There has been considerable interest in the use of
thrombin inhibitors to reduce the occurrence of
stroke or to potentiate
tissue plasminogen activator-induced reperfusion. However, there is growing evidence that
thrombin may also have extravascular effects that influence ischemic
brain injury. Male Sprague-Dawley rats were subjected to either 90 minutes of temporary middle cerebral artery (MCA) occlusion or
sham operation to examine
thrombin and
protease activated receptor-1 (PAR-1) expression. In another set of rats, the MCA was occluded for 90 minutes and 10 U of
hirudin or the same volume of vehicle was injected into the caudate followed by reperfusion for up to 28 days, to test the effects of local
thrombin inhibition on ischemic damage, neurologic outcome and cerebral blood flow (CBF).
Thrombin immunoreactivity was increased in the ischemic caudate at 4 and 24 hours, whereas PAR-1 expression was unchanged.
Hirudin reduced
infarct volume in the caudate at 24 hours (79 +/- 41 vs. 115 +/- 20 mm3, P < 0.05) and resulted in a larger residual tissue volume in the caudate at 28 days (17.6 +/- 3.9 vs. 11.8 +/- 6.3 mm3, P < 0.05).
Hirudin treatment also had a beneficial effect on
body weight and ameliorated
neurologic deficits tested by forelimb placing and forelimb use asymmetry during 28 days survival. These beneficial effects of
hirudin were not associated with improved regional CBF during reperfusion. These results suggest that, in addition to their effects on coagulation and circulation,
thrombin inhibitors also have direct neuroprotective properties and may be considered in
stroke therapy.