Complement inhibition attenuates brain edema and neurological deficits induced by thrombin

Summary

The present study examined whether thrombin activates the complement cascade in the brain and whether N-acetylheparin, an inhibitor of complement activation, attenuates brain injury induced by thrombin. There were three sets of studies. In the first set, rats had an intracerebral infusion of either five-unit thrombin or a needle insertion. Brains were sampled at 24 hours for Western blot analysis and immuno-histochemistry. In the second set, rats received either five-unit thrombin+saline, five-unit thrombin+25 µg N-acetylheparin or five-unit thrombin+100 µg N-acetylheparin infusion. Brains were sampled 24 hours later for water content measurement. In the third set, rats received either five-unit thrombin+saline or five-unit thrombin+100 µg N-acetylheparin. Behavioral tests sensitive to unilateral striatal damage were carried out for two weeks. Western blotting demonstrated that complement C9 and clusterin levels increase 24 hours after thrombin infusion (P<0:01). Both C9 and clusterin positive cells were found around the injection site. High-dose (100-µg) but not low-dose (25-µg) N-acetylheparin attenuated thrombin-induced brain edema (81.5 ± 0.4% vs. 83.7 ± 0.3% in the vehicle, P<0:05). Behavior was also significantly improved by N-acetylheparin (P<0:05). In conclusion, thrombin-induced edema formation and neurological deficits were both reduced by N-acetylheparin. This suggests that inhibition may be a novel treatment for the thrombin-induced brain injury that occurs in intracerebral hemorrhage.

This study was supported by grants NS-17760 (J.T.H), NS-39866 and NS-47245 (G.X) from the National Institutes of Health.