Open AccessSevoflurane preconditioning protects experimental ischemic stroke by enhancing anti‐inflammatory microglia/macrophages phenotype polarization through GSK‐3β/Nrf2 pathway
Author(s) -
Cai Min,
Sun Sisi,
Wang Jin,
Dong Beibei,
Yang Qianzi,
Tian Li,
Dong Hailong,
Wang Shiquan,
Hou Wugang
Publication year - 2021
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13715
Subject(s) - microglia , neuroprotection , sevoflurane , pharmacology , inflammation , neuroinflammation , gsk3b , lipopolysaccharide , chemistry , phosphorylation , gsk 3 , cancer research , medicine , immunology , biochemistry
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 expression, promoted anti‐inflammatory markers level, and elicited a neuroprotective effect. Nrf2 deficiency abolished the promoted anti‐inflammatory microglia/macrophages polarization and ischemic tolerance induced by TDZD treatment. The reduced percentage of pro‐inflammatory positive cells and super‐oxidants generation induced by SFC or TDZD was also reversed by Nrf2 knockdown. Conclusions Our results indicated that SPC exerts brain ischemic tolerance and promotes anti‐inflammatory microglia/macrophages polarization by GSK‐3β‐dependent Nrf2 activation, which provides a novel mechanism for SPC‐induced neuroprotection.