title: Novel antidepressant candidate RO-05 modulated glucocorticoid receptors activation and FKBP5 expression in chronic mild stress model in rats.
abstract: In this study, a novel TRI (triple reuptake inhibitors) antidepressant candidate RO-05 (4-[1-[1-(benzoyloxy)cyclohexyl]-2-(dimethylamino)ethyl]-phenyl benzoate) was investigated in TST (tail suspension test), FST (forced swimming test) and CMS (chronic mild stress) model. Results showed RO-05 significantly decreased the immobility time in FST and TST at 4.5-, 9-, 18-mg/kg in rats and 9-, 18-, 36-mg/kg in mice. Chronic administration of 18-mg/kg RO-05 improved the behavioral index, anhedonia and normalized the hyperactivity of HPA (hypothalamic-pituitary-adrenal axis) of CMS rats. We further investigated the possible mechanisms of RO-05 in the CMS model. Eighteen milligrams per kilogram of RO-05 chronic administration significantly reversed the increase of mRNA and protein expression of FKBP5 in the CMS rat hippocampus, which facilitated the activation of GR- (glucocorticoid receptor) and GR-responsive gene Foxo1 expression. RO-05 also elevated the expression of BDNF (brain-derived neurotrophic factor) in CMS rat hippocampus. In summary, our results indicated that RO-05 is a promising antidepressant candidate. The possible antidepressant mechanisms of RO-05 were the modulation of FKBP5 expression, GR activation, corresponding inhibition of HPA axis hyperactivity, and the increase of BDNF expression.
authors: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
authors: Y
authors: Y
authors: Xing
authors: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
authors: J
authors: J
authors: Hou
authors: School of Pharmacy, Yantai University & State Key Laboratory of Long Acting and Targetin Drug Delivery Technologies, Yantai, Shandong 264003, PR China.
authors: Q
authors: Q
authors: Meng
authors: Shandong Luye Pharmaceutical Co. Ltd., Yantai, Shandong 264003, PR China.
authors: M
authors: M
authors: Yang
authors: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China. Electronic address: kurihara_hiroshi@163.com.
authors: H
authors: H
authors: Kurihara
authors: School of Pharmacy, Yantai University & State Key Laboratory of Long Acting and Targetin Drug Delivery Technologies, Yantai, Shandong 264003, PR China. Electronic address: tianjingwei@luye.cn.
authors: J
authors: J
authors: Tian
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002908:Chronic Disease; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5; D000071161:Forkhead Box Protein O1
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
keywords: FKBP5; chronic mild stress; depression; glucocorticoid receptors