DELAYED REPERFUSION WITH TPA IN THROMBOEMBOLIC STROKE

TPA 延迟再灌注治疗血栓栓塞性中风

• 批准号: 2267106
• 负责人: CORDELL E GROSS
• 金额: $ 16.45万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2267106
• 关键词: antioxidants; blood chemistry; brain circulation; brain edema; brain injury; cardiovascular disorder chemotherapy; cardiovascular pharmacology; cerebral hemorrhage; cerebral ischemia /hypoxia; disease /disorder model; free radical scavengers; inhibitor /antagonist; laboratory rabbit; membrane channels; myeloperoxidase; neutrophil; plasminogen activator; reperfusion; respiratory gas analyzer; stroke; thromboembolism

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.

随着纤维蛋白特异性溶栓剂的可用，出现了 对中风的溶栓治疗感兴趣。目前对 中风的病理生理学表明再通的安全性 脑血管阻塞，因为它与神经元挽救和 再灌注损伤，是强度、持续时间和体积的函数 对缺血症的侮辱。此外，越来越多的证据表明 中性粒细胞在再灌注损伤中可能起重要作用。这 该提案旨在批判性地确定 在血栓栓塞性卒中模型中用tPA建立再灌注 随后单独和结合地审查 阴离子通道阻滞剂L644,711和抗氧化剂U74006F 时间限制，并评估其对中性粒细胞激活和 损伤脑组织的渗出。提出了一种兔模型，建立了兔模型。 有初步数据支持。该模型涉及到标准化 通过确保将脑血流量临界减少到 确保氢气记录的标准水平的缺血血流量 通行证。TPA(3.5 mg/kg)，作为方波脉冲给药，将是 在注射锡后的不同时间(O-8小时)开始 受孕的颈内动脉血栓。颅内压， 局部脑血流量、动脉血气、红细胞压积、血清 血糖、血尿酸、白细胞聚集和血管通畅性 在整个实验过程中都受到监控。大脑将被收获， 切片，在三苯基四氮唑氯化物中孵育，以记录 梗死灶的范围。日冕截面将是平面测量的。 分析出血和梗死灶的体积。大脑半球水肿会 使用平面测量法和干湿重相结合的方法来确定。这个 来自梗死区和非梗死区的干燥(冻干)脑组织 将分析髓过氧化物酶活性作为一种定量测量 中性粒细胞的渗入。延迟再灌流，有或没有 L644,711和U74006F单独和联合应用对动物的影响 组合在一起，将与这些结果在统计上相关 措施。