Maresin 1 alleviates sevoflurane-induced neuroinflammation in neonatal rats via JAK2/STAT3/IL-6 pathways

Developmental neurotoxicity is a serious consequence of repeated exposure to sevoflurane during the postnatal period. Neuroinflammation is closely related to sevoflurane-induced developmental neurotoxicity. The present study explored the potential effect of maresin 1 (MaR1), an anti-inflammatory agent, on neuroinflammation and neurotoxicity induced by repeated sevoflurane exposure. In this study, MaR1 ameliorated sevoflurane-induced cognitive dysfunction, Tau hyperphosphorylation, and synaptic protein reduction. The protein level of the proinflammatory factor interleukin-6 (IL-6) and its upstream regulator Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway were substantially upregulated by sevoflurane in rat brains, but downregulated after MaR1 administration. To confirm the involvement of this pathway, we used coumermycin A1 (CA1), a chemical dimeric natural product that induced dimerization and activation of JAK2, and observed that the protective effect of MaR1 against sevoflurane-induced toxicity was completely blocked, as shown by decreased synaptic protein levels and increased Tau phosphorylation. Furthermore, it confirmed by dual luciferase reporter assay that there existed a STAT3's binding motif on the promoter sequence of IL-6. These results suggest that the protective effect of MaR1 against developmental neurotoxicity is mediated through the JAK2/STAT3/IL-6 signaling pathway and provide an experimental basis for clinical guidance on the use of sevoflurane.