ANTI ICAM 1 ANTOBODY TREATMENT AFTER MCA OCCLUSION

MCA 闭塞后抗 ICAM 1 抗体治疗

• 批准号: 2272529
• 负责人: MICHAEL CHOPP
• 金额: $ 20.33万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2272529
• 关键词: artery occlusion; autoradiography; blocking antibody; brain circulation; cell adhesion molecules; cerebral ischemia /hypoxia; cerebrovascular occlusions; gene expression; histology; immunocytochemistry; immunotherapy; laboratory rat; magnetic resonance imaging; monoclonal antibody; neutrophil; northern blottings; nuclear magnetic resonance spectroscopy; reperfusion

Ischemic brain injury evokes an endogenous brain parenchymal cell damage as well as an exogenous inflammatory response, which includes infiltration and accumulation of polymorphonuclear leukocytes and monocytes/macrophages, and microvascular proliferation. The migration and accumulation of neutrophils into the ischemic tissue after reperfusion is not only associated with tissue repair processes, but also may result in injury to potentially viable tissue. We propose to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking the intercellular adhesion molecule 1 (ICAM-1), a glycoprotein expressed on endothelial cells that facilitates leukocyte adhesion. Three specific aims and hypotheses will be tested. Aim 1: The effect of administration of a monoclonal antibody to the rat ICAM-1 on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) and permanent MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with the ICAM-1 glycoprotein reduces ischemic cell damage after transient MCA occlusion. Aim 2: We will measure the temporal profiles of expression of ICAM-1 and ICAM-1 mRNA in brain after transient MCA occlusion. Hypothesis: MCA occlusion results in an increase of both ICAM-1 message and protein in ischemic brain. Aim 3: Mechanisms by which the anti-ICAM-1 reactive antibody reduces ischemic cell damage will be investigated. 3(a): We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis: Anti-ICAM-1 antibody causes a reduction of neutrophils in the ischemic tissue. Infiltration of neutrophils into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. We will perform quantitative autoradiographic measurements of local cerebral blood flow at time points after transient MCA occlusion. Hypothesis: Neutrophils may contribute to ischemic cell damage in reperfusion injury by reducing local cerebral blood flow (CBF) and extending the duration of ischemia. Our long term objective is to develop a therapeutic intervention (anti- ICAM-1 antibody) to be employed after the onset of ischemic stroke.

缺血性脑损伤引起内源性脑实质细胞损伤 以及外源性炎症反应，包括渗透 和多形核白细胞的聚集以及 单核/巨噬细胞和微血管增殖。迁移和 再灌注后中性粒细胞在缺血组织中的积聚 不仅与组织修复过程有关，而且还可能导致 对可能存活的组织的损伤。我们建议减少缺血细胞 大鼠大脑中动脉闭塞后的损伤 选择性阻断细胞间黏附分子1(ICAM-1)，a 内皮细胞上表达的促进白细胞的糖蛋白 粘附力。我们将测试三个具体的目标和假设。 目的1：单抗对大鼠的影响 ICAM-1减轻大鼠缺血细胞损伤的实验研究 接受短暂(2小时)和永久性大脑中动脉闭塞。缺血型 细胞损伤将作为抗体剂量和时间的函数来测量 行政管理。 假设：一种与ICAM-1糖蛋白反应的单抗 减少短暂大脑中动脉闭塞后的缺血细胞损伤。 目的2：测定细胞间黏附分子-1和细胞间黏附分子-1的表达 短暂性大脑中动脉闭塞后脑内ICAM-1mRNA的表达 假设：大脑中动脉闭塞导致ICAM-1消息增加 和蛋白质在缺血脑中的表达。 目的3：抗ICAM-1反应性抗体降低的机制 将对缺血细胞损伤进行调查。3(A)：我们将衡量和 中性粒细胞渗入程度的时间分布 进入有缺血细胞损伤的缺血组织。 假设：抗ICAM-1抗体导致中性粒细胞减少 缺血组织。中性粒细胞在缺血组织中的渗入 先于或伴随着缺血细胞损伤，并有助于 短暂性局灶性脑缺血后的缺血细胞损伤。 我们将对局部进行定量放射自显影测量 短暂性大脑中动脉闭塞后各时间点的脑血流量。 假设：中性粒细胞可能参与脑缺血细胞损伤 局部脑血流量(CBF)减少和再灌注损伤 延长缺血持续时间。 我们的长期目标是开发一种治疗干预(抗- ICAM-1抗体)在缺血性中风发作后使用。