TITLE:
Shuganheweitang Ameliorates Chronic Unpredictable Mild Stress-Induced Depression-Like Behaviors in Rats through the PI3K/AKT/mTOR Pathway: Involvement of Amino Acids, Glycerophospholipids, and Energy Metabolism
AUTHORS:
Qi Li, Junjie Hu, Zhenpeng Qiu, Juan Li, Misi Zhou, Xiao Huang, Di He, Chuanyu Yuan, Kang Yin, Yanwen Liu, Songlin Liu, Xin Chen
KEYWORDS:
Shuganheweitang, Chronic Unpredictable Mild Stress, Depression, Metabolomics, PI3K/AKT/mTOR
JOURNAL NAME:
Chinese Medicine,
Vol.14 No.1,
March
29,
2023
ABSTRACT: Background: Depression is a typical psychosomatic disease. Shuganheweitang (SGHWT)
is a clinical formula that effectively treats depression. However, the
potential mechanism used by SGHWT to ameliorate depression-like behaviors is
still unclear. This study investigated the effects of SGHWT on metabolic change
in the liver and hypothalamus with signaling pathways involved in chronic unpredictable mild stress (CUMS)-induced
depression in rats to explore the mechanism of the anti-depressive effect. Methods: A total of 52 rats were used to
create a model of depression by CUMS combined with solitary rearing for 6
weeks. Open field test (OFT), sucrose preference test (SPT), forced swim test
(FST), and body weight (BW) were performed to analyze the pharmacodynamic
effects of SGHWT. H&E staining, Nissl staining, immunofluorescence, immunohistochemistry, and western blot were used to evaluate the
mechanism of action. Untargeted metabolomics techniques by ultra-performance
liquid chromatography-quantitative time-of-flight tandem mass spectrometry
(UPLC-Q-TOF-MS/MS) were used to analyze all the metabolic differences in the
liver and hypothalamus. Results: SGHWT improved CUMS-induced depression-like behaviors in vivo. SGHWT reduced hepatic c-Fos
protein expression and increased hypothalamic c-Fos protein expression. Moreover, p-PI3K, p-AKT473, p-AKT308, and
p-mTOR protein expressions were significantly downregulated in the liver
and hypothalamus of CUMS rats. Notably, these alterations were reversed by the
SGHWT administration. Furthermore, the metabolomic analysis identified 15 and 5
key differential SPT-associated metabolites in the liver and hypothalamus,
respectively. Conclusion: This study suggests that SGHWT ameliorates chronic unpredictable mild
stress-induced depression-like behaviors, by the involvement of amino acids,
glycerophospholipids, energy metabolism, and the PI3K/AKT/mTOR pathway. Highlights: 1) Shuganheweitang was derived from the TCM
herbal formula Sinisan. 2) SGHWT treatment reverses depression-like behaviors
in CUMS-induced rats. 3) The mechanism of SGHWT on depression by the liver and
hypothalamus metabolomics. 4) SGHWT regulates amino acids,
glycerophospholipids, and energy metabolism. 5) SGHWT exerts antidepressant
effects through the PI3K/AKT/mTOR pathway.