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，预防剂对缓解或抑制的影响 脑脉管系统中的血栓形成。 次要目标是确定 脂质过氧化是否与血栓性中风有关 表征脂质过氧化物在实质中的分布和 受影响组织区的内皮，并将其与 随着中风的进展，形态学指标。 拟议的研究将 利用我们最近表征的可重复性局灶性大脑模型 由光化学诱导的皮质血栓形成沉淀的梗塞 脉管系统，在全身注射有效的光敏的大鼠中 染料玫瑰孟加拉。 血栓形成的进展将由 带有iiiindium和局部脑血流的辐射标记的血小板将 通过14C标记的碘氨酰胺成像进行评估。 微血管 闭塞将通过碳黑灌注直接可视化。 这 对已知减轻单一的血栓形成的药物参数的影响 体内的船只将在当前的情况下进行评估 阻塞脉管系统；这样的药物包括钙通道拮抗剂 （Nimodipine，Nifedipine，Verapamil），抗血小板药物（阿司匹林，， 吲哚美辛，前列环素），自由基清除剂（乙醇，， 二甲基氧化物，甘油）和凝块特异性纤维蛋白水解剂， 组织纤溶酶原活化剂（T-PA）。 增强T-PA的影响 事先将乳肌蛋白原的给药也将进行测试。 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脂质的形成，则可以研究缺血损害 在特定的组织带中诱导。 在这个模型中，血小板很可能 粘附和随后的聚集被光化学刺激 内皮脂质的过氧化。 由于可再现的进展 光诱导病变中的血流不足，本模型可能 促进稳定的脂质过氧化条件，可观察到 同时，在实质中也有共轭二烯。 相对内容 内皮脂质过氧化物的（预测为低），效率 内皮缺陷的光化学诱导将由 在培养中用内皮细胞进行的类似实验。 拟议的工作使对血小板过程及其ITS的严格研究 在大脑微血管中控制良好的情况下缓解措施， 因此对潜在的中风患者有好处。