PMID- 34645472 OWN - NLM STAT- MEDLINE DCOM- 20220209 LR - 20220209 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 18 IP - 1 DP - 2021 Oct 13 TI - Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke. PG - 230 LID - 10.1186/s12974-021-02284-y [doi] LID - 230 AB - BACKGROUND: Astrocytic 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. METHODS: Astrocytic 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-kappaB (NF-kappaB) 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. RESULTS: Here, 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-kappaB 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. CONCLUSIONS: Our data suggest that ROS-mediated NF-kappaB 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. CI - (c) 2021. The Author(s). FAU - Guo, Haiyun AU - Guo H AD - Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Fan, Ze AU - Fan Z AD - Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Wang, Shiquan AU - Wang S AD - Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Ma, Lina AU - Ma L AD - Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Wang, Jin AU - Wang J AD - Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Yu, Doutong AU - Yu D AD - Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Zhang, Zhen AU - Zhang Z AD - Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Wu, Lin AU - Wu L AD - Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Peng, Zhengwu AU - Peng Z AD - Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Liu, Wenming AU - Liu W AD - Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. FAU - Hou, Wugang AU - Hou W AD - Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. gangwuhou@163.com. FAU - Cai, Yanhui AU - Cai Y AUID- ORCID: 0000-0002-3087-2569 AD - Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. MD_CAI@163.com. LA - eng GR - 82001384/National Natural Science Foundation of China/ GR - 81971226/National Natural Science Foundation of China/ GR - 81771411/National Natural Science Foundation of China/ GR - 81901079/National Natural Science Foundation of China/ PT - Journal Article DEP - 20211013 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Reactive Oxygen Species) RN - 9005-79-2 (Glycogen) SB - IM MH - Animals MH - Animals, Newborn MH - Astrocytes/*metabolism/pathology MH - Brain Ischemia/*metabolism/pathology/prevention & control MH - Coculture Techniques MH - Female MH - Glycogen/*metabolism MH - Ischemic Stroke/*metabolism/pathology/prevention & control MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neuroprotection/*physiology MH - Reactive Oxygen Species/metabolism MH - Reperfusion Injury/*metabolism/pathology/prevention & control PMC - PMC8513339 OTO - NOTNLM OT - Astrocyte OT - Glycogen OT - Glycogen mobilization OT - Ischemia/reperfusion injury OT - Neuroprotection COIS- The authors declare no conflict of interest. EDAT- 2021/10/15 06:00 MHDA- 2022/02/10 06:00 PMCR- 2021/10/13 CRDT- 2021/10/14 05:30 PHST- 2021/05/16 00:00 [received] PHST- 2021/09/27 00:00 [accepted] PHST- 2021/10/14 05:30 [entrez] PHST- 2021/10/15 06:00 [pubmed] PHST- 2022/02/10 06:00 [medline] PHST- 2021/10/13 00:00 [pmc-release] AID - 10.1186/s12974-021-02284-y [pii] AID - 2284 [pii] AID - 10.1186/s12974-021-02284-y [doi] PST - epublish SO - J Neuroinflammation. 2021 Oct 13;18(1):230. doi: 10.1186/s12974-021-02284-y.