title: Complement component C3 mediates inflammatory injury following focal cerebral ischemia.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Columbia University, 710 W 168th St, New York, NY 10032, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mocco
authors.forename: William J
authors.initials: WJ
authors.lastname: Mack
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ducruet
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Sosunov
authors.forename: Michael E
authors.initials: ME
authors.lastname: Sughrue
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Hassid
authors.forename: M Nathan
authors.initials: MN
authors.lastname: Nair
authors.forename: Ilya
authors.initials: I
authors.lastname: Laufer
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Komotar
authors.forename: M
authors.initials: M
authors.lastname: Claire
authors.forename: H
authors.initials: H
authors.lastname: Holland
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
mesh_terms: 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
chemical_list: D003176:Complement C3; D008565:Membrane Proteins; D011951:Receptors, Complement; C085567:complement C3a receptor