Chaihu Shugan San alleviates depression-like behavior in rats exposed to chronic unpredictable mild stress by targeting α2δ-1-NR1 complex in hypothalamus.

OBJECTIVE

Chaihu Shugan San (CSS) is a classical traditional Chinese medicine formula widely used in improving depression. The purpose of this study was to investigate the molecular mechanisms underlying the antidepressant effects of CSS.

METHODS

Behavioral experiments and ELISA were employed to assess depressive-like behaviors and measure serum ACTH and CORT levels in chronic unpredictable mild stress (CUMS) rats. Western blotting, immunofluorescence, and Co-Immunoprecipitation were used to analyze α2δ-1 and NMDAR subunit NR1 expression and interactions in the hypothalamus. Cacna2d1 gene knockout and a disruptive peptide (α2δ-1 Tat) were applied in vitro to investigate the α2δ-1-NR1 complex.

KEY FINDINGS: CSS ameliorated depressive-like behaviors in CUMS rats and decreased serum levels of ACTH and CORT. CSS reversed the upregulated expression of α2δ-1 and NR1 in the hypothalamus of CUMS rats, weakening the α2δ-1-NR1 complex binding. When the Cacna2d1 gene was knocked out or the α2δ-1-NR1 complex was disrupted with α2δ-1 Tat peptide, CSS-containing serum failed to significantly enhance NR1 expression in PC12 cells.

CONCLUSION

CSS ameliorates depressive-like behaviors in CUMS rats by interfering with the α2δ-1-NR1 complex, reducing the expression levels of α2δ-1 and NR1 in the hypothalamus, and consequently inhibiting the excessive excitability of the hypothalamic-pituitary-adrenal axis.