Sevoflurane affects neurogenesis through cell cycle arrest via inhibiting wnt/β-catenin signaling pathway in mouse neural stem cells

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Aims:The development of central nervous system requires proliferation of neural stem cells followed by differentiation. Cell cycle parameters are closely related with cell fate specification and differentiation. Recent researches indicated that wnt/β-catenin signaling pathway might cause proliferation inhibition and differentiation abnormality through interfering NSCs cell cycle. Our previous research also showed that multiple sevoflurane exposure to neural stem cells inhibited proliferation via repressing transcription factor Pax6 and cyclin D1 through inhibiting wnt/β-catenin pathway. All above encouraged us to figure out the effect of sevoflurane on cell cycle and neurogenesis.Main methods:Primary mouse cultured neural stem cells were used and exposed to 4.1% sevoflurane for 6 h in this study. The expression of β-catenin, GSK-3β, c-myc and cyclin D1 were determined by western blot and qRT-PCR. FACS was used to measure the cell cycle. The proliferation of NSCs was evaluated by EdU staining while the differentiation was evaluated by Tuj1 and GFAP staining on immunocytochemistry.Key findings:We found that exposure to sevoflurane at a concentration of 4.1% for 6 h induced inhibition of wnt/β-catenin pathway, cell cycle arrest at G0/G1 phase and an earlier switch from proliferation to differentiation. GSK-3β specific inhibitor, CHIR99021, attenuated sevoflurane-induced cell cycle arrest and abnormality of neurogenesis in neural stem cells.Significance:Our research suggested that sevoflurane arrested cell cycle at G0/G1 phase through inhibition of wnt/β-catenin signaling pathway thus resulting in a premature differentiation in NSCs. This study presents a deeper understanding of the mechanism on cognitive impairment by sevoflurane exposure.

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