title: Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke.
abstract: OBJECTIVE
  The restoration of blood-flow following cerebral ischemia incites a series of deleterious cascades that exacerbate neuronal injury. Pharmacologic inhibition of the C3a-receptor ameliorates cerebral injury by attenuating post-ischemic inflammation. Recent reports also implicate C3a in the modulation of tissue repair, suggesting that complement may influence both injury and recovery at later post-ischemic time-points.
  
  
  METHODS
  To evaluate the effect of C3a-receptor antagonism on post-ischemic neurogenesis and neurological outcome in the subacute period of stroke, transient focal cerebral ischemia was induced in adult male C57BL/6 mice treated with multiple regimens of a C3a receptor antagonist (C3aRA).
  
  
  RESULTS
  Low-dose C3aRA administration during the acute phase of stroke promotes neuroblast proliferation in the subventricular zone at 7 days. Additionally, the C3a receptor is expressed on T-lymphocytes within the ischemic territory at 7 days, and this cellular infiltrate is abrogated by C3aRA administration. Finally, C3aRA treatment confers robust histologic and functional neuroprotection at this delayed time-point.
  
  
  CONCLUSIONS
  Targeted complement inhibition through low-dose antagonism of the C3a receptor promotes post-ischemic neuroblast proliferation in the SVZ. Furthermore, C3aRA administration suppresses T-lymphocyte infiltration and improves delayed functional and histologic outcome following reperfused stroke. Post-ischemic complement activation may be pharmacologically manipulated to yield an effective therapy for stroke.
authors: Department of Neurological Surgery, Columbia University, New York, New York, United States of America. afd12@columbia.edu
authors: Andrew F
authors: AF
authors: Ducruet
authors: Brad E
authors: BE
authors: Zacharia
authors: Sergey A
authors: SA
authors: Sosunov
authors: Paul R
authors: PR
authors: Gigante
authors: Mason L
authors: ML
authors: Yeh
authors: Justin W
authors: JW
authors: Gorski
authors: Marc L
authors: ML
authors: Otten
authors: Richard Y
authors: RY
authors: Hwang
authors: Peter A
authors: PA
authors: DeRosa
authors: Zachary L
authors: ZL
authors: Hickman
authors: Paulina
authors: P
authors: Sergot
authors: E Sander
authors: ES
authors: Connolly
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology; D015926:Complement C3a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011951:Receptors, Complement / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000401:mortality / Q000517:prevention & control; D020521:Stroke / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a