title: Rapamycin Protects Sepsis-Induced Cognitive Impairment in Mouse Hippocampus by Enhancing Autophagy.
abstract: The purpose of this study is to test the hypothesis that the mammalian target of rapamycin (mTOR) signaling pathway might mediate neuroprotection in a mouse model of septic encephalopathy and also to identify the role of autophagy. Mice were subjected to cecal ligation and puncture (CLP) or a sham operation, and all 50 mice were randomly assigned to five groups: sham, CLP+ saline, CLP+ rapamycin (1, 5, 10 mg/kg) groups. Two weeks after the operation, Morris water maze was conducted for behavioral test; Nissl staining was used for observing glia infiltration; immunohistochemical staining and biochemical measures in hippocampi were performed to detect mTOR targets and autophagy indicators. Immunochemistry revealed significant loss of neurons and increased glia infiltration in hippocampus after CLP operation. Inhibition of mTOR by rapamycin rescued cognitive deficits caused by sepsis (p < 0.05). Rapamycin did not affect total mTOR targets, while phosphorylated mTOR targets (p-mTOR-Ser2448, p-p70S6k-Thr389, p-AKT-S473) decreased (p < 0.05) and autophagy indicators (LC3-II, Atg5, Atg7) were increased, and P62 was decreased in rapamycin-treated CLP mice compared with the untreated (p < 0.05) in hippocampus. Rapamycin improves learning after sepsis through enhancing autophagy and may be a potentially effective therapeutic agent for the treatment of sepsis-induced cognitive impairment.
authors.affiliation: Departments of Neurology, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, China.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Liu
authors.affiliation: Departments of Neurology, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, China.
authors.forename: Jia'nan
authors.initials: J
authors.lastname: Guo
authors.affiliation: Departments of Neurology, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Mu
authors.affiliation: Departments of Neurology, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, China. tianlinyu@sina.com.
authors.forename: Linyu
authors.initials: L
authors.lastname: Tian
authors.affiliation: Departments of Neurology, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, 610041, China. zhoudong66@yahoo.de.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D060825:Cognitive Dysfunction / Q000473:pathology / Q000517:prevention & control*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D065166:Sepsis-Associated Encephalopathy / Q000473:pathology / Q000517:prevention & control*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D018696:Neuroprotective Agents; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Autophagy; Cognitive impairment; Hippocampus; Mammalian target of rapamycin (mTOR); Sepsis