Evaluation of Antioxidant Suppl in Focal CNS Ischemia

描述(申请人提供)：中风是导致死亡的主要原因 美国的残疾问题。有证据表明，即使血液流动 最初恢复的额外“再灌流损伤”过程可能会发生 加强脑损伤，减少现有的血流量。一些调解人 这种“再灌注损伤”似乎是由炎症反应引起的 涉及自由基的产生、白细胞的激活和血小板的激活 因素。各种商业上可以买到的“抗氧化剂补充剂”似乎 在几种疾病中产生临床效益。这些补充剂包括 银杏叶提取物(EGB)和α-硫辛酸(LA)具有丰富的生物活性 生物效应，包括减少自由基的产生，抑制PAF和 激活白细胞(抑制NFalphaB)，改善脑血流。 抗氧化剂已在多种疾病模型中显示出益处，包括 再灌注损伤，但尚未完全评估再灌注损伤 与中风有关。该项目将调查治疗潜力和 用动物模型研究选定抗氧化剂的保护机制 与临床中风非常相似。这项研究的具体目的如下 目的1：确定和表征银杏叶提取物的神经保护作用 局灶性中枢神经系统缺血时银杏叶提取物对炎症反应的影响 反应和CBF，并评估使用其他药物的安全干预措施 在中风中。目的2：证实和表征黄连素的神经保护作用 LA和二氢硫辛酸(DHL)对局灶性中枢神经系统缺血的影响 对炎症反应和脑血流的影响。本研究将使用大脑中脑 小鼠动脉细丝闭塞(MCAO)模型，并将利用 缺血性损害(病变大小)和神经功能的组合 用于确定疗效的测量。每种药物的潜在疗效机制 将评估抗氧化剂对体内脑血流量(激光多普勒血流量测量)和炎症反应的影响 (分子和流式细胞术)。从这个项目中获得的信息将 在规划未来涉及这些药物的临床中风试验时要非常关键。

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.