REDUCED MICROVASCULAR THROMBOSIS AND IMPROVED OUTCOME IN ACUTE MURINESTROKE BY INHIBITING GP IIB IIIA RECEPTOR-MEDIATED PLATELET-AGGREGATION/

Treatment options in acute stroke are limited by a dearth of safe and effective regimens for recanalization of an occluded cerebrovascular t ributary, as well as by the fact that patients present only after the occlusive event is established. We hypothesized that even if the site of major arterial occlusion is recanalized after stroke, microvascular thrombosis continues to occur at distal sites, reducing postischemic flow and contributing to ongoing neuronal death. To test this hypothes is, and to show that microvascular thrombosis occurs as an ongoing, dy namic process after the onset of stroke, we tested the effects of a po tent antiplatelet agent given both before and after the onset of middl e cerebral arterial (MCA) occlusion in a murine model of stroke. After 45 min of MCA occlusion and 23 h of reperfusion, fibrin accumulates i n the ipsilateral cerebral hemisphere, based upon immunoblotting, and localizes to microvascular lumena, based upon immunostaining. In conco rdance with these data, there is a nearly threefold increase in the ip silateral accumulation of In-111-labeled platelets in mice subjected t o stroke compared with mice not subjected to stroke. When a novel inhi bitor of the glycoprotein IIb/IIIa receptor (SDZ GPI 562) was administ ered immediately before MCA occlusion, platelet accumulation was reduc ed 48%, and fibrin accumulation was reduced by 47% by immunoblot densi tometry, GPI 562 exhibited a dose-dependent reduction of cerebral infa rct volumes measured by triphenyltetrazolium chloride staining, as wel l as improvement in postischemic cerebral blood flow, measured by lase r doppler, GPI 562 caused a dose-dependent increase in tail vein bleed ing time, but intracerebral hemorrhage (ICH) was not significantly inc reased at therapeutic doses; however, there was an increase in ICH at the highest doses tested, When given immediately after withdrawal of t he MCA occluding suture, GPI 562 was shown to reduce cerebral infarct volumes by 70%, These data support the hypothesis that in ischemic reg ions of brain, microvascular thrombi continue to accumulate even after recanalization of the MCA, contributing to postischemic hypoperfusion and ongoing neuronal damage.