ANTI-ICAM-1 ANTIBODY TREATMENT AFTER MCA OCCLUSION

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，包括浸润 和多形核白细胞的积累， 单核细胞/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是 不仅与组织修复过程有关，而且还可能导致 对潜在活性组织的损伤。我们建议减少缺血细胞 大脑中动脉（MCA）闭塞后的大鼠损伤 选择性阻断细胞间粘附分子1（ICAM-1）， 内皮细胞上表达的一种糖蛋白， 粘连三个具体的目标和假设将进行测试。 目的1：单克隆抗体对大鼠给药的影响 将在大鼠中研究ICAM-1对减少缺血性细胞损伤的作用 短暂性（2小时）和永久性MCA闭塞。缺血性 细胞损伤将作为抗体剂量和时间的函数来测量 局 假设：与ICAM-1糖蛋白反应的单克隆抗体 减少短暂MCA闭塞后的缺血性细胞损伤。 目的2：我们将测量ICAM-1表达的时间曲线， 大脑中动脉短暂闭塞后ICAM-1 mRNA的表达。 假设：大脑中动脉闭塞导致ICAM-1信息增加， 和蛋白质的含量。 目的3：抗ICAM-1反应性抗体减少的机制 将研究缺血性细胞损伤。 3（a）：我们将衡量和 与中性粒细胞浸润程度的时间曲线相关 进入缺血性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向缺血组织的浸润 在缺血性细胞损伤之前或伴随缺血性细胞损伤，并有助于 短暂局灶性脑缺血后缺血细胞损伤。 我们将进行定量放射自显影测量局部 短暂MCA闭塞后各时间点的脑血流量。 假设：中性粒细胞可能有助于缺血性细胞损伤， 通过减少局部脑血流量（CBF）和 延长缺血时间。 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。

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.