With the availability of fibrin-specific thrombolytic agents, there is renewed interest in thrombolytic therapy for stroke. Current understanding of the pathophysiology of stroke suggests that the safety of reperfusion, as it relates to neuronal salvage and reperfusion injury, is a function of the intensity, duration, and volume of the ischemic insult. This proposal is designed to first determine the safe time limit for establishing reperfusion with the thrombolytic agent t-PA in a rabbit model of thromboembolic stroke and to subsequently examine strategies to effectively extend this safe time limit. Regarding the latter, preliminary studies support a role for neutrophil-mediated injury in cerebral ischemia. An autologous clot embolus, delivered via the internal carotid artery simulates the human condition of thromboembolic stroke. Cerebral blood flow (CBF) determinations by the hydrogen clearance technique ensure that the critical reduction in CBF, derived from previous studies, is obtained prior to study inclusion. Intracranial pressure (ICP, fiberoptic monitor), CBF, arterial blood gases, hematocrit, serum glucose, complement levels, ex-vivo neutrophil and platelet function/aggregation and vessel patency will be monitored throughout the experiment. t-PA (2.5 mg/kg I.V.) will be initiated at variable times (2-8 hours) after embolization. The delay to t-PA therapy will be correlated with the degree of brain injury, as assessed by ICP, CBF, intracranial hemorrhage, cerebral edema (gravimetric and planimetric analysis) and infarct size (triphenyltetrazolium chloride dye) as well as the degree of neutrophil accumulation in ischemic brain regions (myeloperoxidase assay). The earliest time point consistently demonstrating exacerbation of brain injury secondary to thrombolytic therapy will then be used to examine interventions designed to reduce brain injury and extend the period of time during which thrombolytic therapy may be effectively initiated. Both biochemical and cellular mechanisms will be examined for their potential efficacy in limiting brain injury following ischemia-reperfusion. These interventions will be initiated 30 minutes prior to t-PA therapy in order to simulate the time constraints encountered in the clinical setting. These interventions will include agents 1] that deplete neutrophils or inhibit neutrophil activation/accumulation, 2] that deplete platelets or inhibit platelet activation/accumulation, 3] that inhibit the synthesis/action of biochemical mediators co-derived from platelets and/or neutrophils, 4] that inhibit astrocyte cell swelling and excitotoxin release, and 5] that reduce system complement activity.
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