PHOTOINDUCED THROMBOTIC STROKE--MECHANISMS AND THERAPY

光诱发血栓性中风——机制和治疗

• 批准号: 3406506
• 负责人: BRANT D WATSON
• 金额: $ 12.44万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 1988-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3406506
• 关键词: anticoagulants; artificial intelligence; autoradiography; brain edema; calcium channel blockers; cardiovascular pharmacology; diene; disease /disorder model; electron microscopy; fibrinolytic agents; histopathology; lipid peroxides; model design /development; photochemistry; plasminogen activator; platelet aggregation; platelet aggregation inhibitors; radiotracer; stroke; tissue /cell culture

The major goal of this project is to document patterns of platelet deposition, blood flow and edema during the development of focal thrombotic stroke, and the effects of prophylactic agents on mitigating or inhibiting thrombus formation in brain vasculature. A secondary goal is to determine whether lipid peroxidation is associated with thrombotic stroke, and to characterize the distribution of lipid peroxides in parenchyma and endothelium of the affected tissue zone and correlate this with morphological indices as the stroke progresses. The proposed studies will utilize our recently characterized model of reproducible focal cerebral infarction precipitated by photochemically induced thrombosis of cortical vasculature, in rats injected systemically with the potent photosensitizing dye Rose Bengal. The progression of thrombosis will be represented by platelets radiolabeled with IIIindium, and local cerebral blood flow will be evaluated by 14C-labeled iodoantipyrine imaging. Microvascular occlusion will be visualized directly by carbon-black perfusion. The effect on these parameters of agents known to mitigate thrombosis of single vessels in vivo will be evaluated in the present context of a network of occluded vasculature; such agents include calcium channel antagonists (nimodipine, nifedipine, verapamil), antiplatelet drugs (aspirin, indomethacin, prostacyclin), free radical scavengers (ethanol, dimethylsufoxide, glycerol) and the clot-specific fibrinolytic agent, tissue plasminogen activator (t-PA). Enhancement of the effect of t-PA by prior administration of lys-plasminogen will be tested also. The hypothesis that lipid peroxidation inhibits the recovery of tissue compromised by ischemia can be studied if lipid peroxide formation can be induced in specific tissue zones. In this model it is likely that platelet adhesion and subsequent aggregation are stimulated by photochemical peroxidation of endothelial lipids. Owing to the reproducible progression of blood flow deficit in the photoinduced lesion, the present model may facilitate stable conditions for lipid peroxidation, observable as conjugated dienes, in the parenchyma as well. The relative content (predicted to be low) of endothelial lipid peroxides, and the efficiency of photochemical induction of endothelial defects will be determined by similar experiments conducted with endothelial cells in culture. The proposed work enables rigorous study of the thrombotic process and its mitigation under well-controlled condition in brain microvessels, with consequent benefit to potential stroke patients.

该项目的主要目标是记录血小板的模式 局灶性血栓形成过程中的沉积、血流和水肿 中风，以及预防药物对缓解或抑制中风的作用 脑血管系统中血栓形成。 第二个目标是确定 脂质过氧化是否与血栓性中风有关，以及 表征脂质过氧化物在实质中的分布和 受影响组织区域的内皮细胞并将其与 中风进展时的形态学指数。 拟议的研究将 利用我们最近表征的可重复的局灶性大脑模型 光化学诱导皮质血栓形成引发的梗死 全身注射强效光敏剂的大鼠的脉管系统 染玫瑰红。 血栓形成的进展情况可表示为 用 III 铟放射性标记的血小板，局部脑血流量将 通过 14C 标记的碘安替比林成像进行评估。 微血管 闭塞将通过炭黑灌注直接显现。 这 已知可减轻单一血栓形成的药物对这些参数的影响 体内血管将在目前的网络背景下进行评估 脉管系统闭塞；此类药物包括钙通道拮抗剂 （尼莫地平、硝苯地平、维拉帕米）、抗血小板药物（阿司匹林、 消炎痛、前列环素）、自由基清除剂（乙醇、 二甲基亚砜、甘油）和凝块特异性纤溶剂， 组织纤溶酶原激活剂（t-PA）。 增强 t-PA 的效果 还将测试之前施用的赖氨酸纤溶酶原。 脂质过氧化抑制组织恢复的假设 如果可以研究脂质过氧化物的形成，则可以研究缺血所造成的损害 在特定组织区域诱导。 在这个模型中，血小板很可能 光化学刺激粘附和随后的聚集 内皮脂质过氧化。 由于可重复的进展 光诱导损伤中的血流缺陷，本模型可以 促进脂质过氧化的稳定条件，可观察为 共轭二烯，也在薄壁组织中。 相关内容 （预计较低）内皮脂质过氧化物，以及效率 内皮缺陷的光化学诱导将通过以下方式确定 对培养的内皮细胞进行了类似的实验。 拟议的工作能够对血栓形成过程及其发生进行严格的研究 在脑微血管的良好控制条件下缓解 从而使潜在的中风患者受益。