Ghrelin exhibited antidepressant and anxiolytic effect via the p38-MAPK signaling pathway in hippocampus.

Ghrelin, a peptide derived from stomach, is an endogenous ligand for growth hormone secretagogue receptor (GHSR). So far, the exact role of ghrelin in depression and anxiety is still being debated. The p38 mitogen-activated protein kinase (p38-MAPK) is known to be activated in response to various stress stimuli. Thus, we hypothesize that ghrelin has an antidepressant effect, to which the p38-MAPK signaling pathway significantly contributes. To test this hypothesis, chronic social defeat stress (CSDS) was used as a model of depression. We employed the adeno-associated virus-mediated siRNA approach to down-regulate GHSR expression in the hippocampus of mice in vivo. Both ghrelin and the p38 inhibitor, SB203580, were administered to identify the effect of ghrelin on depressive-like behavior of stressed mice and to better assess the role of the p38-MAPK signaling pathway in this process. We found that CSDS activated the endogenous ghrelin-GHSR in hippocampal neurons, which possibly resulted in opposing the formation of depression- and anxiety-like behaviors in mice. Furthermore, the p38-MAPK signaling pathway had an important role in the antidepressant effect of ghrelin. Therefore, we conclude that ghrelin may reduce CSDS-induced depression- and anxiety-like behaviors via inhibiting the p38-MAPK signaling pathway in hippocampal neurons of mice.

Ghrelin alleviates anxiety- and depression-like behaviors induced by chronic unpredictable mild stress in rodents.

As a regulator of food intake, ghrelin also plays a key role in mood disorders. Previous studies reported that acute ghrelin administration defends against depressive symptoms of chronic stress. However, the effects of long-term ghrelin on rodents under chronic stress hasn't been revealed. In this study, we found chronic peripheral administration of ghrelin (5nmol/kg/day for 2 weeks, i.p.) could alleviate anxiety- and depression-like behaviors induced by chronic unpredictable mild stress (CUMS). The depression-like behaviors were assessed by the forced swimming test (FST), and anxiety-like behaviors were assessed by the open field test (OFT) and the elevated plus maze test (EPM). Meanwhile, we observed that peripheral acylated ghrelin, together with gastral and hippocampal ghrelin prepropeptide mRNA level, were significantly up-regulated in CUMS mice. Besides, the increased protein level of growth hormone secretagogue receptor (GHSR) in hippocampus were also detected. These results suggested that the endogenous ghrelin/GHSR pathway activated by CUMS plays a role in homeostasis. Further results showed that central treatment of ghrelin (10µg/rat/day for 2 weeks, i.c.v.) or GHRP-6 (the agonist of GHSR, 10µg/rat/day for 2 weeks, i.c.v.) significantly alleviated the depression-like behaviors induced by CUMS in FST and sucrose preference test (SPT). Based on these results, we concluded that central GHSR is involved in the antidepressant-like effect of exogenous ghrelin treatment, and ghrelin/GHSR may have the inherent neuromodulatory properties against depressive symptoms.

[Effect of Electroacupuncture Stimulation of "Baihui" (GV 20) , etc. on Changes of Behavior and Plasma Ghrelin Content in Depression Rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Baihui" (GV 20) + "Anmian" (EX-HN 16) and "Baihui" (GV 20) + "Zusanli" (ST 36) on behavior reactions and plasma ghrelin level in depression rats, so as to explore the correlation between its antidepressant effect and plasma ghrelin level. METHODS: A total of 45 SD rats were randomly divided into 5 groups: normal control, model, Baihui (GV 20) + Anmian (EX-HN 16), Baihui (GV 20) + Zusanli (ST 36) and medication (clomipramine) groups, with 9 rats in each group. The depression model (unpredictable chronic mild stresses, UC-MS) was established by giving the animals with higher temperature environment (45 °C, 5 min), forced ice-water swimming (0- 4 °C, 5 min) , day and night reversal environment (12 h), stroboflash stimulation (12 h), noisy stimulation (12 h), rocking-bed movement (30 min) and damp pad dwelling (6-24 h), etc. for 4 weeks. EA was applied to GV 20-EX-HN 16, and GV 20-ST 36 for 30 min once every other day for 4 weeks after modeling. For rats of the medication group, clomipramine (5 mg/kg) was given (i. p. ) once a day for 4 weeks after modeling. The forced swimming test, sucrose preference test and open field test were used to evaluate the rats depressive-like behavior. Plasma ghrelin content was assayed by ELISA. RESULTS: After exposure to UCMS for 4 weeks, the immobility time was significantly increased, and the struggling time was significantly decreased in the model group (P < 0.05, P < 0.01). In comparison with the model group, the immobility time levels were obviously decreased, while the struggling time and sucrose preference were markedly increased in the Baihui (GV 20) + Anmian (EX-HN 16) , Baihui (GV 20) + Zusanli (ST 36) and medication groups (P < 0.05, P < 0.01). No significant changes were found in the rearing times and total distance of open-field test (locomotor activity) and plasma ghrelin content among the 5 groups among all the groups (P > 0.05). No significant differences were found among the two EA and medication groups in the decreased immobility time and the increased struggling times and sucrose preference levels (P > 0.05). CONCLUSION: EA intervention can improve the depression rats' hopeless behavior of forced swimming test and anhedonia behavior (sucrose preference test) , which may be not correlated to plasma ghrelin level at the late-stages and the antidepressant effect of EA intervention.