DELAYED REPERFUSION WITH TPA IN THROMBOEMBOLIC STROKE

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With the availability of fibrin specific thrombolytics, there is renewed interest in thrombolytic therapy for stroke. Current understanding of the pathophysiology of stroke suggests that the safety of recanalizing obstructed brain vessels, as it relates to neuronal salvage and reperfusion injury, is a function of the intensity, duration and volume of the ischemic insult. Additionally, there is increasing evidence that neutrophils may play an important role in reperfusion injury. This proposal is designed to critically determine the safe time limit for establishing reperfusion with tPA in a thromboembolic stroke model, and to subsequently examine, alone and in combination, the capacity of the anion channel blocker L644,711 and the antioxidant U74006F to extend this time limit and to assess their impact on neutrophil activation and infiltration of the injured brain tissue. A rabbit model is proposed and supported by preliminary data. The model involves standardization of infarct size by ensuring a critical reduction of cerebral blood flow to insure a standard level of ischemic blood flow as documented by hydrogen clearance. tPA (3.5mg/kg), given as a square wave pulse, will be initiated at variable times (O-8 hours) following injection of a tin impregnated internal carotid artery embolus. Intracranial pressure, regional cerebral blood flow, arterial blood gases, hematocrit, serum glucose, serum uric acid, white cell aggregation and vessel patency will be monitored throughout the experiment. The brain will be harvested, sectioned and incubated in triphenyltetrazolium chloride to document the extent of the infarct. The coronal sections will be planimetrically analyzed for volume of hemorrhage and infarct. Hemispheric edema will be determined using a combination of planimetry and wet-dry weights. The dry (lyophilized) brain tissue from infarcted and non-infarcted areas will be analyzed for myeloperoxidase activity as a quantitative measure of neutrophil infiltration. Delay to reperfusion, with and without treatment of the animals with L644,711 and U74006F, alone and in combination, will be statistically correlated with these outcome measures.