Suppression of lncRNA Xist Improves Sevoflurane-Induced Social and Emotional Impairment by Activating miR-98-5p/EDEM1 Signaling Axis in Neonatal Mice

Abstract

Numerous animal studies have suggested that sevoflurane can induce neuronal cell death and damage social and emotional behaviors and endoplasmic reticulum stress is a crucial underlying mechanism. The goal of this study was to investigate the role and the mechanisms of long noncoding RNA X-inactive specific transcript (XIST) in sevoflurane-induced social and emotional impairment and neuron apoptosis in neonatal mice. The performance in social and emotional tests and the expression levels of lncRNA-XIST after sevoflurane exposure in neonatal mice and hippocampal neuronal cells were measured. Also, the effects of the suppression of lncRNA-XIST on neuron apoptosis and endoplasmic reticulum stress were determined. Subsequently, the association between lncRNA-XIST and miR-98-5p as well as EDEM1 in hippocampal neuronal cells was explored. Our results showed that social and emotional behaviors were impaired in neonatal mice and lncRNA-XIST and EDEM1were increasingly expressed in hippocampal neuronal cells after sevoflurane exposure and suppression of lncRNA-XIST decreased sevoflurane-induced neuron apoptosis and endoplasmic reticulum stress in vitro. Further in vitro studies showed that overexpression of miR-98-5p decreased apoptosis and endoplasmic reticulum stress while lncRNA Xist negative regulated miR-98-5p expression and the effects of lncRNA Xist on apoptosis and endoplasmic reticulum stress through sponging miR-98-5p. Moreover, suppression of lncRNA-XIST improved sevoflurane-induced social and emotional impairment and alleviated sevoflurane-induced apoptosis and endoplasmic reticulum stress accompanied in neonatal mice. Our findings reveal that knockdown of lncRNA-XIST may contribute to ameliorating sevoflurane-induced social and emotional impairment via inhibiting neuron apoptosis and endoplasmic reticulum stress, which may be achieved by regulating miR-98-5p/EDEM1 axis.

Funding Statement: This work was supported by the National Natural Science Foundation of China (81400929, 81471240, 81641042 and 81603545), the Bureau of Chinese Medicine, Zhejiang, China (2018ZB065) and the Innovative Talents Project of Zhejiang province (2016).

Declaration of Interests: There is no conflict of interest in the authors.

Ethics Approval Statement: The study protocol was approved by the Zhejiang University Institutional review board of Animal studies (ZJU2019-16778). The Guidance Recommendations for Experimental Animal Care and Use of the Ministry of Science and Technology of the People’s Republic of China supervised all experimental procedures.