Sevoflurane Induces Endoplasmic Reticulum Stress Mediated Apoptosis in Hippocampal Neurons of Aging Rats

Gang Chen,Xiaoming Zhang,Ming Gong,Min Yan,Giovanni Landoni

doi:10.1371/journal.pone.0057870

Gang Chen, Xiaoming Zhang + Show 3 more

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https://doi.org/10.1371/journal.pone.0057870

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Abstract

Elderly patients are more likely to suffer from postoperative memory impairment for volatile anesthetics could induce aging neurons degeneration and apoptosis while the mechanism was still elusive. Therefore we hypothesized that ER stress mediated hippocampal neurons apoptosis might play an important role in the mechanism of sevoflurane-induced cognitive impairment in aged rats. Thirty 18-month-old male Sprague-Dawley rats were divided into two groups: the sham anesthesia group (exposure to simply humidified 30–50% O2 balanced by N2 in an acrylic anesthetizing chamber for 5 hours) and the sevoflurane anesthesia group (received 2% sevoflurane in the same humidified mixed air in an identical chamber for the same time). Spatial memory of rats was assayed by the Morris water maze test. The ultrastructure of the hippocampus was observed by transmission electron microscopy (TEM). The expressions of C/EBP homologous protein (CHOP) and caspase-12 in the hippocampus were observed by immunohistochemistry and real-time PCR analysis. The apoptosis neurons were also assessed by TUNEL assay. The Morris water maze test showed that sevoflurane anesthesia induced spatial memory impairment in aging rats (P<0.05). The apoptotic neurons were condensed and had clumped chromatin with fragmentation of the nuclear membrane, verifying apoptotic degeneration in the sevoflurane group rats by TEM observation. The expressions of CHOP and caspase-12 increased, and the number of TUNEL positive cells of the hippocampus also increased in the sevoflurane group rats (P<0.05). The present results suggested that the long time exposure of sevoflurane could induce neuronal degeneration and cognitive impairment in aging rats. The ER stress mediated neurons apoptosis may play a role in the sevoflurane-induced memory impairment in aging rats.

Highlights

There is extensive literature reporting that elderly patients are more likely than young patients to suffer from postoperative memory and cognitive deficits [1]
We found that sevoflurane anesthesia had a significant effect on spatial orientation in the navigation task because it impaired the performance of the sevoflurane group
Volatile anesthetics may contribute to memory impairment by neurons lost in hippocampus through cells apoptosis [23,24]

Summary

Introduction

There is extensive literature reporting that elderly patients are more likely than young patients to suffer from postoperative memory and cognitive deficits [1]. Potential mechanisms for postoperative memory impairment are still elusive, such as brain cell apoptosis, accumulation of amyloid deposits in aging brain and suppression of synaptic transmission [4,5,6,7]. Endoplasmic reticulum (ER) has several important functions, involving synthesis, folding, and posttranslational modification of secretory and membrane proteins [8]. ER stress under any harmful conditions could lead to decrease protein synthesis and increase the expression of molecular chaperones that promote proper folding and cellular recovery [9]. Prolonged activation of ER stress initiates the apoptotic pathway [10]. Several proteins have been implicated in this apoptotic pathway, including a transcription factor, C/EBP homologous protein (CHOP), and the ER-resident caspase, caspase-12 [11,12]

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