Resveratrol Attenuates Neuroinflammation and Myelination Deficits in Repeated Sevoflurane‐Exposed Neonatal Mice

BACKGROUND: It is reported that repeated neonatal exposure to sevoflurane, a widely used volatile anaesthetic in paediatric anaesthesia, impairs cognitive and fine-motor functions. Resveratrol has potent anti-inflammatory and antioxidant properties; however, its role in sevoflurane-induced hypomyelination is not known. METHODS: Neonatal C57BL/6J mice were exposed to 3.5% sevoflurane 2 h daily for 3 consecutive days. Resveratrol of 30 mg/kg was administered intraperitoneally 1 h before each exposure. Cognitive and fine-motor functions were evaluated by the Morris water maze and single-pellet reaching task, respectively. Myelination and neuroinflammatory responses in the hippocampus and corpus callosum were examined using immunofluorescence and western blot analyses. In vitro primary microglia and oligodendrocyte precursor cells (OPCs) were used to assess microglia-mediated inflammation on OPC differentiation. Furthermore, a selective Nrf2 inhibitor ML385 was co-administered to understand the mechanistic role of resveratrol. RESULTS: Repeated neonatal sevoflurane exposure impaired spatial learning/memory and fine-motor performance, reduced myelin basic protein (MBP) expression and increased pro-inflammatory marker (iNOS, CD86, IL-1β and TNF-α) expression in both hippocampus and corpus callosum. Resveratrol treatment ameliorated these deficits, evidenced by restoring MBP levels and improving behavioural outcomes. Mechanistically, resveratrol activated the Nrf2/HO-1 pathway, suppressed microglial M1 polarization and normalized the microglial secretome, thereby promoting OPC differentiation, whereas ML385 attenuated these resveratrol's neuroprotective effects. CONCLUSIONS: Resveratrol mitigates sevoflurane-induced OPCs differentiation impairments and hypomyelination via inhibiting microglial activation, which may be mediated by Nrf2/HO-1 signalling.