title: Flupirtine attenuates chronic restraint stress-induced cognitive deficits and hippocampal apoptosis in male mice.
abstract: Chronic restraint stress (CRS) causes hippocampal neurodegeneration and hippocampus-dependent cognitive deficits. Flupirtine represents neuroprotective effects and we have previously shown that flupirtine can protect against memory impairment induced by acute stress. The present study aimed to investigate whether flupirtine could alleviate spatial learning and memory impairment and hippocampal apoptosis induced by CRS. CRS mice were restrained in well-ventilated Plexiglass tubes for 6h daily beginning from 10:00 to 16:00 for 21 consecutive days. Mice were injected with flupirtine (10mg/kg and 25mg/kg) or vehicle (10% DMSO) 30min before restraint stress for 21 days. After stressor cessation, the spatial learning and memory, dendritic spine density, injured neurons and the levels of Bcl-2, Bax, p-Akt, p-GSK-3β, p-Erk1/2 and synaptophysin of hippocampal tissues were examined. Our results showed that flupirtine significantly prevented spatial learning and memory impairment induced by CRS in the Morris water maze. In addition, flupirtine (10mg/kg and 25mg/kg) treatment alleviated neuronal apoptosis and the reduction of dendritic spine density and synaptophysin expression in the hippocampal CA1 region of CRS mice. Furthermore, flupirtine (10mg/kg and 25mg/kg) treatment significantly decreased the expression of Bax and increased the p-Akt and p-GSK-3β, and flupirtine (25mg/kg) treatment up-regulated the p-Erk1/2 in the hippocampus of CRS mice. These results suggested that flupirtine exerted protective effects on the CRS-induced cognitive impairment and hippocampal neuronal apoptosis, which is possibly associated with the activation of Akt/GSK-3β and Erk1/2 signaling pathways.
authors: Department of Pharmacology, School of Basic Medicine, Tongji medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Pengcheng
authors: P
authors: Huang
authors: Department of Pharmacology, School of Basic Medicine, Tongji medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Cai
authors: C
authors: Li
authors: Department of Pharmacology, School of Basic Medicine, Tongji medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Tianli
authors: T
authors: Fu
authors: Department of Pharmacology, School of Basic Medicine, Tongji medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Dan
authors: D
authors: Zhao
authors: Department of Pharmacology, School of Basic Medicine, Tongji medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Zhen
authors: Z
authors: Yi
authors: Department of Pharmacology, School of Basic Medicine, Tongji medical college, Huazhong University of Science and Technology, Wuhan 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China; The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Qing
authors: Q
authors: Lu
authors: Department of Pharmacology, School of Basic Medicine, Tongji medical college, Huazhong University of Science and Technology, Wuhan 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China; The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors: Lianjun
authors: L
authors: Guo
authors: Department of Pharmacology, School of Basic Medicine, Tongji medical college, Huazhong University of Science and Technology, Wuhan 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China; The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: xulinxu@hust.edu.cn.
authors: Xulin
authors: X
authors: Xu
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002908:Chronic Disease; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology; D011897:Random Allocation; D012149:Restraint, Physical; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000631:Aminopyridines; D018696:Neuroprotective Agents; D018697:Nootropic Agents; C034161:flupirtine
keywords: Akt (protein kinase B); Chronic restraint stress; Cognitive impairment; Flupirtine; Glycogen synthase kinase 3 beta