Sevoflurane induces neurotoxic effects on developing neurons through the WNK1/NKCC1/Ca2+/Drp‐1 signalling pathway

Abstract

AbstractChildren repeatedly exposed to anaesthesia have a high risk of cognitive impairment, but the mechanism of its regulation in this context is unknown. The objective of this study was to investigate the possible toxic mechanism of sevoflurane through the WNK1/NKCC1/Ca2+/Drp‐1 signalling pathway. The hippocampal neuronal HT22 cell line was used in this study. The intervention group was treated with the WNK1 inhibitor WNK‐463, CaN inhibitor FK506 and Drp‐1 inhibitor Mdivi‐1 respectively in the medium for 30 min before sevoflurane anaesthesia. The sevofluane group and all intervention group treated with 4.1% sevoflurane for 6 h. Compared with the control group, sevoflurane treatment decreased cell viability and increased cellular apoptosis. Our study found that WNK‐463, FK506 and Mdivi‐1 can all alleviate the sevoflurane‐induced reduction in cell viability, decrease the cell apoptosis. In addition, WNK‐463 pretreatment could inhibit the increase of WNK1 kinase and NKCC1 protein concentration caused by sevoflurane. Further, sevoflurane anaesthesia causes intracellular calcium overload, increases the expression of CaN and induces the dephosphorylation of Drp‐1 protein at ser637, while CaN inhibitor FK506 pretreatment could reduce the dephosphorylation of Drp‐1. Therefore, the WNK1/NKCC1/Ca2+/Drp‐1 signalling pathway plays an important role in sevoflurane‐related neurotoxicity. Reducing intracellular calcium influx may be one of the important mechanism to ameliorate sevoflurane toxicity.