PHOTOINDUCED THROMBOTIC STROKE--MECHANISMS AND THERAPY

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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.