MicroRNA-325-3p prevents sevoflurane-induced learning and memory impairment by inhibiting Nupr1 and C/EBPβ/IGFBP5 signaling in rats.

Lili Xu,Fang Xu,Qi Xu,Qing Chen,Xinzhong Chen,Hui Wu,Wenxin Zhang

doi:10.18632/aging.102942

Abstract

Endoplasmic reticulum stress-induced neuronal apoptosis contributes to neurotoxicity observed after sevoflurane exposure. However, the molecular mechanism underlying the resulting learning and memory impairments remains unknown. Here, we investigated the roles of miR-325-3p and Nupr1 in sevoflurane-induced learning and memory impairments in neonatal rats and HCN-2 human cortical neuronal cells. We found that in both neonatal rats and HCN-2 cells, sevoflurane exposure impairs learning and memory in neonatal rats and increases expression of Nupr1, the endoplasmic reticulum stress marker proteins C/EBPβ and IGFBP5, and the apoptosis-related protein markers cleaved-Caspase-3 and Bax. Using bioinformatics tools to identify microRNAs that bind to Nupr1, we found that miR-325-3p is downregulated in hippocampal neurons exposed to sevoflurane. Moreover, Nupr1 knockdown and miR-325-3p overexpression improved the rats’ performance in learning and memory tests and reduced sevoflurane-induced apoptosis in vitro and in vivo. These results suggest that miR-325-3p blocks sevoflurane-induced learning and memory impairments by inhibiting Nupr1 and the downstream C/EBPβ/IGFBP5 signaling axis in neonatal rats. MiR-325-3p may therefore be a useful therapeutic target in sevoflurane-induced neurotoxicity.

Highlights

Exposure to sevoflurane during brain development can cause long-term learning and memory deficits, longlasting complex social and emotional behavior disorders, and even increase the risk of Alzheimer's disease [1]
There were no signs of cardiorespiratory dysfunction after sevoflurane administration, and SaO2, PaO2, PaCO2, pH, and Mean arterial blood pressure (MAP) did not differ between the two groups. (Table 1)
In a novel object recognition test, neonatal rats exposed to sevoflurane exhibited shorter exploration times for the novel object during the recognition session and a lower discrimination index compared to the control group; the two groups did not differ in time spent exploring the familiar object (Figure 1A, 1B)

Summary

Introduction

Exposure to sevoflurane during brain development can cause long-term learning and memory deficits, longlasting complex social and emotional behavior disorders, and even increase the risk of Alzheimer's disease [1]. Sevoflurane exposure can increase the expression of endoplasmic reticulum (ER) stress markers such as CCAAT/enhancer-binding protein homologous (C/EBPβ) and Caspase-3 both in vitro and in vivo, suggesting that ER stress response might play an important role in sevoflurane-induced neurotoxicity [4, 5]. Both IRE1 and PERK are crucial for the detection of and injury induced by ER stress [6]. Continuous upregulation of C/EBPβ and JNK can promote cell death [7]

Methods

Results

Conclusion