Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke

PLoS One. 2012;7(6):e38664. doi: 10.1371/journal.pone.0038664. Epub 2012 Jun 26.

Abstract

Background and purpose: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Brain Ischemia / complications
  • Brain Ischemia / pathology
  • Complement C3a / antagonists & inhibitors*
  • Complement C3a / metabolism
  • Disease Models, Animal
  • Inflammation / etiology
  • Inflammation / metabolism
  • Inflammation / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurogenesis / drug effects*
  • Neurogenesis / physiology
  • Neuroprotective Agents / pharmacology*
  • Receptors, Complement / antagonists & inhibitors*
  • Receptors, Complement / metabolism
  • Reperfusion Injury / etiology
  • Reperfusion Injury / mortality
  • Reperfusion Injury / prevention & control
  • Stroke / etiology
  • Stroke / mortality
  • Stroke / prevention & control*
  • Survival Rate
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology

Substances

  • Anti-Inflammatory Agents
  • Neuroprotective Agents
  • Receptors, Complement
  • complement C3a receptor
  • Complement C3a