Complement Component C3 Mediates Inflammatory Injury Following Focal Cerebral Ischemia

The complement cascade has been implicated in ischemia/reperfusion injury, and recent studies have shown that complement inhibition is a promising treatment option for acute stroke. The development of clinically useful therapies has been hindered, however, by insufficient understanding of which complement subcomponents contribute to post-ischemic injury. To address this issue, we subjected mice deficient in selected complement proteins (C1q, C3, C5) to transient focal cerebral ischemia. Of the strains investigated, only C3 −/− mice were protected, as demonstrated by 34% reductions in both infarct volume ( P <0.01) and neurological deficit score ( P <0.05). C3-deficient mice also manifested decreased granulocyte infiltration ( P <0.02) and reduced oxidative stress ( P <0.05). Finally, administration of a C3a-receptor antagonist resulted in commensurate neurological improvement and stroke volume reduction ( P <0.05). Together, these results establish C3 activation as the key constituent in complement-related inflammatory tissue injury following stroke and suggest a C3a anaphylatoxin-mediated mechanism.