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

Document Type

Article

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.

Medical Subject Headings

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

Publication Date

1-1-2012

Publication Title

PloS one

E-ISSN

1932-6203

Volume

7

Issue

6

First Page

e38664

PubMed ID

22761695

Digital Object Identifier (DOI)

10.1371/journal.pone.0038664

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