Oxidative stress interferes with white matter renewal after prolonged cerebral hypoperfusion in mice.
Oxidative stress interferes with white matter renewal after prolonged cerebral hypoperfusion in mice.
复制标题
氧化应激会在小鼠长期脑部灌注延长后干扰白质的更新。
DOI：
10.1161/strokeaha.113.002813
复制
发表时间：
2013-12
期刊：
影响因子：
8.3
通讯作者：
Arai K
中科院分区：
文献类型：
--
作者：
Miyamoto N;Maki T;Pham LD;Hayakawa K;Seo JH;Mandeville ET;Mandeville JB;Kim KW;Lo EH;Arai K
脑灌注不足引起的白色物质损伤可能与血管性痴呆和卒中的病理生理学有关，但其潜在机制仍有待充分阐明。在这里，我们测试的假设，即氧化应激干扰内源性白色物质修复破坏少突胶质细胞前体细胞（OPCs）介导的更新过程。在体外，原代大鼠OPCs暴露于亚致死量的氯化钴7天，以诱导长期的化学缺氧应激。然后，评估OPC增殖/分化。在体实验中，双侧颈总动脉狭窄可导致小鼠长时间脑低灌注。然后，活性氧的产生，髓鞘密度，少突胶质细胞与OPC计数，和认知功能进行了评价。为了阻断氧化应激，OPCs和小鼠用自由基清除剂依达拉奉处理。长时间的化学低氧应激抑制体外OPC分化。自由基清除与依达拉奉改善这些影响。在体内脑灌注不足28天后，受损的白色物质中活性氧水平增加，沿着OPC向少突胶质细胞分化的抑制和髓鞘染色的丧失。同时，小鼠在工作记忆中表现出功能缺陷。用依达拉奉清除自由基可挽救OPC分化，改善髓鞘丢失，并恢复工作记忆功能。我们的概念验证研究表明，在长时间的脑灌注不足后，氧化应激通过破坏OPC更新机制来干扰白色物质修复。自由基清除剂可能为血管性痴呆和中风中的白色物质损伤提供潜在的治疗方法。
White matter injury caused by cerebral hypoperfusion may contribute to the pathophysiology of vascular dementia and stroke, but the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that oxidative stress interferes with endogenous white matter repair by disrupting renewal processes mediated by oligodendrocyte precursor cells (OPCs). In vitro, primary rat OPCs were exposed to sublethal CoCl2 for 7 days to induce prolonged chemical hypoxic stress. Then, OPC proliferation/differentiation was assessed. In vivo, prolonged cerebral hypoperfusion was induced by bilateral common carotid artery stenosis in mice. Then, reactive oxygen species production, myelin density, oligodendrocyte versus OPC counts, and cognitive function were evaluated. To block oxidative stress, OPCs and mice were treated with the radical scavenger edaravone. Prolonged chemical hypoxic stress suppressed OPC differentiation in vitro. Radical scavenging with edaravone ameliorated these effects. After 28 days of cerebral hypoperfusion in vivo, reactive oxygen species levels were increased in damaged white matter, along with the suppression of OPC-to-oligodendrocyte differentiation and loss of myelin staining. Concomitantly, mice showed functional deficits in working memory. Radical scavenging with edaravone rescued OPC differentiation, ameliorated myelin loss, and restored working memory function. Our proof-of-concept study demonstrates that after prolonged cerebral hypoperfusion, oxidative stress interferes with white matter repair by disrupting OPC renewal mechanisms. Radical scavengers may provide a potential therapeutic approach for white matter injury in vascular dementia and stroke.