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 th at follows a subsequent intracerebral infusion of a high dose of thrombin o r an intracerebral hemorrhage. In vitro studies have also demonstrated that low concentrations of thrombin protect neurons and astrocytes from hypogly cemia and oxidative stress-induced damage. This study, therefore, examines the hypothesis that TPC would offer protection from ischemic brain damage i n vivo. This was a blinded design study. The rat brain was preconditioned w ith 1 U thrombin by direct infusion into the left caudate nucleus. Seven da ys after thrombin pretreatment, permanent middle cerebral artery occlusion (MCAO) was induced. Twenty-four hours post-ischemia, neurological deficit w as evaluated and infarction volume, brain water and ion contents were measu red. Compared to saline-treated rats, thrombin pretreatment significantly a ttenuated brain infarction in cortex (90+/-33 vs. 273+/-22 mm(3); P<0.05) a nd 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 gangl ia by 50 and 53% (P<0.05). Neurological deficit was improved in thrombin pr etreatment group (P<0.05). These effects of TPC were, in part, prevented by co-injection of hirudin, a thrombin inhibitor, indicating that the protect ion was indeed thrombin mediated. Cerebral TPC significantly reduces ischem ic brain damage, perhaps by activation of the thrombin receptor. This findi ng provides a new mechanism by which to study ischemic tolerance. (C) 2000 Elsevier Science B.V. All rights reserved.