Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke.
Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke.
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星形胶质细胞A1/A2范式参与糖原动员介导的缺血性中风后再灌注损伤的神经保护
DOI：
10.1186/s12974-021-02284-y
复制
发表时间：
2021-10-13
影响因子：
9.3
通讯作者：
Cai Y
中科院分区：
文献类型：
--
作者：
Guo H;Fan Z;Wang S;Ma L;Wang J;Yu D;Zhang Z;Wu L;Peng Z;Liu W;Hou W;Cai Y
背景星形胶质细胞糖原是周围神经元的重要能量储备，在脑缺血/再灌注（I/R）损伤中大量积累。我们以前的研究发现，积累的糖原动员表现出对I/R损伤的神经保护作用。此外，缺血可将星形胶质细胞转化为A1样（毒性）和A2样（保护性）亚型。然而，背后积累的糖原动员介导的脑再灌注损伤的神经保护和其关系的星形胶质细胞A1/A2 paradigm.MethodsAstrocytic糖原磷酸化酶，糖原动员的限速酶，背后的潜在机制是未知的，具体过表达和敲落在小鼠和培养的星形胶质细胞。采用小鼠大脑中动脉闭塞/再灌注模型和培养细胞的氧-糖剥夺/复氧模型来模拟I/R损伤。RNA测序、免疫荧光和免疫印迹法检测A1样和A2样星形胶质细胞的变化以及磷酸化核转录因子-κB（NF-κB）和磷酸化信号转导子和转录激活子3（STAT 3）的表达。代谢，包括糖原，NADPH，谷胱甘肽和活性氧（ROS），进行了分析，通过生化analysis.ResultsHere，我们观察到，星形胶质细胞糖原动员抑制A1样星形胶质细胞和增强A2样星形胶质细胞再灌注后在体内和体外的实验性缺血性中风模型。此外，糖原动员可通过磷酸戊糖途径（PPP）增加NADPH和谷胱甘肽的产生，并降低再灌注期间的ROS水平。NF-κB抑制和STAT 3激活是I/R后糖原动员诱导的A1样和A2样星形胶质细胞转化的原因。星形胶质细胞A1/A2模式与糖原动员介导的脑再灌注损伤的神经保护密切相关。ConclusionsOur data suggest，ROS介导的NF-κB抑制和STAT 3激活是糖原动员诱导的神经保护的关键途径，并为缺血性卒中脑再灌注损伤提供了一个有前途的代谢靶点。
BackgroundAstrocytic glycogen works as an essential energy reserve for surrounding neurons and is reported to accumulate excessively during cerebral ischemia/reperfusion (I/R) injury. Our previous study found that accumulated glycogen mobilization exhibits a neuroprotective effect against I/R damage. In addition, ischemia could transform astrocytes into A1-like (toxic) and A2-like (protective) subtypes. However, the underlying mechanism behind accumulated glycogen mobilization-mediated neuroprotection in cerebral reperfusion injury and its relationship with the astrocytic A1/A2 paradigm is unknown.MethodsAstrocytic glycogen phosphorylase, the rate-limiting enzyme in glycogen mobilization, was specifically overexpressed and knocked down in mice and in cultured astrocytes. The I/R injury was imitated using a middle cerebral artery occlusion/reperfusion model in mice and an oxygen–glucose deprivation/reoxygenation model in cultured cells. Alterations in A1-like and A2-like astrocytes and the expression of phosphorylated nuclear transcription factor-κB (NF-κB) and phosphorylated signal transducer and activator of transcription 3 (STAT3) were determined by RNA sequencing, immunofluorescence and immunoblotting. Metabolites, including glycogen, NADPH, glutathione and reactive oxygen species (ROS), were analyzed by biochemical analysis.ResultsHere, we observed that astrocytic glycogen mobilization inhibited A1-like astrocytes and enhanced A2-like astrocytes after reperfusion in an experimental ischemic stroke model in vivo and in vitro. In addition, glycogen mobilization could enhance the production of NADPH and glutathione by the pentose phosphate pathway (PPP) and reduce ROS levels during reperfusion. NF-κB inhibition and STAT3 activation caused by a decrease in ROS levels were responsible for glycogen mobilization-induced A1-like and A2-like astrocyte transformation after I/R. The astrocytic A1/A2 paradigm is closely correlated with glycogen mobilization-mediated neuroprotection in cerebral reperfusion injury.ConclusionsOur data suggest that ROS-mediated NF-κB inhibition and STAT3 activation are the key pathways for glycogen mobilization-induced neuroprotection and provide a promising metabolic target for brain reperfusion injury in ischemic stroke.
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DOI：
10.1007/978-3-030-27480-1_1
发表时间：
2019-01-01
期刊：
BRAIN GLYCOGEN METABOLISM
影响因子：
--
作者：
Dienel, Gerald A.;Carlson, Gerald M.
通讯作者：
Carlson, Gerald M.
影响因子：
6.3
作者：
Li, Liaoliao;Zuo, Zhiyi
通讯作者：
Zuo, Zhiyi
影响因子：
5.8
作者：
Li, Lin;Jin, Jianliang;Yang, Xiang-Jiao
通讯作者：
Yang, Xiang-Jiao
影响因子：
4.4
作者：
Chen, Zhenzhen;Hu, Quan;Chen, Xiang
通讯作者：
Chen, Xiang
影响因子：
5.8
作者：
Grimm A;Cummins N;Götz J
通讯作者：
Götz J