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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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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. |
format | Online Article Text |
id | pubmed-9534309 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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