Evaluation of Antioxidant Suppl in Focal CNS Ischemia

局灶性中枢神经系统缺血抗氧化剂供应的评价

• 批准号: 6457228
• 负责人: WAYNE M CLARK
• 金额: $ 18.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6457228
• 关键词: alternative medicine; anticoagulants; antioxidants; aspirin; brain circulation; cardiovascular disorder risk; central nervous system; cerebral hemorrhage; cerebral ischemia /hypoxia; combination therapy; dietary supplements; disease /disorder model; dosage; enzyme linked immunosorbent assay; fatty acids; flow cytometry; ginkgo biloba; inflammation; laboratory mouse; messenger RNA; neuroprotectants; nonhuman therapy evaluation; nutrition related tag; outcomes research; placebos; polymerase chain reaction; stroke therapy; ultrasound blood flow measurement

DESCRIPTION (provided by applicant): Stroke is a major cause of death and disability in the United States. Evidence suggests that even if blood flow is initially restored additional "reperfusion injury" processes can occur that can potentiate brain injury and reduce existing blood flow. Some of the mediators of this "reperfusion injury" appear to be due to an inflammatory responsive involving free radical generation, activated leukocytes, and platelet activated factor. Various commercially available "antioxidant supplements" appear to produce clinical benefit in several diseases. These supplements including Ginkgo biloba extract (EGb) and alpha lipoic acid (LA) have multitude of biologic effects including reducing free radical generation, inhibiting PAF and leukocyte activation (inhibit NFalphaB), and improving cerebral blood flow. Antioxidants have shown benefits in multiple disease models involving reperfusion injury but have yet to be fully evaluated in reperfusion injury related to stroke. This project will investigate the treatment potential and protective mechanisms of selected antioxidants using an animal model that closely approximates clinical stroke. The specific aims of the study are as follows: Aim 1: To confirm and characterize the neuroprotective efficacy of EGb in focal CNS ischemia, determine the effects of EGb on the inflammatory response and CBF, and evaluate safety interventions with other medications used in stroke. Aim 2: To confirm and characterize the neuroprotective efficacy of LA and dihydro lipoic (DHLA) in focal CNS ischemia and determine their effects on the inflammatory response and CBF. This study will use the middle cerebral artery filament occlusion (MCAO) model in the mouse and will utilize a combination of ischemic damage (lesion size) and neurologic functional measurements to determine efficacy. Potential mechanisms of efficacy for each antioxidant will be assessed including effects on in vivo cerebral blood flow (laser doppler measurement of blood flow) and the inflammatory response (molecular and flow cytometry). The information obtained from this project will be critical in planning future clinical stroke trials involving these agents.

描述（由申请人提供）： 中风是死亡的主要原因， 在美国的残疾。有证据表明，即使血流 最初恢复的额外“再灌注损伤”过程可能会发生 加剧脑损伤并减少现有的血流量。部分调解员 这种“再灌注损伤”似乎是由于炎症反应 涉及自由基生成、白细胞活化和血小板活化 因素。各种市售“抗氧化剂补充剂”似乎 对多种疾病产生临床益处。这些补充剂包括 银杏叶提取物 (EGb) 和 α 硫辛酸 (LA) 具有多种功效 生物效应包括减少自由基的产生、抑制 PAF 和 白细胞活化（抑制 NFalphaB），并改善脑血流量。 抗氧化剂在多种疾病模型中显示出益处，包括 再灌注损伤，但尚未对再灌注损伤进行充分评估 与中风有关。该项目将调查治疗潜力并 使用动物模型研究选定抗氧化剂的保护机制 非常接近临床中风。研究的具体目的如下 目标 1：确认并表征 EGb 的神经保护功效 在局灶性中枢神经系统缺血中，确定 EGb 对炎症的影响 反应和 CBF，并评估使用其他药物的安全干预措施 中风。目标 2：确认和表征神经保护功效 LA 和二氢硫辛酸 (DHLA) 在局灶性中枢神经系统缺血中的作用并确定其作用 炎症反应和 CBF 的影响。这项研究将使用中脑 小鼠动脉细丝闭塞（MCAO）模型，并将利用 缺血性损伤（病变大小）和神经功能的结合 测量以确定功效。每种药物的潜在功效机制 将评估抗氧化剂，包括对体内脑血流量（血流量的激光多普勒测量）和炎症反应的影响 （分子和流式细胞术）。从该项目获得的信息将 对于规划未来涉及这些药物的临床卒中试验至关重要。