Oxiracetam Mediates Neuroprotection Through the Regulation of Microglia Under Hypoxia-Ischemia Neonatal Brain Injury in Mice
Oxiracetam Mediates Neuroprotection Through the Regulation of Microglia Under Hypoxia-Ischemia Neonatal Brain Injury in Mice
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奥拉西坦通过调节小鼠缺氧缺血新生儿脑损伤下的小胶质细胞介导神经保护
DOI：
10.1007/s12035-021-02376-z
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发表时间：
2021-04-22
影响因子：
5.1
通讯作者：
Liu, Qian
中科院分区：
文献类型：
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作者：
Wang, Dan;Wei, Yanbang;Liu, Qian
在新生儿缺氧缺血性脑损伤（HIBD）中，除了缺氧缺血造成的损伤外，炎症的过度激活导致病情进一步恶化，从而大大缩短了最佳治疗时间窗。缺血半暗带，即包围梗死核心的水肿区域，其特征在于典型的小胶质细胞活化和明显的炎症，并且在缺血发作后易于逐渐并入梗死核心。如果及时治疗，位于半暗带的细胞可以存活，从而阻止梗死的扩大。我们首次证明，在新生小鼠HIBD的急性期，奥拉西坦（ORC）的治疗显着减少缺血半暗带的大小以及梗死的急剧减少。通过对各种细胞标记物进行染色，我们发现半暗带被定义并集中了活化的小胶质细胞。我们还分析了透射电子显微镜和Luminex测定结果，以阐明所涉及的机制。我们进一步证实，ORC将小胶质细胞的极化从炎性表型转变为交替活化表型，从而促进小胶质细胞从神经毒性转变为神经保护性。同时，ORC抑制了小胶质细胞的增殖，但增强了其吞噬和自噬功能。最后，我们阐明了ORC通过AMPK/mTOR通路促进自噬，从而进一步诱导小胶质细胞中炎性表型向替代活化表型的转变。促炎因子的分泌也受到抑制，从而减少了梗死的进展。结论：奥拉西坦通过调节小胶质细胞活化与自噬的相互作用，延缓HIBD的进展，有效延长HIBD临床治疗的时间窗，从而减少缺血性脑梗死的扩大。
In neonatal hypoxic-ischemic brain damage (HIBD), in addition to damage caused by hypoxia and ischemia, over-activation of inflammation leads to further deterioration of the condition, thus greatly shortening the optimal treatment time window. Ischemic penumbra, the edematous area encompassing the infarct core, is characterized by typical activation of microglia and overt inflammation, and prone to incorporate into the infarct core gradually after ischemia onset. If treated in time, the cells located in the penumbra can survive, thereby impeding the expansion of the infarction. We demonstrated for the first time that in the acute phase of HIBD in neonatal mice, treatment of Oxiracetam (ORC) significantly curtailed the size of ischemic penumbra together with drastic reduction of infarction. By staining various cellular markers, we found that the penumbra was defined and concentrated with activated microglia. We also analyzed transmission electron microscopy and Luminex assay results to elucidate the mechanisms involved. We further confirmed that ORC switched polarization of microglia from the inflammatory towards the alternatively activated phenotype, thus promoting microglia from being neurotoxic into neuroprotective. Meanwhile, ORC decreased proliferation of microglia; however, their functions of phagocytosis and autophagy were otherwise enhanced. Last, we clarified that ORC promoted autophagy through the AMPK/mTOR pathway, which further induced the transition of the inflammatory to the alternatively activated phenotype in microglia. The pro-inflammatory factors secretion was inhibited as well, thereby reducing the progression of the infarction. Taken together, it is concluded that Oxiracetam reduced the expansion of ischemic infarction in part via regulating the interplay between microglia activation and autophagy, which would delay the progression of HIBD and effectively prolong the time window for the clinical treatment of HIBD.