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Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction

Postoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery that might lead to a decline in learning and memory. Oxidative stress damage is one of the pathogenic mechanisms underlying POCD. Recent studies had shown that the integrated stress response (ISR) is...

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Autores principales: Jiang, Linhao, Dong, Rui, Xu, Minhui, Liu, Yujia, Xu, Jiyan, Ma, Zhengliang, Xia, Tianjiao, Gu, Xiaoping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9534309/
https://www.ncbi.nlm.nih.gov/pubmed/36212697
http://dx.doi.org/10.3389/fncel.2022.992869
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author Jiang, Linhao
Dong, Rui
Xu, Minhui
Liu, Yujia
Xu, Jiyan
Ma, Zhengliang
Xia, Tianjiao
Gu, Xiaoping
author_facet Jiang, Linhao
Dong, Rui
Xu, Minhui
Liu, Yujia
Xu, Jiyan
Ma, Zhengliang
Xia, Tianjiao
Gu, Xiaoping
author_sort Jiang, Linhao
collection PubMed
description Postoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery that might lead to a decline in learning and memory. Oxidative stress damage is one of the pathogenic mechanisms underlying POCD. Recent studies had shown that the integrated stress response (ISR) is closely related to oxidative stress. The core response of the ISR is phosphorylation of eIF2α. Various cellular stress stimuli trigger activation of eIF2α kinases, thus causing phosphorylation of eIF2α. ISR is associated with many neurodegenerative diseases; however, the relationship between POCD and ISR has not been defined. In the present study, the tibias in 4-month-old male C57BL/6 mice were fractured under isoflurane anesthesia to establish the POCD animal model. Cognitive function was assessed by fear conditioning tests and the Y-maze from 3 to 14 days post-surgery. Western blot was used to determine the levels of PeIF2α, eIF2α, ATF4, GADD34, CHOP, BDNF, proBDNF, and p-NR2B expression. The levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured to determine oxidative stress in hippocampal tissues. After tibial fracture surgery in mice, the hippocampus had increased levels of PeIF2α, ATF4, GADD34, and CHOP protein, ROS-positive cells, and average fluorescence intensity, SOD activity was decreased, and the MDA level was increased. The ISR inhibitor, ISRIB, reduced the levels of PeIF2α, ATF4, GADD34, and CHOP protein, and alleviated oxidative stress in the hippocampus of POCD mice. Moreover, ISRIB ameliorated cognitive dysfunction in POCD mice. Our findings suggested that targeting ISR may represent an effective approach to combat POCD.
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spelling pubmed-95343092022-10-06 Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction Jiang, Linhao Dong, Rui Xu, Minhui Liu, Yujia Xu, Jiyan Ma, Zhengliang Xia, Tianjiao Gu, Xiaoping Front Cell Neurosci Cellular Neuroscience Postoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery that might lead to a decline in learning and memory. Oxidative stress damage is one of the pathogenic mechanisms underlying POCD. Recent studies had shown that the integrated stress response (ISR) is closely related to oxidative stress. The core response of the ISR is phosphorylation of eIF2α. Various cellular stress stimuli trigger activation of eIF2α kinases, thus causing phosphorylation of eIF2α. ISR is associated with many neurodegenerative diseases; however, the relationship between POCD and ISR has not been defined. In the present study, the tibias in 4-month-old male C57BL/6 mice were fractured under isoflurane anesthesia to establish the POCD animal model. Cognitive function was assessed by fear conditioning tests and the Y-maze from 3 to 14 days post-surgery. Western blot was used to determine the levels of PeIF2α, eIF2α, ATF4, GADD34, CHOP, BDNF, proBDNF, and p-NR2B expression. The levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured to determine oxidative stress in hippocampal tissues. After tibial fracture surgery in mice, the hippocampus had increased levels of PeIF2α, ATF4, GADD34, and CHOP protein, ROS-positive cells, and average fluorescence intensity, SOD activity was decreased, and the MDA level was increased. The ISR inhibitor, ISRIB, reduced the levels of PeIF2α, ATF4, GADD34, and CHOP protein, and alleviated oxidative stress in the hippocampus of POCD mice. Moreover, ISRIB ameliorated cognitive dysfunction in POCD mice. Our findings suggested that targeting ISR may represent an effective approach to combat POCD. Frontiers Media S.A. 2022-09-21 /pmc/articles/PMC9534309/ /pubmed/36212697 http://dx.doi.org/10.3389/fncel.2022.992869 Text en Copyright © 2022 Jiang, Dong, Xu, Liu, Xu, Ma, Xia and Gu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular Neuroscience
Jiang, Linhao
Dong, Rui
Xu, Minhui
Liu, Yujia
Xu, Jiyan
Ma, Zhengliang
Xia, Tianjiao
Gu, Xiaoping
Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction
title Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction
title_full Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction
title_fullStr Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction
title_full_unstemmed Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction
title_short Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction
title_sort inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction
topic Cellular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9534309/
https://www.ncbi.nlm.nih.gov/pubmed/36212697
http://dx.doi.org/10.3389/fncel.2022.992869
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