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

Abstract

BACKGROUND AND PURPOSE:

To simulate human stroke, we developed a model of focal 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 reducing 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 catheter. 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 volume 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 MCA 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, body weight loss and infarct volume (22.8+/-2.1%) without an increase in gross hemorrhage (10%) compared with the non treated ischemic rats (25%). Although treatment with TNK-tPA of ischemic rats (n=12) at 4 h did not significantly (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 neurological deficits and ischemic lesion volume without increasing hemorrhagic transformation and that administration of TNK-tPA at 4 h of ischemia does not increase the incidence of hemorrhagic transformation.

• Authors: R L Zhang, L Zhang, Q Jiang, Z G Zhang, A Goussev, M Chopp
• Journal: Brain research (Brain Res) Vol. 878 Issue 1-2 Pg. 64-71 (Sep 29 2000) ISSN: 0006-8993 [Print] Netherlands
• PMID: 10996136 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• TNK-tissue plasminogen activator
• Tissue Plasminogen Activator

Topics

• Animals
• Brain Ischemia (complications, drug therapy)
• Carotid Arteries
• Cerebral Infarction (etiology, pathology)
• Injections, Intra-Arterial
• Intracranial Embolism (complications)
• Male
• Nervous System Diseases (drug therapy, etiology, physiopathology)
• Rats
• Rats, Wistar
• Stroke (complications)
• Tissue Plasminogen Activator (administration & dosage, therapeutic use)