PHOTOINDUCED THROMBOTIC STROKE--MECHANISMS AND THERAPY

这个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，以及预防性药物在缓解或抑制方面的作用 脑血管系统的血栓形成。次要目标是确定 脂质过氧化是否与血栓性中风有关，并与 表征脂质过氧化产物在实质和组织中的分布 受影响组织区的内皮，并与此相关 随着中风的进展，形态指标也随之增加。拟议的研究将 利用我们最近鉴定的可复制局灶性大脑模型 光化学诱导的皮质血栓形成所致的脑梗塞 系统注射强光敏剂的大鼠的血管系统 染成玫瑰色的孟加拉。血栓形成的进展将表现为 放射性标记的血小板和局部脑血流量将 通过~(14)C标记的安替比林显像法进行评价。微血管 闭塞将通过碳黑灌流直接显示。这个 单用抗血栓药物对上述参数的影响 体内的血管将在目前的网络环境下进行评估 闭塞的血管系统；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、 吲哚美辛、前列环素)、自由基清除剂(乙醇、 二甲基亚砜、甘油)和血栓特异性纤溶剂， 组织纤溶酶原激活物(t-PA)。对t-PA作用的增强 先前给予赖氨酸-纤溶酶原也将进行测试。 脂质过氧化抑制组织恢复的假说 如果脂质过氧化的形成可以通过缺血来研究 在特定的组织区域诱导。在这个模型中，很可能是血小板 附着和随后的聚集是由光化学刺激的 内皮脂过氧化。由于可重现的进程 对于光致损伤中的血流缺陷，本模型可以 促进稳定的脂质过氧化条件，观察到 共轭双烯，在实质中也是如此。相对内容 (预计较低)内皮细胞过氧化脂质，以及 血管内皮细胞缺陷的光化学诱导将由 对培养中的内皮细胞进行了类似的实验。 拟议的工作使对血栓形成过程和其 在控制良好的条件下缓解脑微血管， 从而使潜在的中风患者受益。

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.