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
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
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