Sevoflurane preconditioning protects experimental ischemic stroke by enhancing anti‐inflammatory microglia/macrophages phenotype polarization through GSK‐3β/Nrf2 pathway

作者：Min Cai, Sisi Sun, Jin Wang, Beibei Dong, Qianzi Yang, Tian Li, Hailong Dong, Shiquan Wang, Wugang Hou · 发表于：CNS Neuroscience & Therapeutics · 年份：2021 · DOI：10.1111/cns.13715 · 被引用次数：49 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Intensive Care Unit Cognitive Disorders、Traumatic Brain Injury and Neurovascular Disturbances

AIMS: Sevoflurane preconditioning (SPC) results in cerebral ischemic tolerance; however, the mechanism remains unclear. Promoting microglia/macrophages polarization from pro-inflammatory state to anti-inflammatory phenotype has been indicated as a potential treatment target against ischemic stroke. In this study, we aimed to assess the effect of SPC on microglia polarization after stroke and which signaling pathway was involved in this transition. METHODS: Mouse primary microglia with SPC were challenged by oxygen-glucose deprivation (OGD) or lipopolysaccharide (LPS), and mice with SPC were subjected to middle cerebral artery occlusion (MCAO). Then, the mRNA and protein levels of pro-inflammatory/anti-inflammatory factors were analyzed. GSK-3β phosphorylation and Nrf2 nuclear translocation were measured. The mRNA and protein expression of pro-inflammatory/anti-inflammatory factors, neurological scores, infarct volume, cellular apoptosis, the proportion of pro-inflammatory/anti-inflammatory microglia/macrophages, and the generation of super-oxidants were examined after SPC or GSK-3β inhibitor TDZD treatment with or without Nrf2 deficiency. RESULTS: Sevoflurane preconditioning promoted anti-inflammatory and inhibited pro-inflammatory microglia/macrophages phenotype both in vitro and in vivo. GSK-3β phosphorylation at Ser9 was increased after SPC. Both SPC and TDZD administration enhanced Nrf2 nuclear translocation, reduced pro-inflammatory microglia/macrophages markers expressi...