The Antidepressant Effects Of New Compound RO-05 And GR Related Mechanism

As the predominant pharmacotherapy for major depressive disorder(MDD),there are still many disadvantages in using serotonin(5-HT)selective reuptake inhibitors(SSRIs)or 5-HT/norepinephrine(NE)reuptake inhibitors(SNRIs),such as slow onset and cannot alleviate anhedonia,cognitive impairment and sexual dysfunction.Meanwhile,the usage of SNDRIs gains a lot of research interests,as it can inhibit the reuptake of 5-HT,NE and dopamine(DA),which provides superior efficacy in MDD treatment and overcome the short comings associated with SSRIs and SNRIs.An in vitro competitive radio ligand binding assay and reuptake inhibition assay were employed to screen for a promsing SNDRI drug candidate from seven compounds,which were synthesized based on the structure of O-desmethylvenlafaxine(ODV).RO-05(1.0 X 10 5M)could inhibit the specific binding of norepinephrine transporter,dopamine transporter,and 5-HT transporter with inhibition rate of 86.7%,101.9%and 82.4%respectively.Uptake inhibition of[3H]NE,[3H]5-HT or[3H]DA by RO-05 for hNET,hDAT or hSERT produced IC50 values of 4.2 ?M,1.5 ?M and 3.4 ?M,respectively.Therefore RO-05 was selected as the research subject in the following research.In this part of the study,a novel TRI(triple reuptake inhibitors)antidepressant candidate RO-05 was investigated by TST(tail suspension test),FST(forced swimming test)and CMS(chronic mild stress)model.Results showed that 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.RO-05 also restored the sensitivity of HPA to dexamethasone.We further investigated the possible mechanisms of RO-05 in the CMS model.18 mg/kg RO-05 chronic administration significantly reversed the increase of mRNA and protein expression of FKBP5 in the hippocampus of CMS rat,which facilitated the activation of GR(glucocorticoid receptor),phosphorylation of GR(Ser211),and GR responsive gene Foxo1 expression.RO-05 also elevated the expression of BDNF(brain derived neurotrophic factor)in the hippocampus of CMS rat.We also confirmed the effects of RO-05 in hippocampal neurons derived from fetal rats.Corticosterone was used to imitate the stressed situation in depression.Results showed that RO-05 enhanced the GR activation,which was similar to the results of animal study.In summary,our results indicated that RO-05 is a promising antidepressant candidate.The possible mechanisms of RO-05 were the modulation of FKBP5 expression,GR activation,corresponding inhibition of HPA axis hyperactivity,and the increase of BDNF expression.