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Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats.

ABSTRACT: Sevoflurane is one of the most commonly used volatile anaesthetics for children, but the safety of prolonged or repeated clinical use of sevoflurane in infants or children is controversial. Here, we investigated the effects of sevoflurane on rats in early life and the time scale of those effects. Our behavioral results indicated that repeated short-term exposure of new-born rats to sevoflurane caused learning and memory impairment, while a single exposure of rats to sevoflurane was relatively safe. Further mechanistic investigation revealed that repeated sevoflurane exposure impaired long-term potentiation (LTP), downregulated the expression of certain synaptogenesis-related proteins (GluR1, PSD95) and upregulated proteins related to endoplasmic reticulum (ER) stress in the hippocampus. An ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), reversed the changes in the levels of synaptic plasticity proteins. Our results provide new evidence for the clinical concerns regarding repeated sevoflurane anesthesia.

SUBMITTER: Shen FY

PROVIDER: S-EPMC6083612 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats.

Shen Fu-Yi FY Song Ying-Cai YC Guo Fei F Xu Zhen-Dong ZD Li Qian Q Zhang Bing B Ma Yu-Qin YQ Zhang Yue-Qi YQ Lin Rong R Li Yang Y Liu Zhi-Qiang ZQ

Frontiers in psychiatry 20180802

Sevoflurane is one of the most commonly used volatile anaesthetics for children, but the safety of prolonged or repeated clinical use of sevoflurane in infants or children is controversial. Here, we investigated the effects of sevoflurane on rats in early life and the time scale of those effects. Our behavioral results indicated that repeated short-term exposure of new-born rats to sevoflurane caused learning and memory impairment, while a single exposure of rats to sevoflurane was relatively sa ...[more]

PMID: 30116207

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Project description:Sevoﬂurane, a commonly used anesthetic agent has been confirmed to induce cognitive impairment in aged rats. Normobaric hyperoxia preconditioning has been demonstrated to induce neuroprotection in rats. The present study aimed to determine whether normobaric hyperoxia preconditioning could ameliorate cognitive deficit induced by sevoflurane and the possible mechanism by which it may exert its effect. A total of 66, 20-month-old male Sprague-Dawley rats were randomly divided into 3 groups (n=22 each): Rats in the control (C) and sevoflurane anesthesia (S) groups received no normobaric hyperoxia preconditioning before sevoflurane exposure, rats in the normobaric hyperoxia pretreatment (HO) group received normobaric hyperoxia preconditioning before sevoflurane exposure (95% oxygen for 4 continuous h daily for 6 consecutive days). The anesthesia rats (S and HO groups), were exposed to 2.5% sevoflurane for 5 h, while the sham anesthesia rats (C group) were exposed to no sevoflurane. The neurobehavioral assessment was performed using a Morris water maze test, the expressions of the apoptosis proteins were determined using western blot analysis, and the apoptosis rate and cytosolic calcium concentration were measured by flow cytometry. Normobaric hyperoxia preconditioning improved prolonged escape latency and raised the number of platform crossings induced by sevoflurane in the Morris water maze test, increased the level of bcl-2 protein, and decreased the level of bax and active caspase-3 protein, the apoptosis rate and cytosolic calcium concentration in the hippocampus 24 h after sevoflurane exposure. The findings of the present study may imply that normobaric hyperoxia preconditioning attenuates sevoflurane-induced spatial learning and memory impairment, and this effect may be partly related to apoptosis inhibition in the hippocampus. In conclusion, normobaric hyperoxia preconditioning may be a promising strategy against sevoflurane-induced cognitive impairment by inhibiting the hippocampal neuron apoptosis.

Project description:Background Postoperative cognitive dysfunction (POCD) is a clinically frequent postoperative complication in the elderly, which is mainly manifested by the occurrence of cognitive dysfunction after anesthetized surgery in patients. To explore the involvement of C/EBPα in microglial polarization in sevoflurane anesthesia induced cognitive impairment in aged rats. Methods Sprague-Dawley (SD) rats were anesthetized by inhalation of 3% sevoflurane for 6 h to establish the POCD model. The histopathological structure of hippocampus was observed by hematoxylin and eosin (HE) staining. Associative learning and memory function and spatial learning and memory function were assessed by conditioned fear test and water maze test. The concentrations of inflammatory factors in the hippocampus were measured by ELISA. The levels of microglial activation marker (Iba1) and microglial M1 (CD86) and M2 (CD206) polarization markers were determined by immunofluorescence staining and RT-qPCR, respectively. The transcriptional regulation of HDAC1 by C/EBPα was confirmed by dual luciferase reporter assay and ChIP assay. Results Sevoflurane-induced pathomorphological damage in the hippocampal tissue of aged rats, accompanied by elevated expression of C/EBPα. Silencing of C/EBPα alleviated hippocampal histopathological injury, inhibited M1 microglial activation and the expression of M1 marker CD86, enhanced the expression of M2 marker CD206. C/EBPα transcriptionally activated HDAC1. Knockdown of C/EBPα downregulated the expression of HDAC1 and STAT3 phosphorylated proteins, which inhibited the pro-inflammatory factors (IL-6 and TNF-α) and accelerated anti-inflammatory factors (IL-10 and TGF-β) secretion. In addition, silencing of C/EBPα caused rats to have a delayed freezing time in contextual conditioned fear, a shorter escape latency, and an increased number of platform crossings. Conclusion Inhibition of C/EBPα promotes the M2 polarization of microglia and reduces the production of pro-inflammatory cytokines to alleviate the cognitive dysfunction of sevoflurane-induced elderly rats by HDAC1/STAT3 pathway.

