Complement activation in the brain after experimental intracerebral hemorrhage

Ya Hua M.D.1, Guohua Xi M.D.1, Richard F. Keep Ph.D.1, and Julian T. Hoff M.D.1
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  • 1 Department of Surgery (Neurosurgery), University of Michigan, Ann Arbor, Michigan
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Object. Brain edema formation following intracerebral hemorrhage (ICH) appears to be partly related to erythrocyte lysis and hemoglobin release. Erythrocyte lysis may be mediated by the complement cascade, which then triggers parenchymal injury. In this study the authors examine whether the complement cascade is activated after ICH and whether inhibition of complement attenuates brain edema around the hematoma.

Methods. This study was divided into three parts. In the first part, 100 µl of autologous blood was infused into the rats' right basal ganglia, and the animals were killed at 24 and 72 hours after intracerebral infusion. Their brains were tested for complement factors C9, C3d, and clusterin (a naturally occurring complement inhibitor) by using immunohistochemical analysis. In the second part of the study, the rats were killed at 24 or 72 hours after injection of 100 µl of blood. The C9 and clusterin proteins were quantitated using Western blot analysis. In the third part, the rats received either 100 µl of blood or 100 µl of blood plus 10 µg of N-acetylheparin (a complement activation inhibitor). Then they were killed 24 or 72 hours later for measurement of brain water and ion contents. It was demonstrated on Western blot analysis that there had been a sixfold increase in C9 around the hematoma 24 hours after the infusion of 100 µl of autologous blood. Marked perihematomal C9 immunoreactivity was detected at 72 hours. Clusterin also increased after ICH and was expressed in neurons 72 hours later. The addition of N-acetylheparin significantly reduced brain edema formation in the ipsilateral basal ganglia at 24 hours (78.5 ± 0.5% compared with 81.6 ± 0.8% in control animals, p < 0.001) and at 72 hours (80.9 ± 2.2% compared with 83.6 ± 0.9% in control animals, p < 0.05) after ICH.

Conclusions. It was found that ICH causes complement activation in the brain. Activation of complement and the formation of membrane attack complex contributes to brain edema formation after ICH. Blocking the complement cascade could be an important step in the therapy for ICH.

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