Low polarity fraction of Radix Bupleuri alleviates chronic unpredictable mild stress-induced depression in rats through FXR modulating bile acid homeostasis in liver, gut, and brain

Nov 3, 2024Journal of pharmaceutical and biomedical analysis

Low polarity extract of Radix Bupleuri may reduce depression in rats by affecting bile acid balance through FXR in the liver, gut, and brain

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Abstract

A dosage of 12.5 g crude drug/kg/d of the low-polarity fraction of Radix Bupleuri significantly improved depression-like behavior in rats after 4 weeks of treatment.

The low-polarity fraction of Radix Bupleuri (LBR) demonstrated antidepressant effects in chronic unpredictable mild stress (CUMS) rats.
Marked improvements were observed in the levels of total bile acids in the blood, liver, and ileum following LBR treatment.
Liver transcriptome analysis indicated that bile secretion may play a crucial role in alleviating depression through LBR intervention.
Specific bile acids were identified as potential therapeutic targets in various tissues, including the liver, ileum, and hippocampus.
LBR appears to influence depression by regulating specific pathways related to bile acid metabolism in the liver, ileum, and hippocampus.

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Radix Bupleuri (BR, Bupleurum chinense DC.) is a well-known traditional Chinese medicine (TCM) known for its effects on soothing the liver and alleviating depression, and is widely used in clinical settings to manage depressive symptoms. A dosage of 12.5 g crude drug/kg/d of the low-polarity fraction of Radix Bupleuri (LBR) demonstrated effectiveness in treating depression in our previous study. However, the mechanism through which BR ameliorates depression remains unclear. This study aimed to explore the polar fractions of BR and their mechanisms of action in the treatment of depression. Chronic unpredictable mild stress (CUMS) rats were continuously administered BR by oral gavage for 4 weeks. Behavioral and biochemical indicators were evaluated to assess the antidepressant effects of LBR, and transcriptomics was used to explore the relevant pathways. In addition, pseudo-targeted bile acid (BA) metabonomics was used to quantify the BA profiles. Molecular biology techniques have been used to investigate the underlying mechanisms. LBR serves as a more effective active fraction with antidepressant activity. Intervention with LBR, which is characterized by a clearly defined chemical composition, significantly ameliorated depression-like behavior and biochemical indicators in rats subjected to CUMS. Notably, marked improvements were observed in the levels of total bile acids (TBAs) in the blood, liver, and ileum. Mechanistically, liver transcriptome analysis suggested that bile secretion may be a crucial pathway for alleviating depression after LBR treatment. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) BA metabonomics indicated that TCA, β-MCA, γ-MCA, Tβ-MCA, and UDCA in the liver, Tβ-MCA, TCA, βMCA, GHDCA, and GLCA in the ileum, and β-MCA, CA, and DCA in the hippocampus were the potential therapeutic targets. In addition, molecular biology experiments showed that LBR exerts antidepressant effects by regulating the FXR/SHP/CYP7A1 pathway in the liver, the FXR/FGF15/ASBT pathway in the ileum, and the FXR/CREB/BDNF pathway in the hippocampus. In conclusion, LBR attenuated depression by moderating BA homeostasis through FXR and related genes within the liver-gut-brain axis.

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Low polarity fraction of Radix Bupleuri alleviates chronic unpredictable mild stress-induced depression in rats through FXR modulating bile acid homeostasis in liver, gut, and brain

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