Postischemic intracarotid treatment with TNK-tPA reduces infarct volume and improves neurological deficits in embolic stroke in the unanesthetized rat

Background and purpose: To simulate human stroke, we developed a model of f ocal cerebral embolic ischemia in the unanesthetized rat. Using this model, we tested the hypothesis that intra-arterial administration of TNK-tPA, a fibrin specific second generation thrombolytic agent, is effective in reduc ing ischemic volume without increasing intra-cerebral hemorrhage. Methods: Under anesthesia, a catheter was inserted to the origin of the MCA of male Wistar rats. Forty-five minutes after recovery from anesthesia, the MCA was occluded in the awake rat by a single fibrin rich clot placed via the cath eter. TNK-tPA (1.5 mg/kg) was administered intraarterially via the catheter at either 2 h or 4 h after stroke. All rats were sacrificed at 48 h after ischemia. Neurological deficits, gross hemorrhage and ischemic lesion volum e were measured. Results: A clot was detected at the origin of the MCA 4 h after MCA occlusion in the awake rats (n = 4). Rats (n = 12) subjected to M CA occlusion showed immediate neurological deficits which persisted for 48 h of ischemia. Ischemic rats had a lesion volume of 38.2+/-3.8% and 25% of rats exhibited gross hemorrhage. Ischemic rats (n=10) treated with TNK-tPA at 2 h showed a significant (P<0.05) reduction of neurological deficits, bo dy weight loss and infarct volume (22.8+/-2.1%) without an increase in gros s hemorrhage (10%) compared with the non treated ischemic rats (25%). Altho ugh treatment with TNK-tPA of ischemic rats (n=12) at 4 h did not significa ntly (P=0.06) reduce infarct volume (28.6+/-3.0%), it also did not increase gross hemorrhage (25%) compared with the control group (25%). Conclusions: This study demonstrates that intraarterial administration of TNK-tPA at 2 h of ischemia in the unanesthesthetized rat is effective in reducing neurol ogical deficits and ischemic lesion volume without increasing hemorrhagic t ransformation and that administration of TNK-tPA at 4 h of ischemia does no t increase the incidence of hemorrhagic transformation. (C) 2000 Elsevier S cience B.V. All rights reserved.