ACTIVE THROMBOSIS, THROMBOLYSIS, AND STROKE OUTCOME

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DESCRIPTION: Although thrombolysis by plasminogen activators is an accepted acute clinical treatment for stroke there is still a need to evaluate fully, in a relevant animal model, the consequences of the resultant reperfusion for metabolically compromised brain tissue. A reversible model of thrombotic stroke has been developed, in which the ictus is initiated by photochemically mediated (photothrombotic) occlusion of the rat middle cerebral artery, resulting in a fibrin-free platelet thrombus resistant to conventional (rt-PA) thrombolytic treatment. Such thrombi may account for the majority of recanalization failures seen clinically. Reperfusion is then achieve photophysically by a proprietary process that facilitates dethrombosis, evidently by enhanced penetration of antithrombotic plasma factors. For occlusion times less than 2 hr, cortical cerebral blood flow (CBF) is established within 5-30 min, but full flow restoration at later times will likely require thrombin inhibitor (or plasminogen activator) administration to clear stasis-induced distal secondary thrombi. Although tissue recovery is expected to coincide with flow recovery at early times, "reperfusion injury" concomitant with irreversible cellular changes presaging infarction may occur at later times, even if the microcirculation is preserved by antithrombin treatment via inhibition of the expression of P-selectin, which precedes leukocyte stasis. Indicators of developing reperfusion injury such as expression of P-selectin on endothelium and on thrombin-activated platelets, myeloperoxidase activity, and lipid peroxidation byproducts malondialdehyde and 4-hydroxy-2-nonenal will be monitored by immunostaining procedures at times up to 1 day. The effect of reperfusion on endothelial nitric oxide synthase protein and gene expression will be assessed by immunostaining and in situ hybridization. Outcome at 3 days, monitored by histological evaluation of regions of frank and incomplete infarction, will be correlated with the time course of reperfusion-inducing treatments and associated molecular changes.