Evaluation of Antioxidant Suppl in Focal CNS Ischemia

描述（由申请人提供）：中风是死亡的主要原因， 残疾在美国。有证据表明，即使血流 初始恢复的额外“再灌注损伤”过程可发生， 加重脑损伤并减少现有的血流量。一些调解员 这种“再灌注损伤”似乎是由于炎症反应， 涉及自由基生成、活化白细胞和血小板活化 因子各种市售的“抗氧化剂补充剂”似乎 在几种疾病中产生临床益处。这些补充包括 银杏叶提取物（EGb）和α-硫辛酸（LA）具有多种 生物学效应包括减少自由基的产生，抑制PAF， 白细胞活化（抑制NFalphaB）和改善脑血流量。 抗氧化剂在多种疾病模型中显示出益处， 但在再灌注损伤中尚未得到充分评价 与中风有关。该项目将研究治疗潜力， 使用动物模型选择的抗氧化剂的保护机制， 非常接近临床中风研究的具体目标如下： 目的1：确认和表征EGb的神经保护作用 在局灶性CNS缺血中，确定EGb对炎性 反应和CBF，并评估使用其他药物的安全性干预 在中风中。目的2：确认和表征 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 对炎症反应和脑血流量的影响这项研究将使用大脑中 动脉丝闭塞（MCAO）模型，并将利用 缺血性损伤（病变大小）和神经功能 测量以确定功效。每种药物的潜在疗效机制 将评估抗氧化剂，包括对体内脑血流（血流的激光多普勒测量）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 在计划未来涉及这些药物的临床中风试验中至关重要。

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.