Abstract
Background and PurposeThe 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.MethodsTo 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).ResultsLow-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.ConclusionsTargeted 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.
Highlights
The complement cascade is a component of the innate immune system that plays a critical role in post-ischemic inflammation [1]
Given the proposed role for C3a in stimulating post-ischemic neurogenesis [11], we evaluated baseline expression and the effect of low-dose C3a receptor (C3aR) antagonism (Figure S1 A-D) on ischemiainduced neurogenesis in the subventricular zone (SVZ) at 7 days post-reperfusion
Analysis of serial H&E-stained coronal sections (Figure S4A) at 7 days revealed significantly decreased volume of subcortical infarction following C3a receptor antagonist (C3aRA) administration in all treatment groups compared to vehicle (Figure 5A). These findings indicate that C3aRA administration decreases, rather than delays, tissue injury, and that this protection occurs predominantly in subcortical regions in this model of middle cerebral artery occlusion (MCAO)
Summary
The complement cascade is a component of the innate immune system that plays a critical role in post-ischemic inflammation [1]. Of the numerous peptides generated though sequential complement cleavage, the anaphylatoxins, C3a and C5a, are among the most potent of all known inflammatory mediators. By binding to their cognate receptors, the C3a receptor (C3aR) and C5a receptor (C5aR), these peptides mediate their inflammatory effects across a variety of pathologic settings by promoting vascular permeability, leukocyte activation, and chemotaxis [2,3]. C3and C3aR-deficient mice exhibit impaired basal neurogenesis in the subventricular zone (SVZ). These data argue that long-term administration of anti-complement therapeutics may impair neurorestorative processes in the brain, potentially exacerbating post-ischemic neurological injury. Recent reports implicate C3a in the modulation of tissue repair, suggesting that complement may influence both injury and recovery at later post-ischemic time-points
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