title: Endoplasmic reticulum stress pathway mediates isoflurane-induced neuroapoptosis and cognitive impairments in aged rats.
abstract: Postoperative cognitive dysfunction (POCD) is increasingly being recognized as an important clinical syndrome. Although it has been documented that volatile anesthetics induce neuronal apoptosis and cognitive deficits in several aged animal models, the underlying mechanisms are not well understood. Endoplasmic reticulum stress (ERS) is considered as an initial or early response of cells under stress and linked to neuronal death in various neurodegenerative diseases. The study was designed to explore the possible role of ERS pathway in isoflurane-induced neuroapoptosis and cognitive impairments. In the present study, twenty-month-old rats were exposed to 1.3% isoflurane for 4h. Two weeks later, the rats were subjected to behavioral study. Protein and mRNA expressions of ERS markers were evaluated. Meanwhile, hippocampal neuronal apoptosis was also detected. We found that isoflurane triggered ERS as evidenced by increased phosphorylation of eukaryotic initiation factor (EIF) 2α, and increased expression of 78-kDa glucose-regulated protein (GRP78), activating transcription factor (ATF) 4 and C/EBP homologous protein (CHOP). Furthermore, the level of apoptosis in the hippocampus was significantly up-regulated after isoflurane exposure, and salubrinal (ERS inhibitor) treatment attenuated the increase. More importantly, cognitive impairments caused by isoflurane were also effectively alleviated by salubrinal pretreatment. These results indicate that ERS-mediated apoptotic pathway is involved in isoflurane neurotoxicity in aged rats. Inhibition of ERS overactivation contributes to the relief of isoflurane-induced neurohistopathologic changes.
authors.affiliation: Department of Anesthesiology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Ge
authors.affiliation: Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Hu
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China. Electronic address: kongfeijuan@163.com.
authors.forename: Fei-Juan
authors.initials: FJ
authors.lastname: Kong
mesh_terms: D051696:Activating Transcription Factors / Q000378:metabolism; D000375:Aging / Q000187:drug effects / Q000502:physiology / Q000523:psychology; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D007530:Isoflurane / Q000633:toxicity*; D008297:Male; D010766:Phosphorylation; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D051742:Transcription Factor CHOP / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051696:Activating Transcription Factors; D018685:Anesthetics, Inhalation; D006360:Heat-Shock Proteins; D007530:Isoflurane; D051742:Transcription Factor CHOP; D020931:ran GTP-Binding Protein; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP
keywords: C/EBP homologous protein; Cognitive impairments; Endoplasmic reticulum stress; Isoflurane; Neuroapoptosis