Delayed (6h) Intracarotid Treatment with TNK-tPA Improves Neurological Functional Recovery after Embolic Stroke in the Unanesthetized Rat
We tested the hypothesis that delayed intra-arterial administration of TNK-tPA increases functional recovery in a model of focal cerebral embolic ischemia in the unanesthetized rat. Male unanesthetized Wistar rats (n=22) were subjected to middle cerebral artery (MCA) occlusion using a single fibrin rich clot. TNK-tPA (1.5 mg/kg) was administered intraarterially via an internal carotid catheter at 2 h (n=4), 4 h (n=6) or 6 h (n=6) after MCA occlusion. Non-treated ischemic rats (n=6) were used as a control group. A battery of tests (1. Rotarod test, 2. Adhesive-removal test and 3. Footfault test) was used to evaluate neurological function. Animal body weights were measured before and after MCA occlusion. All rats were sacrificed 28 days after ischemia. Infract volume and gross hemorrhage was measured. Intra-arterial treatment with TNK-tPA at 2h after ischemia significantly (p<0.01) reduced infarct volume (18.6“2.6 % of the contralateral hemisphere) and improved neurological functional recovery compared with the control rats (37.5 ”0.7%). Although infarct volumes were not significantly reduced for rats treated with intra-arterial TNK-tPA at 4h (31.2“3.1 %) and at 6h (32.9”3.1 %) after ischemia, significant (p<0.05) improvements on sensorimotor functions (adhesive removal test at 4, 14, 21, and 28 d ) and significant increases in animal body weight (7 d) were detected in rats treated with TNK-tPA at 4 h and 6h. Gross hemorrhage was 25% (2h), 33% (4h) and 33% (6h), which was not significantly different from gross hemorrhage in the control group (17 %). This study demonstrates that intra-carotid treatment with TNK-tPA even at 6h of the onset of stroke improves neurological functional recovery from brain damage without significantly increasing the incidence of intra-cerebral hemorrhage in the unanesthetized ischemic rat.