Complement inhibition attenuates brain edema and neurological deficits induced by thrombin.
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 microg N-acetylheparin or five-unit thrombin+100 microg 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 microg 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-microg) but not low-dose (25-microg) 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.
Gong
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Y
Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109-0532, USA.
Xi
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Keep
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Hoff
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JT
Hua
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001929:Brain Edema / Q000139:chemically induced* / Q000276:immunology / Q000517:prevention & control*; D003167:Complement Activation / Q000187:drug effects* / Q000276:immunology; D051056:Complement Inactivating Agents / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006493:Heparin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000276:immunology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000009:adverse effects*; D016896:Treatment Outcome
D051056:Complement Inactivating Agents; D004338:Drug Combinations; C089591:N-acetylheparin; D006493:Heparin; D013917:Thrombin