title: Internalization of GluA2 and the underlying mechanisms of cognitive decline in aged rats following surgery and prolonged exposure to sevoflurane.
abstract: BACKGROUND
  We revealed that a high concentration of sevoflurane exacerbated cognitive impairment in aged rats, and the inhibition of GluA2 subunit internalization facilitated neuroprotection after a cerebral ischemic injury. However, the trafficking of GluA2 in POCD and its underlying mechanism are not clear. We thus detected the effects of sevoflurane for different inhalation durations on postoperative cognitive function and investigated the role of GluA2 subunit trafficking in this process.
  
  
  METHODS
  A rat model of orthopedic surgery was performed with different durations of 1.5 MAC sevoflurane inhalation. Cognitive function was evaluated by manipulating the Y maze and fear conditioning tests for 7 days after experiments. Western blot, ELISA and coimmunoprecipitation were applied to analyze GluA2 internalization, PI3K expression and its activity, as well as alterations to the MEF2-Arc pathway in the hippocampus. Neuron apoptosis and the spine morphology in the hippocampus were also observed.
  
  
  RESULTS
  We found that neuron apoptosis and GluA2 internalization increased following surgery and 1.5 MAC sevoflurane inhalation for 2h, possibly due to the decrease of the PI3K-GluA2 complex and PI3K activity in the hippocampus after prolonged 1.5 MAC sevoflurane inhalation. We also observed that the MEF2-Arc pathway contributed to long-term cognitive function, which also impaired the spinal morphology after 1.5 MAC sevoflurane inhalation for 2h.
  
  
  CONCLUSIONS
  The above results suggest that 1.5 MAC sevoflurane inhalation for 2h potentiated surgery-impaired cognitive function and that the inhibition of PI3K-AMPAR GluA2 as well as activation of the MEF2-Arc signal pathway contributes to different stages of POCD.
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: hunan1987222@sina.com.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: wangmiaohappy2007@126.com.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: 58159529@qq.com.
authors.forename: Keliang
authors.initials: K
authors.lastname: Xie
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: wanghy819@hotmail.com.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: 5427417082@qq.com.
authors.forename: Chenxu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: doctorwangchao@Gmail.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: 0208wcy@163.com.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: liyizelisa@126.com.
authors.forename: Yize
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: yuyonghao@126.com.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China; Department of Critical Care Medicine of Tianjin Medical University General Hospital, Tianjin 300052, PR China. Electronic address: wangguolin_mazui@sina.com.
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
mesh_terms: D000375:Aging / Q000187:drug effects*; D018685:Anesthetics, Inhalation / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology; D003213:Conditioning, Psychological; D005239:Fear / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D008297:Male; D018782:Maze Learning; D008738:Methyl Ethers / Q000009:adverse effects* / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010027:Osteotomy / Q000009:adverse effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011183:Postoperative Complications / Q000503:physiopathology*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D019869:Phosphatidylinositol 3-Kinases; D018091:Receptors, AMPA; D000077149:Sevoflurane; C104722:glutamate receptor ionotropic, AMPA 2
keywords: Glutamate receptor subunit 2; Myocyte enhancer factor 2; Orthopedic surgery; Phosphoinositide-3-kinase; Sevoflurane; a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor