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

by Selleckchem | Jul 30 2023

Children 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.

Comments:

The study you described aimed to investigate the potential toxic mechanism of sevoflurane, an anesthesia agent, on cognitive impairment in children. The researchers focused on the WNK1/NKCC1/Ca2+/Drp-1 signaling pathway in the hippocampal neuronal HT22 cell line to understand its involvement in sevoflurane-induced neurotoxicity.

In the study, the intervention group was treated with specific inhibitors targeting different components of the signaling pathway. The WNK1 inhibitor (WNK-463), CaN inhibitor (FK506), and Drp-1 inhibitor (Mdivi-1) were added to the cell culture medium 30 minutes before exposing the cells to sevoflurane anesthesia. The sevoflurane group and the intervention groups were exposed to 4.1% sevoflurane for 6 hours.

The results of the study showed that sevoflurane treatment decreased cell viability and increased cellular apoptosis (programmed cell death). However, the administration of WNK-463, FK506, or Mdivi-1 alleviated these negative effects induced by sevoflurane. Furthermore, pretreatment with WNK-463 inhibited the increase of WNK1 kinase and NKCC1 protein concentration caused by sevoflurane.

Additionally, sevoflurane anesthesia led to intracellular calcium overload, increased the expression of CaN (calcineurin), and induced the dephosphorylation of Drp-1 protein at ser637. However, pretreatment with the CaN inhibitor FK506 reduced the dephosphorylation of Drp-1.

Based on these findings, the study suggests that the WNK1/NKCC1/Ca2+/Drp-1 signaling pathway plays a significant role in sevoflurane-related neurotoxicity. The reduction of intracellular calcium influx may be an important mechanism to mitigate the toxicity caused by sevoflurane.

It is worth noting that this study was conducted using a cell line, and further research, including in vivo studies and clinical trials, would be necessary to validate these findings and determine their relevance to human patients.