We propose to administer reproducible thrombotic stroke to rats, and to assess histopathologic, rheologic and physiological indicators of tissue status during ischemia and following vascular recanalization by the unique thrombolytic agent, hementin. Of particular interest is to determine, following the ictus, the time domain for which recanalization can be achieved without inducing hemorrhage from ischemically compromised distal vascular segments. Evidence of postischemic reperfusion injury will be sought in terms of oxygen radical-stimulated tissue edema, neutrophil infiltration and lipid peroxidation. The degree of inhibition of these mediators of tissue destruction will be examined following administration of specifically targeted quenching agents, such as the stable prostacyclin analog iloprost, and the enzymatic scavenger of superoxide radical, superoxide dismutase in both the short-lived (in plasma) copper/zinc form and the unique long-lived manganese form. Inasmuch as these studies encompass thrombotic stroke in the induction phase and its therapy in the recovery phase, as aided by mitigation of several deleterious aspects of reperfusion in metabolically compromise brain tissue, clinically relevant information may result. Our models of thrombotic stroke are mediated by photoexcitation of intravenously injected rose bengal dye, either by argon ion laser irradiation of the middle cerebral artery, or by xenon arc lamp irradiation of the exposed, translucent skull and the underlying cortical microvasculature. Occlusion(s) appear in as white thrombi containing agglutinated platelets in response to photochemically damaged endothelium. Following hementin-induced recanalization at clinically relevant times (less than 6 hours following the ictus), edema will be assayed as brain water content, blood flow by the 14C-iodoantipyrine technique, metabolic status by oxygen tension, potassium ion activity and hydrogen clearance, lipid peroxidation by Schiff-base autofluorescence or conjugated dienes, and neutrophil content by antimyeloperoxidase staining, and fluorescent antibody or indium labeling. In terms of these indicators of reperfusion injury, the ameliorating effect of the antioxidative and antineutrophil agents will also be assessed. We will also investigate optical means to improve the efficiency of photochemically induced vascular occlusion; this development is projected to benefit surgery of neovasculature in the brain and eye.
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