PHOTOINDUCED THROMBOTIC STROKE--MECHANISMS AND THERAPY

该项目的主要目标是记录血小板的模式， 在局灶性血栓形成过程中的沉积、血流和水肿 中风，以及预防剂对减轻或抑制 脑血管系统血栓形成。 第二个目标是确定 脂质过氧化是否与血栓性卒中有关， 表征脂质过氧化物在薄壁组织中的分布， 受影响组织区的内皮细胞，并将其与 形态学指标。 拟议的研究将 利用我们最近表征的可再生局灶性脑 光化学诱导皮质血栓形成引起的急性梗塞 血管，在大鼠全身注射有效的光敏 染玫瑰红。 血栓形成的进展将由 用III铟放射性标记的血小板和局部脑血流量将 通过14 C标记的碘安替比林成像进行评价。 微血管 通过碳黑灌注直接观察闭塞。 的 已知可减轻单次血栓形成的药物对这些参数的影响 将在本发明的网络背景下评估体内血管， 闭塞的脉管系统;这类药剂包括钙通道拮抗剂 （尼莫地平，硝苯地平，维拉帕米），抗血小板药物（阿司匹林， 吲哚美辛，前列环素），自由基清除剂（乙醇， 二甲基亚砜，甘油）和凝块特异性纤维蛋白溶解剂， 组织型纤溶酶原激活剂（t-PA）。 增强t-PA的作用 还将测试在此之前施用溶血素-纤溶酶原。 脂质过氧化抑制组织恢复的假说 如果脂质过氧化物的形成可以 在特定的组织区域诱导。 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 内皮脂质过氧化。 由于可重复的进展 在光诱导的损伤中的血流缺陷，本模型可以 促进脂质过氧化的稳定条件，可观察到 在薄壁组织中也有共轭二烯。 相对含量 （预测为低）的内皮脂质过氧化物，以及 内皮缺陷的光化学诱导将通过 用培养的内皮细胞进行类似的实验。 拟议的工作使严格的研究血栓形成的过程及其 在脑微血管中良好控制的条件下缓解， 对潜在的中风患者有益。

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.