title: Fluoxetine ameliorates cognitive impairments induced by chronic cerebral hypoperfusion via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats.
abstract: Chronic cerebral hypoperfusion (CCH) causes cognitive impairments and increases the risk of Alzheimer's disease (AD) and vascular dementia (VD) through several biologically plausible pathways, yet the underlying neurobiological mechanisms are still poorly understood. In this study, we investigated whether fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could play a neuroprotective role against chronic cerebral hypoperfusion injury and to clarify underlying mechanisms of its efficacy. Rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). Two weeks later, rats were treated with 30 mg/kg fluoxetine (intragastric injection, i.g.) for 6 weeks. Cognitive function was evaluated by Morris water maze (MWM) and novel objects recognition (NOR) test. Long-term potentiation (LTP) was used to address the underlying synaptic mechanisms. Western blotting was used to quantify the protein levels. Our results showed that fluoxetine treatment significantly improved the cognitive impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, 2VO caused an up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) surface expressions in the hippocampal CA1 area and fluoxetine also effectively recovered the disorder of HCN2 surface expressions, which may be a possible mechanism that fluoxetine treatment ameliorates cognitive impairments in rats with CCH.
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Luo
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Neurology Department, Huanggang Central Hospital, Hubei Province Huanggang 438000, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xulin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: shenguanxin@hust.edu.cn.
authors.forename: Guanxin
authors.initials: G
authors.lastname: Shen
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: ljguo@hust.edu.cn.
authors.forename: Lianjun
authors.initials: L
authors.lastname: Guo
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism*; D016893:Carotid Stenosis / Q000188:drug therapy / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D015536:Down-Regulation / Q000187:drug effects; D005473:Fluoxetine / Q000627:therapeutic use*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000096:biosynthesis* / Q000235:genetics; D007859:Learning Disabilities / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D015221:Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D013569:Synapses / Q000187:drug effects
chemical_list: D005473:Fluoxetine; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D017367:Selective Serotonin Reuptake Inhibitors; C578712:Hcn2 protein, rat
keywords: Chronic cerebral hypoperfusion; Cognitive impairments; Fluoxetine; HCN2 subunit