REDUCTION OF BRAIN INJURY USING HEPARIN TO INHIBIT LEUKOCYTE ACCUMULATION IN A RAT MODEL OF TRANSIENT FOCAL CEREBRAL-ISCHEMIA .2. DOSE-RESPONSE EFFECT AND THE THERAPEUTIC WINDOW

The administration of massive doses of heparin has been demonstrated t o reduce reperfusion injury. The authors have found that heparin's ant ileukocyte adhesion property may play a more important role than its a nticoagulant property in preventing ischemia and reperfusion injury. A lthough the administration of massive doses of heparin has been demons trated to reduce brain injury ischemia and reperfusion, the optimum do sage and timing for heparin administration remain unknown. The purpose of this study was to evaluate the dose-response effect and determine the time during which heparin must be administered to inhibit leukocyt e accumulation, reduce infarct size, and improve neurological outcome in rats subjected to 1 hour of cerebral ischemia and 48 hours of reper fusion. Forty-nine animals were included in the study. The animals rec eiving commercial unfractionated heparin at a total dose of 2.67 to 4 mg/kg showed a significant inhibition of leukocyte accumulation, reduc ed infarct size, and lessened neurological dysfunction 48 hours after reperfusion (p<0.05) when compared to untreated animals. The animals r eceiving unfractionated heparin within 3 hours after reperfusion also showed significantly better results than untreated animals. These indi cate that standard doses of heparin prevent reperfusion injury, and re latively late postischemic administration of heparin also is effective in brain protection. These findings may have therapeutic potential as an adjunct to thrombolytic therapy and possibly for other prefusion d eficiencies with leukocyte-endothelial interaction. In view of these e ncouraging experimental findings, the clinical application of heparin administration after ischemia and reperfusion warrants serious conside ration.