Novel antidepressant candidate RO-05 modulated glucocorticoid receptors activation and FKBP5 expression in chronic mild stress model in rats. (2nd April 2015)

• Record Type: Journal Article
• Authors: Xing, Y.; Hou, J.; Meng, Q.; Yang, M.; Kurihara, H.; Tian, J.
• Is Part Of: Neuroscience. Volume 290(2015)
• Page Start: 255
• Page End: 265
• Publication Date: 2015-04-02
• Subjects: ANOVA analysis of variance -- BDNF brain-derived neurotrophic factor -- CMC-Na sodium carboxymethyl cellulose -- CMS chronic mild stress -- DVS desvenlafaxine succinate -- ELISA Enzyme-Linked Immunosorbent Assay -- FST forced swimming test -- GR glucocorticoid receptor -- hDAT human dopamine transporter -- hNET human norepinephrine transporter -- HPA hypothalamic–pituitary–adrenal axis -- hSERT human serotonin transporter -- ODV O-desmethylvenlafaxin -- p11 S-100 calcium-binding protein -- PCR Polymerase Chain Reaction -- RO-05 4-[1-[1-(benzoyloxy)cyclohexyl]-2-(dimethylamino)ethyl]-phenyl benzoate -- SNPs single-nucleotide polymorphisms -- TRI triple reuptake inhibitors -- TST tail suspension test -- VEH-control Vehicle Control; depression -- chronic mild stress -- glucocorticoid receptors -- FKBP5; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.01.044
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: RO-05 is a novel compound which has antidepressant characteristics. RO-05 is the first potential TRI found to modulate the GR and FKBP5. Chronic RO-05 treatment increased the BDNF expression. 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.