New antidepressant mechanism of Yueju Pill: Increasing ghrelin level by inhibiting gastric mTOR/S6K signaling pathway and sensitizing hippocampal GHS-R
Zhentao Zhang,
Dan Su,
Meixizi Lai,
Yonggui Song,
Huizhen Li,
Ming Yang,
Genhua Zhu,
Hong Liu,
Zhifu Ai
Affiliations
Zhentao Zhang
Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Diseases with Mental Disorders), Key Laboratory of Depression Animal Model Based on TCM Syndrome, Jiangxi Administration of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330006, China
Dan Su
Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Diseases with Mental Disorders), Key Laboratory of Depression Animal Model Based on TCM Syndrome, Jiangxi Administration of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330006, China
Meixizi Lai
Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Diseases with Mental Disorders), Key Laboratory of Depression Animal Model Based on TCM Syndrome, Jiangxi Administration of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330006, China
Yonggui Song
Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Diseases with Mental Disorders), Key Laboratory of Depression Animal Model Based on TCM Syndrome, Jiangxi Administration of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330006, China
Huizhen Li
Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Diseases with Mental Disorders), Key Laboratory of Depression Animal Model Based on TCM Syndrome, Jiangxi Administration of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330006, China
Ming Yang
Jiangxi Guxiang Jinyun Comprehensive Health Industry Co., Ltd., Nanchang, China
Genhua Zhu
Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Diseases with Mental Disorders), Key Laboratory of Depression Animal Model Based on TCM Syndrome, Jiangxi Administration of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330006, China
Hong Liu
Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330006, China; Corresponding author.
Zhifu Ai
Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Diseases with Mental Disorders), Key Laboratory of Depression Animal Model Based on TCM Syndrome, Jiangxi Administration of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, 1688 Meiling Road, Nanchang, 330006, China; Corresponding author.
Background and aim: Yueju Pill (YJ) not only has good antidepressant effect but also can effectively treat digestive system diseases. However,it remains unclear whether the mechanism of antidepressant action of YJ is related to the peripheral digestive system. The purpose of this study was to elucidate the antidepressant mechanism of YJ on ghrelin level based on gastric mTOR/S6K signal pathway and sensitized hippocampal Ghrelin/GHS-R system in CUMS mice. Experimental procedure: The depression model was induced by chronic unpredictable mild stress (CUMS) and social isolation. The antidepressant effect of YJ was observed by behavioral experiment and hemodynamic experiments. Ghrelin levels in in hippocampus and blood were measured by Elisa kit, and the mRNA of ghrelin in mice stomach was measured by Real-time Quantitative PCR (RT-qPCR). The activation level of gastric mTOR/S6K signal pathway was detected by Western Blot (WB). Rapamycin (Rapa) and L-Leucine (L-Leu) were used to verify the effects of YJ on the synthesis and release of ghrelin. The activity of GHS-R in hippocampus was observed by immunofluorescence. Hippocampal neuronal damage was evaluated by HE staining and Nissl staining. The level of central neurotransmitter was measured by liquid chromatograph mass spectrometer (LC-MS). Results and conclusion: YJ ameliorates CUMS-induced depressive-like behavior by inhibiting the gastric mTOR/S6K signaling pathway and increasing GHR expression in the mouse stomach. However, these effects of YJ could be resisted by L-Leu (a mTOR receptor agonist). Further studies have shown that YJ can sensitize the Ghrelin/GHS-R system in the hippocampus, with significant neuroprotective effects, and is also involved in regulating the levels of key neurotransmitters (5-hydroxytryptamine, Dopamine and γ-aminobutyric acid) in depressive-like states.
