JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE)

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Study on changes of hippocampal bile acid receptors in the depression mouse mod

WU Jing, LI Xue-yi, CHEN Jing-hong, WANG Ze-jian   

  1. 1. Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China; 2. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine,Shanghai 200030, China
  • Received:2021-03-08 Published:2021-09-23
  • Contact: WANG Ze-jian, E-mail: wangzejian@sjtu.edu.cn.
  • Supported by:
    Shanghai Key Laboratory of Psychotic Disorders Research Fund (13dz2260500).

Abstract: Objective·To explore the changes of bile acid receptors in hippocampi of depression mouse models. Methods·Thirty female C57 BL/6 mice with the age of 4 weeks were randomly divided into control(CON, n=10) group, chronic unexpected mild stress(CUMS, n=10) group and dexamethasone(DEX, n=10) group. CUMS group mice were treated with different CUMS every day, DEX group mice were administered with DEX(0.2 mg/kg) by oral gavage twice a day, and CON group and CUMS group were given equal volumes of CMC-Na(solvent) by oral gavage every day. The treatments lasted for 5 weeks, and the mice were weighed once a week. After modeling, the forced swimming test, the tail suspension test and the sucrose preference test were applied to detect the depression-like behavior in mice. After the mice being sacrificed, the hippocampus and the other organs were separated and weighed. The expressions of brain-derived neurotrophic factor(BDNF), farnesoid X receptor(FXR) and G protein-coupled bile acid receptor 1(GPBAR1, also TGR5) in the hippocampus were evaluated by Western blotting. The serum levels of fibroblast growth factor 15(FGF15) and cholecystokinin(CCK) were detected by ELISA kits. Meanwhile, in the rat glioma cell line(C6) incubated with different concentrations of DEX, the expressions of FXR and TGR5 were detected by Western blotting, and the levels of BDNF and glial cell line-derived neurotrophic factor(GDNF) in the cell culture medium were detected by ELISA kits. The ROS assay kit was used to detect intracellular oxidative stress levels. C6 cells were pretreated with5 mmol/L N-acetyl-L-cysteine(NAC) for 2 h, and the effects of DEX on bile acid receptors were observed. Results·Compared with CON group, both DEX group and CUMS group had decreased sucrose preference, prolonged immobility time in the forced swimming test and the tail suspension test(P<0.05) and greater organ relative mass of gallbladder(P<0.05). The level of serum FGF15 in DEX group was significantly higher than that in CON group,but significantly lower in CUMS group(P<0.05); the level of CCK in CUMS group was significantly higher than that in CON group(P<0.05).Additionally, in the hippocampi of the two different depression models, the protein levels of TGR5 and FXR decreased and increased, respectively(P<0.05). The 200 μmol/L and 400 μmol/L DEX increased the expression of FXR, while significantly inhibited the expression of TGR5 in C6 cells; the levels of GDNF and BDNF(BDNF only in 400 μmol/L group) significantly decreased(P<0.05) in the culture medium. DEX at 200 μmol/L significantly increased the levels of ROS in the C6 cells. The cells pretreated with NAC partially reversed the overexpression of FXR and the low expression of TGR5 induced by DEX. Conclusion·The similar changes of bile acid receptors, i. e. decreased TGR5 and increased FXR, are found in the hippocampi of depression mouse models induced by CUMS and DEX, respectively. These changes may be related to the elevated level of oxidative stress.

Key words: depression, bile acid metabolism, bile acid receptor, hippocampus, oxidative stress

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