Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke.
Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke.
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DOI：
10.1371/journal.pone.0038664
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Connolly ES Jr
中科院分区：
文献类型：
--
作者：
Ducruet AF;Zacharia BE;Sosunov SA;Gigante PR;Yeh ML;Gorski JW;Otten ML;Hwang RY;DeRosa PA;Hickman ZL;Sergot P;Connolly ES Jr
脑缺血后血流的恢复会引发一系列有害的级联反应，加剧神经元损伤。 C3a 受体的药物抑制可通过减轻缺血后炎症来改善脑损伤。最近的报告还表明 C3a 参与组织修复的调节，这表明补体可能会影响缺血后后期的损伤和恢复。为了评估 C3a 受体拮抗作用对中风亚急性期缺血后神经发生和神经系统结局的影响，在接受 C3a 受体拮抗剂 (C3aRA) 多种方案治疗的成年雄性 C57BL/6 小鼠中诱导短暂性局灶性脑缺血。中风急性期低剂量 C3aRA 给药可促进 7 天时室下区神经母细胞增殖。此外，7 天时，C3a 受体在缺血区域内的 T 淋巴细胞上表达，并且通过 C3aRA 给药消除了这种细胞浸润。最后，C3aRA 治疗在这个延迟的时间点提供了强大的组织学和功能性神经保护。通过低剂量拮抗 C3a 受体的靶向补体抑制可促进 SVZ 缺血后神经母细胞增殖。此外，C3aRA 给药可抑制 T 淋巴细胞浸润并改善再灌注中风后延迟的功能和组织学结果。缺血后补体激活可以通过药理学操作来产生对中风的有效治疗。
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. 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). 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. 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.
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2.7
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