FOCAL CEREBRAL ISCHEMIA--PATHOPHYSIOLOGY, ACUTE THERAPY, RECOVERY OF FUNCTION

局灶性脑缺血——病理生理学、急性治疗、功能恢复

• 批准号: 6273576
• 负责人: MYRON DAVID GINSBERG
• 金额: $ 15.22万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6273576
• 关键词: amphetamines; apoptosis; autoradiography; bioenergetics; brain disorder chemotherapy; brain metabolism; cerebral ischemia /hypoxia; cerebrovascular occlusions; electrophysiology; free radical oxygen; gene expression; glutamates; hemodynamics; histopathology; in situ hybridization; induced hypothermia; laboratory rat; neural plasticity; neuropharmacology; neuroprotectants; neuropsychological tests; neurotrophic factors; reperfusion

Biochemical and ionic events within the first few hours after focal vascular occlusion critically determine the extent and intensity of cell death and may provide critical stimuli to subsequent functional rearrangement and recovery of the brain. This project employs an extensively characterized, minimally invasive model of photothrombotic middle cerebral artery (MCA) occlusion -a model relevant to human thromboembolic stroke. A major aim is to characterize factors responsible for engendering acute bioenergetic stress in the ischemic penumbra, including excessive local metabolism/blood flow uncoupling and repeated ischemic depolarizations. The relationship of these processes to the local release of glutamate and other neurotransmitters, and to the local production of oxygen radicals, will be explored. Analysis of local cytoskeletal proteolysis and light- and electron microscopic histopathology will provide structural correlates. Modulation of acute metabolic events in the penumbra will be achieved by inducing additional depolarizations, by mild hyperthermia or hypothermia, by early partial reperfusion, and by agents affecting the glutamate system. The second major aim is to determine how these acute events influence subsequent patterns of functional recovery, as assessed by a neurobehavioral battery, by glucose-metabolic activation of affected forelimb areas, and by the expression of messenger RNA and protein for neurotrophin growth factors and their trk receptors. We shall discern whether acute protective strategies might aid or paradoxically hinder later functional reorganization, and we shall assess the mechanisms underlying the enhancement of functional recovery by amphetamine coupled with symptom- relevant experience. The project makes extensive use of novel three- dimensional autoradiographic image-averaging strategies in conjunction with neurobehavior, in situ hybridization, immunohistochemistry and morphologic methods.

焦点后的最初几个小时内生化和离子事件 血管闭塞批判性确定细胞的程度和强度 死亡，可能为随后的功能提供关键的刺激 大脑的重排和恢复。该项目采用 广泛表征了光栓塞的最小侵入性模型 大脑中动脉（MCA）闭塞 - 与人有关的模型 血栓栓塞中风。一个主要目的是表征因素 负责在缺血性中引起急性生物能量 半身，包括过多的局部新陈代谢/血流解偶联和 重复的缺血性去极化。这些过程的关系 到谷氨酸和其他神经递质的局部释放，然后 将探索氧气自由基的局部产生。分析 局部细胞骨架蛋白水解以及光和电子显微镜 组织病理学将提供结构相关。急性调节 通过诱导额外 通过轻微的高温或体温过低的去极化，早期部分部分 再灌注，以及影响谷氨酸系统的药物。第二个 主要目的是确定这些急性事件如何影响随后的 通过神经行为评估的功能恢复模式 电池，通过受影响的前肢区域的葡萄糖代谢激活，以及 通过使神经营养蛋白生长的信使RNA和蛋白质的表达 因素及其TRK受体。我们应辨别是否急性 保护策略可能有助于或矛盾地阻碍后来的功能 重组，我们将评估该机制 苯丙胺增强功能恢复的能力以及症状 - 相关经验。该项目广泛使用新颖的三 尺寸放射自显影图像平衡策略 与神经行为，原位杂交，免疫组织化学和 形态学方法。