There is a compelling need to develop therapies complementary to thrombolysis for the treatment of acute stroke. In this Project, we test the hypothesis that microvascular thrombosis ensues after stroke and that platelet aggregation contributes to progression of the fulminating ischemic lesion. Thus, treatment of embolic stroke with an antagonist to the GPIIb/IIIa receptor, which binds the platelet to fibrinogen and is the terminus of platelet with an antagonist to the GPIIb/IIIa receptor, which binds the platelet to fibrinogen and is the terminus of platelet thrombosis, may enhance cerebral perfusion, reduce thrombosis and complement and enhance thrombolytic therapy of stroke with rtPA. To achieve our goals, we propose four Specific Aims:
Specific Aim 1 : Rats will be subjected to embolic stroke and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 2 : Rats will be subjected to embolic stroke and will be treated with rtPA at specific time paints after stroke (2h, 4h, 6h). The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 3 : Rats will be subjected to embolic stroke and will be treated with GP IIb/IIIa receptor antagonist at specific time points before and after stroke. The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 2 : Rats will be subjected to embolic stroke and will be treated with rtPA and specific time points after stroke (2h, 4h, 6h). The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 3 : Rats will be subjected to embolic stroke and will be treated with a GP IIb/IIIa receptor antagonist at specific time points before and after stroke. The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 4 : Rats will be subjected to embolic stroke and will be treated with a combination of GPIIb/IIIa receptor antagonist and fibrinolysis with rtPA at specific time points after stroke. To test our hypotheses, we employ a clinically relevant model of embolic stroke in the rat and state-of-the-art technology, including quantita6tive scanning confocal microscopy and MRI. Our long term objective of developing anti-platelet aggregation therapy in the human is initiated in the Phase II Clinical Trial to be carried out in Project 3. This Project provides the experimental basis for reducing platelet mediated thrombosis secondary to stroke.
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