title: Endoplasmic reticulum stress is involved in restraint stress-induced hippocampal apoptosis and cognitive impairments in rats.
abstract: Long-term exposure to stressful stimuli can reduce hippocampal volume and cause cognitive impairments, but the underlying mechanisms are not well understood. Endoplasmic reticulum stress (ERS) is considered an early or initial response of cells under stress and linked to neuronal death in various neurodegenerative diseases. The present study investigated the involvement of ERS in restraint stress (RS)-induced hippocampal apoptosis and cognitive impairments. Using the rat RS model for 21 consecutive days, we found that the hippocampal apoptotic rate was significantly up-regulated as compared with unstressed controls, and salubrinal (ERS inhibitor) pretreatment effectively reduced the increase. As the marker of ERS, the 78-kDa glucose-regulated protein (GRP78) and the target molecule of the unfolded protein response (UPR), the splice variant of X-box binding protein 1 (sXBP-1) were also markedly increased in RS rats. Furthermore, in the three possible signaling pathways of ERS-induced apoptosis, the protein and mRNA levels of C/EBP homologous protein (CHOP) were significantly up-regulated, and caspase-12 was activated and cleaved, which suggested that these two pathways crucially contributed to hippocampal cell death. However, we found no changes in protein levels of phosphorylated JNK, implying that the JNK pathway was not the primary pathway involved in hippocampal apoptosis. It is more important that the cognitive impairments caused by RS were also effectively alleviated by salubrinal pretreatment. The present results suggested that ERS in hippocampus was excessively activated under stress, and amelioration of ERS could be a novel strategy to prevent and treat impaired cognitive function induced by RS.
authors.affiliation: Department of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China; Department of Clinical Diagnostics, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Neurology, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Shujin
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: congbin6406@126.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Cong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053454:Caspase 12 / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000071701:Regulatory Factor X Transcription Factors; D013315:Stress, Psychological / Q000503:physiopathology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D053454:Caspase 12; D002491:Central Nervous System Agents; D002934:Cinnamates; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D048670:MAP Kinase Kinase 4; D020033:Protein Isoforms; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D013890:Thiourea; D014157:Transcription Factors; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C496827:salubrinal; C506443:Casp12 protein, rat
keywords: Apoptosis; Cognitive impairment; Endoplasmic reticulum stress; Hippocampus; Restraint stress