Sevoflurane preconditioning reduces brain inflammation after experimental stroke by enhancing glycogen synthesis kinase-3 β/ nuclear factor erythroid 2-related factor - dependent microglial M2 polarization

Abstract

Background: Sevoflurane preconditioning (SPC) results in cerebral ischemic tolerance; however, the mechanism remains unclear. In current study, we aimed to assess the M1/M2 shift in the brain induced by SPC and whether glycogen synthesis kinase-3β (GSK-3β)-regulated nuclear factor erythroid 2-related factor (Nrf2) activation was involved in the M2 polarization mediated by SPC. 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 proinflammatory/anti-inflammatory factors were analysed. GSK-3β phosphorylation and Nrf2 nuclear translocation were measured. The mRNA and protein expression of proinflammatory/anti-inflammatory factors, neurological scores, infarct volume, cellular apoptosis, the proportion of M1/M2-positive cells, and the generation of super-oxidants were examined after SPC or GSK-3β inhibitor TDZD treatment with or without Nrf2 deficiency. Results: SPC promoted M2 phenotype polarization both in vitro and in vivo . GSK-3β phosphorylation at Ser9 was increased after SPC. Both SPC and TDZD administration enhanced Nrf2 nuclear translocation, promoted M2 phenotype polarization and elicited a neuroprotective effect. Nrf2 deficiency abolished the promoted M2 polarization and ischemic tolerance induced by TDZD treatment. The reduced percentage of M1-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 enhances M2 polarization by GSK-3β-dependent Nrf2 activation, which provides a novel mechanism for SPC-induced neuroprotection.