title: Postischemic intracarotid treatment with TNK-tPA reduces infarct volume and improves neurological deficits in embolic stroke in the unanesthetized rat.
abstract: OBJECTIVE
  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.affiliation: Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: Q
authors.initials: Q
authors.lastname: Jiang
authors.forename: Z G
authors.initials: ZG
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Goussev
authors.forename: M
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D002339:Carotid Arteries; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology*; D007269:Injections, Intra-Arterial; D020766:Intracranial Embolism / Q000150:complications*; D008297:Male; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000150:complications*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: C104096:TNK-tissue plasminogen activator; D010959:Tissue Plasminogen Activator