ROLE OF OXYGEN RADICALS AND XANTHINE OXIDASE IN STROKE

中风后24小时内的死亡率经常导致 脑水肿，没有有效的治疗方法， available. 氧自由基对内皮细胞的损伤- 肺和其他器官水肿形成的公认原因 但其在脑缺血中的作用尚不清楚。 我们证明了 酶氧自由基清除剂可以减少 大鼠局灶性中风模型，并假设黄嘌呤氧化酶 (XO)是这些氧自由基的重要来源 证据 显示脑缺血诱导了 正常良性酶，黄嘌呤脱氢酶（XDH）， 一种产生自由基的氧化酶，它将分子氧还原成 有毒的中间体，超氧化物和H2 O2。 大部分大脑 XDH和XO位于内皮细胞内， 血脑屏障有氧自由基损伤的危险。 在这 建议，细胞毒性氧自由基的作用将是 研究了脑缺血后早期的变化 局部出血、水肿形成、中性粒细胞内流和梗死 大鼠中风模型。 中风是由阻塞 右侧大脑中动脉（MCA）和短暂夹闭 颈动脉长达90分钟，这产生了可重复的， 可量化的梗死局限于右侧皮质， 检查药理学功效。 治疗效果 与特定的酶自由基清除剂的发展， 细胞毒性和血管源性水肿，脑血流量变化 MCA-颈动脉闭塞后的组织学损伤将 评估。 优化自由基的释放部位 生产，氧自由基清除酶，超氧化物 歧化酶和过氧化氢酶，将结合到聚乙烯 乙二醇或包埋在脂质体中，这增加了他们的循环 半衰期和细胞进入。 缺血诱导的 XO向损伤的XDH转化将通过消耗 通过三种独立方法测定大鼠XDH/XO活性， 测量对梗塞体积，水肿形成， MCA-颈动脉后脑血流和组织学损伤 procedure. 体内氧自由基产生的速率将是 在用自由基清除剂处理后测量， 黄嘌呤氧化酶抑制剂。 这些研究将有助于确定 氧自由基在脑缺血中的作用，并可能导致新的 治疗中风的方法。

Mortality within the first 24 hours after stroke frequently results from cerebral edema for which no effective treatment is available. Injury to endothelium by oxygen radicals in a well- recognized cause of edema formation in the lung and other organs but its role in cerebral ischemia is poorly defined. We show that enzymatic oxygen radical scavengers can reduce infarct volume in a rat focal stroke model and hypothesize that xanthine oxidase (XO) is an important source of these oxygen radicals. Evidence is presented to show that cerebral ischemia induces the conversion of a normally benign enzyme, xanthine dehydrogenase (XDH), to a free radical-producing oxidase which reduces molecular oxygen to the toxic intermediates, superoxide and H2O2. Most of the brain XDH and XO is localized within the endothelium, putting the blood-brain barrier at risk of oxygen radical injury. In this proposal, the role of cytotoxic oxygen free radicals will be investigated in early post-ischemic changes in cerebral blood flow, edema formation, neutrophil influx and infarction in a focal stroke model in the rat. The stroke is induced by occluding the right middle cerebral artery (MCA) and transiently clamping both carotid arteries for up to 90 minutes, which yields a reproducible, quantifiable infarct restricted to the right cortex and ideal for examining pharmacological efficacy. The effects of treatment with specific enzymatic radical scavengers on the development of cytotoxic and vasogenic edema, changes in cerebral blood flow and histologic injury after the MCA-carotid occlusion will be evaluated. To optimize delivery to sites of free radical production, the oxygen radical scavenging enzymes, superoxide dismutase and catalase, will be either conjugated to polyethylene glycol or entrapped in liposomes, which increases their circulatory half-life and cell entry. The contribution of ischemia-induced XDH conversion of XO to injury will be examined by depleting XDH/XO activity in rats by three independent methods and measuring the effects on infarct volume, edema formation, cerebral blood flow and histologic injury after the MCA-carotid procedure. Rates of oxygen radical production in vivo will be measured after treatment with free radical scavengers and xanthine oxidase inhibitors. These studies will help define the role of oxygen radicals in cerebral ischemia and may lead to new therapeutic approaches in the treatment of stroke.