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.