阻滞剂L 644，711和抗氧化剂U 74006 F，以延长这一点， 时间限制，并评估其对中性粒细胞活化的影响， 受损脑组织的浸润 提出了一种兔子模型， 有初步数据支持。 该模型涉及标准化， 通过确保脑血流量的临界减少来减少梗死面积， 确保缺血性血流标准水平，如氢记录的 间隙tPA（3.5mg/kg），以方波脉冲给药，将被 在注射锡后不同时间（0 -8小时）开始 浸渍的颈内动脉栓子。 颅内压， 局部脑血流量，动脉血气，红细胞压积，血清 葡萄糖、血清尿酸、白色细胞聚集和血管通畅将 在整个实验过程中进行监控。 大脑将被收集， 切片并在氯化三苯基四唑中孵育，以记录 梗塞的范围。 冠状面将在平面上 分析出血量和梗死量。 大脑半球水肿 使用测面积法和湿-干重量的组合来确定。 的 梗死和非梗死区域的干燥（冻干）脑组织 将分析髓过氧化物酶活性作为定量测量 中性粒细胞浸润 再灌注延迟，有和无 用L 644、711和U 74006 F单独和联合治疗动物 组合，将与这些结果统计学相关 措施

With the availability of fibrin specific thrombolytics, there is renewed interest in thrombolytic therapy for stroke. Current understanding of the pathophysiology of stroke suggests that the safety of recanalizing obstructed brain vessels, as it relates to neuronal salvage and reperfusion injury, is a function of the intensity, duration and volume of the ischemic insult. Additionally, there is increasing evidence that neutrophils may play an important role in reperfusion injury. This proposal is designed to critically determine the safe time limit for establishing reperfusion with tPA in a thromboembolic stroke model, and to subsequently examine, alone and in combination, the capacity of the anion channel blocker L644,711 and the antioxidant U74006F to extend this time limit and to assess their impact on neutrophil activation and infiltration of the injured brain tissue. A rabbit model is proposed and supported by preliminary data. The model involves standardization of infarct size by ensuring a critical reduction of cerebral blood flow to insure a standard level of ischemic blood flow as documented by hydrogen clearance. tPA (3.5mg/kg), given as a square wave pulse, will be initiated at variable times (O-8 hours) following injection of a tin impregnated internal carotid artery embolus. Intracranial pressure, regional cerebral blood flow, arterial blood gases, hematocrit, serum glucose, serum uric acid, white cell aggregation and vessel patency will be monitored throughout the experiment. The brain will be harvested, sectioned and incubated in triphenyltetrazolium chloride to document the extent of the infarct. The coronal sections will be planimetrically analyzed for volume of hemorrhage and infarct. Hemispheric edema will be determined using a combination of planimetry and wet-dry weights. The dry (lyophilized) brain tissue from infarcted and non-infarcted areas will be analyzed for myeloperoxidase activity as a quantitative measure of neutrophil infiltration. Delay to reperfusion, with and without treatment of the animals with L644,711 and U74006F, alone and in combination, will be statistically correlated with these outcome measures.