Ro41-5253, a selective antagonist of retinoic acid receptor α, ameliorates chronic unpredictable mild stress-induced depressive-like behaviors in rats: Involvement of regulating HPA axis and improving hippocampal neuronal deficits.

Accumulating reports have highlighted an association between excess retinoids and depression development. Retinoic acid receptor α (RARα) is implicated in the activation of hypothalamus-pituitary-adrenal (HPA) axis and closely involved in the etiology of depression, suggesting it might be a novel target of antidepressant. This study investigated the antidepressant potential of Ro41-5253 (a selective RARα antagonist) and related mechanisms using a depression rat model imitated by social isolation and chronic unpredicted mild stress (CUMS). Sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST) were applied to assess the antidepressant-like effect. HPA axis activity, RARα expression in hypothalamic paraventricular nucleus (PVN) and hypothalamus, and protein levels of brain-derived neurotrophic factor (BDNF) and synapse-related proteins (PSD95, SYP, MAP2) in hippocampus were measured, respectively. We found that Ro41-5253 treatment ameliorated the depressive-like behaviors in CUMS rats, as evidenced by increased sucrose preference in SPT, raised numbers of crossing and rearing in OFT, reduced immobility time and prolonged swimming time in FST. The HPA axis hyperactivity was attenuated by Ro41-5253 (1 mg/kg) treatment, indicated by reduced serum corticosterone level, decreased adrenal gland index, reduced corticotrophin-releasing hormone protein level in hypothalamus, and recovered hypothalamic glucocorticoid receptor protein level. In addition, Ro41-5253 (1 mg/kg) treatment downregulated RARα protein expression in hypothalamic PVN and hypothalamus, and increased the protein levels of BDNF, PSD95, SYP and MAP2 in the hippocampus. We concluded that Ro41-5253 had antidepressant-like effects on CUMS rats by downregulating HPA axis hyperactivity and improving the hippocampal neuronal deficits.

Ke Q ，Li R ，Cai L ，Wu SD ，Li CM ... -  《-》

Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus-pituitary-adrenal axis.

Geniposide as the major active component of Gardenia jasminoides Ellis has neuroprotective activity. This study elucidated the potential antidepressant-like effect of geniposide and its related mechanisms using a depression rat model induced by 3 consecutive weeks of chronic unpredictable mild stress (CUMS). Sucrose preference test, open field test (OFT) and forced swimming test (FST) were applied to evaluate the antidepressant effect of geniposide. Adrenocorticotropic hormone (ACTH) and corticosterone (CORT) serum levels, adrenal gland index and hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression were measured to assess the activity of hypothalamus-pituitary-adrenal (HPA) axis. Hypothalamic glucocorticoid receptor α (GRα) mRNA expression and GRα protein expression in hypothalamic paraventricular nucleus (PVN) were also determined by real-time PCR and immunohistochemistry, respectively. We found that geniposide (25, 50, 100mg/kg) treatment reversed the CUMS-induced behavioral abnormalities, as suggested by increased sucrose intake, improved crossing and rearing behavior in OFT, shortened immobility and prolonged swimming time in FST. Additionally, geniposide treatment normalized the CUMS-induced hyperactivity of HPA axis, as evidenced by reduced CORT serum level, adrenal gland index and hypothalamic CRH mRNA expression, with no significant effect on ACTH serum level. Moreover, geniposide treatment upregulated the hypothalamic GRα mRNA level and GRα protein expression in PVN, suggesting geniposide could recover the impaired GRα negative feedback on CRH expression and HPA axis. These aforementioned therapeutic effects of geniposide were essentially similar to fluoxetine. Our results indicated that geniposide possessed potent antidepressant-like properties that may be mediated by its effects on the HPA axis.

Cai L ，Li R ，Tang WJ ，Meng G ，Hu XY ，Wu TN ... -  《-》

Crassifoside H improve the depressive-like behavior of rats under chronic unpredictable mild stress: Possible involved mechanisms.

Crassifoside (CH) is a novel chlorine-containing compound isolated from rhizomes of Curculigo glabrescens. This study aimed to explore the antidepressant-like effect of CH and involved mechanisms. A rat depression model was established using chronic unpredictable mild stress (CUMS) paradigm. Behavioral tests including sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST) were used to evaluate the antidepressant-like effect of CH. The levels of plasma corticosterone (CORT) and corticotrophin-releasing factor (CRF) in hypothalamus were measured to determine the activity of hypothalamic pituitary-adrenal (HPA) axis. Protein expression of 5-hydroxytryptamine 1A (5-HT1A) receptor, brain-derived neurotrophic factor (BDNF), as well as the total and phosphorylated extracellular signal-regulated kinase (ERK)1/2 in hippocampus were also analyzed by Western blotting. The CH administration effectively ameliorated the depressive-like behaviors of CUMS rats, as indicated by the increased sucrose intake in SPT, reduced immobility time in FST, and the increased rearing and grooming numbers, spent more time in inner zone and less time in outer zone in OFT. CH improved CUMS-induced HPA axis hyperactivity by reduced plasma CORT and CRH expression in hypothalamus. Moreover, CH reversed CUMS-induced decrease of 5-HT1A receptor expression, and up-regulated BDNF and phosphorylated-ERK1/2 levels in hippocampus. These findings suggest that CH improved depressive behaviors of CUMS rats by modulating of HPA axis dysfunction, increasing 5-HT1A receptor expression, and activating BDNF-ERK signaling pathway.

Zhang Y ，Ge JF ，Wang FF ，Liu F ，Shi C ，Li N ... -  《-》

Honokiol Exerts Antidepressant Effects in Rats Exposed to Chronic Unpredictable Mild Stress by Regulating Brain Derived Neurotrophic Factor Level and Hypothalamus-Pituitary-Adrenal Axis Activity.

Wang C ，Gan D ，Wu J ，Liao M ，Liao X ，Ai W ... -  《-》

Saikosaponin D relieves unpredictable chronic mild stress induced depressive-like behavior in rats: involvement of HPA axis and hippocampal neurogenesis.

Li HY ，Zhao YH ，Zeng MJ ，Fang F ，Li M ，Qin TT ，Ye LY ，Li HW ，Qu R ，Ma SP ... -  《-》