Complement Inhibition Promotes Endogenous Neurogenesis and Sustained Anti-Inflammatory Neuroprotection following Reperfused Stroke

作者：Ducruet Andrew F^*; Zacharia Brad E; Sosunov Sergey A; Gigante Paul R; Yeh Mason L; Gorski Justin W; Otten Marc L; Hwang Richard Y; DeRosa Peter A; Hickman Zachary L; Sergot Paulina; Connolly E Sander Jr

来源：PLos One, 2012, 7(6): e38664.

DOI：10.1371/journal.pone.0038664

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.

• 出版日期2012-6-26