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.
Mocco
J
J
Department of Neurosurgery, Columbia University, 710 W 168th St, New York, NY 10032, USA.
Mack
William J
WJ
Ducruet
Andrew F
AF
Sosunov
Sergei A
SA
Sughrue
Michael E
ME
Hassid
Benjamin G
BG
Nair
M Nathan
MN
Laufer
Ilya
I
Komotar
Ricardo J
RJ
Claire
M
M
Holland
H
H
Pinsky
David J
DJ
Connolly
E Sander
ES
D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement; D003176:Complement C3 / Q000502:physiology*; D004195:Disease Models, Animal; D006098:Granulocytes; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D011951:Receptors, Complement / Q000037:antagonists & inhibitors; D020521:Stroke / Q000188:drug therapy / Q000473:pathology
D003176:Complement C3; D008565:Membrane Proteins; D011951:Receptors, Complement; C085567:complement C3a receptor