MECHANISMS OF ISCHEMIC BRAIN DAMAGE

缺血性脑损伤的机制

• 批准号: 2272440
• 负责人: MICHAEL J QUAST
• 金额: $ 21.41万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-15 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2272440
• 关键词: brain injury; cerebral ischemia /hypoxia; enzyme inhibitors; free radical scavengers; free radicals; hyperglycemia; laboratory rat; lactic acidosis; magnetic resonance imaging; microdialysis; nitric oxide synthase; nuclear magnetic resonance spectroscopy; oxidative stress; streptozotocin; superoxide dismutase; superoxides

Clinical and experimental animal studies have implicated preischemic hyperglycemia as a risk factor for increased neuronal damage after ischemic stroke. Although hyperglycemia-induced lactic acidosis under ischemia has been proposed to account for the exaggerated brain damage, the underlying molecular mechanism has not been elucidated. It has recently been demonstrated in vitro that hydroxyl free radical (OH) can be formed by the decomposition of peroxynitric acid and that the yield of hydroxyl radicals is increased in an acidic environment. The hypothesis to be tested in this project is that hydroxyl free radical production is increased in cerebral ischemia in hyperglycemic animals by reaction of nitric oxide with superoxide under hyperglycemia-induced lactic acidosis, thereby worsening the extent of ischemic brain damage. Cerebral ischemia will be induced by permanent or temporary occlusion of middle cerebral artery (MCA) in streptozotozin-induced hyperglycemic rats. The extracellular level of hydroxyl radicals will be continuously monitored in vivo during ischemia/reperfusion by intracranial microdialysis perfusion of the OH trapping agent salicylate. Non-invasive magnetic resonance imaging (MRI) techniques will be employed to monitor brain pathophysiological indicators, including neuronal damage, vasogenic edema and cerebral perfusion, during the course of ischemia/reperfusion. Intracellular pH and the distribution of high energy phosphates within the injured brain region will be measured in vivo using 31/P magnetic resonance spectroscopy (MRS). Liposome-entrapped free radical scavengers superoxide dismutase (SOD) and nitric oxide synthase inhibitor N/G-nitro- L-arginine methyl ester (L-NAME) will be administered to reduce the in vivo concentration of superoxide and nitric oxide respectively. The effects of SOD and L-NAME on the production of hydroxyl radicals and on the attenuation of MRI-measurable brain injury will be compared to the respective control groups. These studies will provide in vivo evidence linking the peroxynitric acid decomposition pathway of OH generation to the exacerbation of ischemic brain damage under hyperglycemic conditions.

临床和实验动物研究已暗示 高血糖作为增加神经元损害后的危险因素 缺血性中风。 尽管高血糖诱导的乳酸性酸中毒 已经提出缺血来解释夸张的脑损伤， 尚未阐明潜在的分子机制。 它有 最近在体外证明了羟基自由基（OH）可以是 由过氧硝酸的分解形成 在酸性环境中，羟基自由基增加。 假设 在这个项目中要测试的是，羟基自由基生产是 通过反应的反应，高血糖动物的脑缺血增加 一氧化氮在高血糖诱导的乳酸酸中毒下， 从而恶化缺血性脑损伤的程度。 脑缺血 将由中大脑永久性或临时阻塞诱导 链霉亲素诱导的高血糖大鼠的动脉（MCA）。 这 羟基自由基的细胞外水平将在 颅内微透析灌注期间缺血/再灌注期间的体内 OH捕获代理水杨酸酯的。 非侵入性磁共振 将采用成像（MRI）技术来监测大脑 病理生理指标，包括神经元损伤，加血管水肿 和脑灌注，在缺血/再灌注过程中。 细胞内pH和高能磷酸盐的分布 损伤的大脑区域将使用31/p磁性在体内测量 共振光谱（MRS）。 脂质体包裹的自由基清除剂 超氧化物歧化酶（SOD）和一氧化氮合酶抑制剂N/G-硝基 将施用L-精氨酸甲酯（L-名）以减少IN 超氧化物和一氧化氮的体内浓度。 这 SOD和L-名称对羟基自由基的产生以及对 将MRI可衡量的脑损伤的衰减与 各自的对照组。 这些研究将提供体内证据 将OH发电的过氧亚硝酸分解途径连接到 在高血糖条件下，缺血性脑损伤加剧。