Complement-Dependent Synaptic Uptake and Cognitive Decline after Stroke and Reperfusion Therapy
Complement-Dependent Synaptic Uptake and Cognitive Decline after Stroke and Reperfusion Therapy
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DOI：
10.1523/jneurosci.2462-19.2020
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发表时间：
2020-05-13
影响因子：
5.3
通讯作者：
Tomlinson, Stephen
中科院分区：
文献类型：
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作者：
Alawieh, Ali M.;Langley, E. Farris;Tomlinson, Stephen
尽管再灌注治疗在显著降低卒中后梗死范围方面取得了成功，但血管重建对卒中后神经炎症的影响以及再灌注后抗炎策略的作用仍有待探讨。在这里，我们调查是否神经炎症反应可能仍然有助于再灌注中风后的神经功能缺损，通过使用有针对性的补体抑制抑制中风后神经炎症的小鼠，有或没有并行再灌注治疗。使用B4 Crry实现补体抑制，B4 Crry是C3活化的损伤位点靶向抑制剂。在雄性C57 bl/6小鼠栓塞性卒中后，使用组织纤溶酶原激活剂（t-PA）进行溶栓可减少损伤并改善运动缺陷，但不能改善认知结果。在再灌注和非再灌注卒中后，海马突触的补体激活和调理素作用在卒中后至少30 d内指导突触的持续小胶质细胞依赖性吞噬作用，导致与认知能力下降相关的突触密度丧失。单独或与tPA组合的B4 Crry治疗限制了病灶周围的补体沉积，减少了小胶质细胞增生和突触摄取，并改善了认知结果，而不影响再生反应。此外，补体抑制通过限制出血性转化改善了t-PA再灌注治疗的安全性、有效性和治疗窗。因此，这项工作表明，卒中后神经炎症有助于出血性转化和脑神经退行性反应的进展，即使在早期和成功的血运重建。
Despite the success of reperfusion therapy in significantly reducing the extent of infarct expansion after stroke, the effect of revascularization on poststroke neuroinflammation and the role of anti-inflammatory strategies in postreperfusion era are yet to be explored. Here, we investigate whether the neuroinflammatory response may still contribute to neurologic deficits after reperfused stroke by using targeted complement inhibition to suppress poststroke neuroinflammation in mice with or without concurrent reperfusion therapy. Complement inhibition was achieved using B4Crry, an injury site-targeted inhibitor of C3 activation. Following embolic stroke in male C57bl/6 mice, thrombolysis using tissue-plasminogen activator (t-PA) reduced injury and improved motor deficits, but did not improve cognitive outcomes. After both reperfused and non-reperfused stroke, complement activation and opsonization of hippocampal synapses directed ongoing microglia-dependent phagocytosis of synapses for at least 30 d after stroke, leading to a loss of synaptic density that was associated with cognitive decline. B4Crry treatment, alone or in combination with tPA, limited perilesional complement deposition, reduced microgliosis and synaptic uptake, and improved cognitive outcome without affecting regenerative responses. Furthermore, complement inhibition improved the safety, efficacy, and treatment window of reperfusion therapy with t-PA by limiting hemorrhagic transformation. This work thus demonstrates that poststroke neuroinflammation contributes to hemorrhagic transformation and progression of neurodegenerative responses in the brain even following early and successful revascularization.