Project description:IntroductionDiabetic cognitive impairment (DCI) is a chronic complication of the central nervous system (CNS) caused by diabetes that affects learning and memory capacities over time. Recently, acupuncture has been shown to improve cognitive impairment in streptozotocin-induced diabetic rats. However, the effects of electroacupuncture on DCI and its underlying mechanism have not yet been elucidated in detail.MethodsIn this study, we used db/db mice as DCI animal models which showed low cognitive, learning and memory functions. Electroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. The db/db mice with cognitive impairment were randomly divided into a model group (Mod) and an electroacupuncture treatment group (Acup), while db/m mice were used as a normal control group (Con). First, the mice were subjected to behavioural tests using the Morris water maze (MWM), and body weight, blood glucose, insulin, triglycerides (TG) and total cholesterol (TC) were observed; HE, Nissl, and TUNEL staining were used to observe the morphological changes and neuronal apoptosis in the mice hippocampus; Finally, Western blot and rt-PCR were applied to detect the essential proteins and mRNA of ERS and insulin signalling pathway, as well as the expression levels of Tau and Aβ.ResultsElectroacupuncture significantly ameliorated DCI, which is reflected by better spatial learning and memory function using behavioral tests. Moreover, electroacupuncture attenuated diabetes-induced morphological structure change, neuronal apoptosis in the hippocampus of db/db mice. Our results revealed that electroacupuncture could regulate the expression levels of Tau and Aβ by improving hippocampal ERS levels in db/db mice, inhibiting JNK activation, attenuating IRS1 serine phosphorylation, and restoring normal transduction of the insulin signaling pathway.DiscussionIn summary, ERS and insulin signaling pathway paly causal roles in DCI development. Electroacupuncture can significantly alleviate the pathogenesis of DCI, improve mice's learning and memory ability, and improve cognitive dysfunction. This study adds to our understanding of the effect of acupuncture on DCI and opens the door to further research on DCI.

Project description:Background: When an imbalance occurs between the demand and capacity for protein folding, unfolded proteins accumulate in the endoplasmic reticulum (ER) lumen and activate the unfolded protein response (UPR). In addition, unfolded proteins are cleared from the ER lumen for ubiquitination and subsequent cytosolic proteasomal degradation, which is termed as the ER-associated degradation (ERAD) pathway. This study focused on changes in the UPR and ERAD pathways induced by the repeated inhalation anesthetic exposure in Caenorhabditis elegans. Methods: Depending on repeated isoflurane exposure, C. elegans was classified into the control or isoflurane group. To evaluate the expression of a specific gene, RNA was extracted from adult worms in each group and real-time polymerase chain reaction was performed. Ubiquitinated protein levels were measured using western blotting, and behavioral changes were evaluated by chemotaxis assay using various mutant strains. Results: Isoflurane upregulated the expression of ire-1 and pek-1 whereas the expression of atf-6 was unaffected. The expression of both sel-1 and sel-11 was decreased by isoflurane exposure, possibly indicating the inhibition of retro-translocation. The expression of cdc-48.1 and cdc-48.2 was decreased and higher ubiquitinated protein levels were observed in the isoflurane group than in the control, suggesting that deubiquitination and degradation of misfolded proteins were interrupted. The chemotaxis indices of ire-1, pek-1, sel-1, and sel-11 mutants decreased significantly compared to N2, and they were not suppressed further even after the repeated isoflurane exposure. Conclusion: Repeated isoflurane exposure caused significant ER stress in C. elegans. Following the increase in UPR, the ERAD pathway was disrupted by repeated isoflurane exposure and ubiquitinated proteins was accumulated subsequently. UPR and ERAD pathways are potential modifiable neuroprotection targets against anesthesia-induced neurotoxicity.

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Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats.

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Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats.

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