{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T16:08:14Z","timestamp":1789142894993,"version":"build-2803163510"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T00:00:00Z","timestamp":1663718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>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 eIF2\u03b1. Various cellular stress stimuli trigger activation of eIF2\u03b1 kinases, thus causing phosphorylation of eIF2\u03b1. 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 PeIF2\u03b1, eIF2\u03b1, 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 PeIF2\u03b1, 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 PeIF2\u03b1, 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.<\/jats:p>","DOI":"10.3389\/fncel.2022.992869","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T04:31:29Z","timestamp":1663734689000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction"],"prefix":"10.3389","volume":"16","author":[{"given":"Linhao","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhui","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengliang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianjiao","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.molcel.2005.09.008","article-title":"Pi release from eIF2, not GTP hydrolysis, is the step controlled by start-site selection during eukaryotic translation initiation","volume":"20","author":"Algire","year":"2005","journal-title":"Mol. Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1093\/jnen\/nlz129","article-title":"The integrated stress response and phosphorylated eukaryotic initiation factor 2\u03b1 in neurodegeneration","volume":"79","author":"Bond","year":"2020","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1007\/s12031-021-01920-9","article-title":"Attenuation of activated eIF2\u03b1 signaling by ISRIB treatment after spinal cord injury improves locomotor function","volume":"72","author":"Chang","year":"2022","journal-title":"J. Mol. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"E6420","DOI":"10.1073\/pnas.1707661114","article-title":"Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury","volume":"114","author":"Chou","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B5","doi-asserted-by":"publisher","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: from mechanism to disease","volume":"368","author":"Costa-Mattioli","year":"2020","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e91229","DOI":"10.1172\/jci.insight.91229","article-title":"Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice","volume":"2","author":"Feng","year":"2017","journal-title":"JCI Insight"},{"key":"B7","doi-asserted-by":"publisher","first-page":"129","DOI":"10.3389\/fnagi.2018.00129","article-title":"Blood-brain barrier disruption induced cognitive impairment is associated with increase of inflammatory cytokine","volume":"10","author":"Geng","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"104702","DOI":"10.1016\/j.nbd.2019.104702","article-title":"Knockdown of GADD34 in neonatal mutant SOD1 mice ameliorates ALS","volume":"136","author":"Ghadge","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1080\/13880209.2020.1730913","article-title":"Protective effects of grape seed procyanidin on isoflurane-induced cognitive impairment in mice","volume":"58","author":"Gong","year":"2020","journal-title":"Pharm. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/s41586-020-2078-2","article-title":"Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway","volume":"579","author":"Guo","year":"2020","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/s1097-2765(03)00105-9","article-title":"An integrated stress response regulates amino acid metabolism and resistance to oxidative stress","volume":"11","author":"Harding","year":"2003","journal-title":"Mol. Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1126\/science.aad9868","article-title":"Translational control by 5\u2019-untranslated regions of eukaryotic mRNAs","volume":"352","author":"Hinnebusch","year":"2016","journal-title":"Science"},{"key":"B13","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/s41398-022-01862-9","article-title":"Inhibition of the ISR abrogates mGluR5-dependent long-term depression and spatial memory deficits in a rat model of Alzheimer\u2019s disease","volume":"12","author":"Hu","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"B14","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1080\/01616412.2016.1251711","article-title":"Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders","volume":"39","author":"Islam","year":"2017","journal-title":"Neurol. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"eabf0971","DOI":"10.1126\/sciadv.abf0971","article-title":"Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR","volume":"7","author":"Kaspar","year":"2021","journal-title":"Sci. Adv."},{"key":"B16","doi-asserted-by":"publisher","first-page":"5737","DOI":"10.1111\/febs.15868","article-title":"CCCP-induced mitochondrial dysfunction - characterization and analysis of integrated stress response to cellular signaling and homeostasis","volume":"288","author":"Koncha","year":"2021","journal-title":"FEBS J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e62048","DOI":"10.7554\/eLife.62048","article-title":"Small molecule cognitive enhancer reverses age-related memory decline in mice","volume":"9","author":"Krukowski","year":"","journal-title":"eLife"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1089\/neu.2019.6827","article-title":"Integrated stress response inhibitor reverses sex-dependent behavioral and cell-specific deficits after mild repetitive head trauma","volume":"37","author":"Krukowski","year":"","journal-title":"J. Neurotrauma"},{"key":"B19","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.neuropharm.2013.04.005","article-title":"BDNF-induced local protein synthesis and synaptic plasticity","volume":"76","author":"Leal","year":"2014","journal-title":"Neuropharmacology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/nature05292","article-title":"Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases","volume":"443","author":"Lin","year":"2006","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"110791","DOI":"10.1016\/j.exger.2019.110791","article-title":"The potential mechanism of postoperative cognitive dysfunction in older people","volume":"130","author":"Lin","year":"2020","journal-title":"Exp. Gerontol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"128","DOI":"10.4103\/1673-5374.264466","article-title":"GLYX-13 pretreatment ameliorates long-term isoflurane exposure-induced cognitive impairment in mice","volume":"15","author":"Liu","year":"2020","journal-title":"Neural Regen. Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s10787-018-00559-0","article-title":"Postoperative cognitive dysfunction in the aged: the collision of neuroinflammaging with perioperative neuroinflammation","volume":"27","author":"Luo","year":"2019","journal-title":"Inflammopharmacology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"a005710","DOI":"10.1101\/cshperspect.a005710","article-title":"NMDA receptor-dependent long-term potentiation and long-term depression (LTP\/LTD)","volume":"4","author":"Luscher","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.bbi.2018.07.016","article-title":"Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats","volume":"73","author":"Netto","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"eabc5429","DOI":"10.1126\/scisignal.abc5429","article-title":"Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity and memory in mouse models of Alzheimer\u2019s disease","volume":"14","author":"Oliveira","year":"2021","journal-title":"Sci. Signal."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1523\/JNEUROSCI.4110-15.2016","article-title":"Integrated stress response: connecting ApoE4 to memory impairment in Alzheimer\u2019s disease","volume":"36","author":"Oliveira","year":"2016","journal-title":"J. Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Pakos-Zebrucka","year":"2016","journal-title":"EMBO Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1073\/pnas.1815767116","article-title":"Small molecule ISRIB suppresses the integrated stress response within a defined window of activation","volume":"116","author":"Rabouw","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B30","doi-asserted-by":"publisher","first-page":"S125","DOI":"10.3233\/JAD-132738","article-title":"Apoptosis and oxidative stress in neurodegenerative diseases","volume":"42","author":"Radi","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e00498","DOI":"10.7554\/eLife.00498","article-title":"Pharmacological brake-release of mRNA translation enhances cognitive memory","volume":"2","author":"Sidrauski","year":"2013","journal-title":"eLife"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e05033","DOI":"10.7554\/eLife.05033","article-title":"The small molecule ISRIB reverses the effects of eIF2\u03b1 phosphorylation on translation and stress granule assembly","volume":"4","author":"Sidrauski","year":"2015","journal-title":"eLife"},{"key":"B33","doi-asserted-by":"publisher","first-page":"108213","DOI":"10.1016\/j.jnutbio.2019.07.004","article-title":"Green tea polyphenols improve isoflurane-induced cognitive impairment via modulating oxidative stress","volume":"73","author":"Song","year":"2019","journal-title":"J. Nutr. Biochem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"bqab185","DOI":"10.1210\/endocr\/bqab185","article-title":"Neurodegenerative disease: roles for sex, hormones and oxidative stress","volume":"162","author":"Sumien","year":"2021","journal-title":"Endocrinology"},{"key":"B35","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.tins.2011.10.003","article-title":"Fear conditioning and extinction: emotional states encoded by distinct signaling pathways","volume":"35","author":"Tronson","year":"2012","journal-title":"Trends Neurosci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1186\/s12871-018-0606-5","article-title":"Effects of resveratrol pretreatment on endoplasmic reticulum stress and cognitive function after surgery in aged mice","volume":"18","author":"Wang","year":"2018","journal-title":"BMC Anesthesiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.physbeh.2017.08.022","article-title":"Long term impairment of cognitive functions and alterations of NMDAR subunits after continuous microwave exposure","volume":"181","author":"Wang","year":"2017","journal-title":"Physiol. Behav."},{"key":"B38","doi-asserted-by":"publisher","first-page":"174524","DOI":"10.1016\/j.ejphar.2021.174524","article-title":"Varenicline improved laparotomy-induced cognitive impairment by restoring mitophagy in aged mice","volume":"916","author":"Wang","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2225","DOI":"10.1096\/fj.13-243329","article-title":"Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation","volume":"28","author":"Wortham","year":"2014","journal-title":"FASEB J."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2415","DOI":"10.1007\/s11064-021-03386-y","article-title":"Dexmedetomidine ameliorates postoperative cognitive dysfunction in aged mice","volume":"46","author":"Xie","year":"2021","journal-title":"Neurochem. Res."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-021-01137-9","article-title":"Impaired restoration of global protein synthesis contributes to increased vulnerability to acute ER stress recovery in Huntington\u2019s disease","author":"Xu","year":"2021","journal-title":"Cell. Mol. Neurobiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"780972","DOI":"10.3389\/fnagi.2022.780972","article-title":"Role of BDNF\/ProBDNF imbalance in postoperative cognitive dysfunction by modulating synaptic plasticity in aged mice","volume":"14","author":"Xue","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"190","DOI":"10.3389\/fncel.2019.00190","article-title":"Endoplasmic Reticulum stress is involved in stress-induced hypothalamic neuronal injury in rats via the PERK-ATF4-CHOP and IRE1-ASK1-JNK pathways","volume":"13","author":"Yi","year":"2019","journal-title":"Front. Cell Neurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.bbr.2015.11.003","article-title":"Cerebral mast cells contribute to postoperative cognitive dysfunction by promoting blood brain barrier disruption","volume":"298","author":"Zhang","year":"2016","journal-title":"Behav. Brain Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/nature07203","article-title":"From endoplasmic-reticulum stress to the inflammatory response","volume":"454","author":"Zhang","year":"2008","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1500","DOI":"10.1161\/CIRCULATIONAHA.120.053125","article-title":"Integrated stress response couples mitochondrial protein translation with oxidative stress control","volume":"144","author":"Zhang","year":"2021","journal-title":"Circulation"},{"key":"B47","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1126\/science.aaw5185","article-title":"Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome","volume":"366","author":"Zhu","year":"2019","journal-title":"Science"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1126\/science.aar5129","article-title":"Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B","volume":"359","author":"Zyryanova","year":"2018","journal-title":"Science"}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2022.992869\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T04:31:32Z","timestamp":1663734692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2022.992869\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,21]]},"references-count":48,"alternative-id":["10.3389\/fncel.2022.992869"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2022.992869","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,21]]},"article-number":"992869"}}