The effects of thrombin preconditioning on focal cerebral ischemia in rats.
Our previous studies have shown that prior intracerebral infusion of a low dose of thrombin (thrombin preconditioning; TPC) reduces the brain edema that follows a subsequent intracerebral infusion of a high dose of thrombin or an intracerebral hemorrhage. In vitro studies have also demonstrated that low concentrations of thrombin protect neurons and astrocytes from hypoglycemia and oxidative stress-induced damage. This study, therefore, examines the hypothesis that TPC would offer protection from ischemic brain damage in vivo. This was a blinded design study. The rat brain was preconditioned with 1 U thrombin by direct infusion into the left caudate nucleus. Seven days after thrombin pretreatment, permanent middle cerebral artery occlusion (MCAO) was induced. Twenty-four hours post-ischemia, neurological deficit was evaluated and infarction volume, brain water and ion contents were measured. Compared to saline-treated rats, thrombin pretreatment significantly attenuated brain infarction in cortex (90+/-33 vs. 273+/-22 mm(3); P<0.05) and basal ganglia (56+/-17 vs. 119+/-12 mm(3); P<0.05) that followed 24 h of permanent MCAO. TPC also reduced the brain edema in cortex and basal ganglia by 50 and 53% (P<0.05). Neurological deficit was improved in thrombin pretreatment group (P<0.05). These effects of TPC were, in part, prevented by co-injection of hirudin, a thrombin inhibitor, indicating that the protection was indeed thrombin mediated. Cerebral TPC significantly reduces ischemic brain damage, perhaps by activation of the thrombin receptor. This finding provides a new mechanism by which to study ischemic tolerance.
Masada
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Department of Surgery (Neurosurgery), University of Michigan, R5550 Kresge I, Ann Arbor, MI 48109-0532, USA.
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D000818:Animals; D001929:Brain Edema / Q000188:drug therapy; D002545:Brain Ischemia / Q000188:drug therapy*; D006490:Hemostatics / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D019194:Ischemic Preconditioning; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D020521:Stroke / Q000188:drug therapy; D013917:Thrombin / Q000494:pharmacology*
D006490:Hemostatics; D013917:Thrombin