As a polyphenol, ellagic acid (EA) has shown potential antidepressant activity. In this study, the effects and serum metabolomic analysis of EA against depression were investigated using a chronic unpredictable mild stress-induced (CUMS) model. EA (20 or 100 mg/kg body weight) significantly ameliorated the CUMS-induced depression-like behaviors, including reduced body weight, decreased sucrose preference, and increased immobility time in both the tail suspension test and the forced swimming test. Furthermore, EA attenuated the CUMS-induced hippocampal damage and significantly increased the brain-derived neurotrophic factor (BDNF) and the serotonin (5-HT) levels as well as suppressed the inflammatory response. The metabolomics analysis showed that the disturbance of glycero­phospholipid (phosphatidyl­ethanolamine and phosphatidyl­inositol), amino acid (l-arginine and N-stearoyl serine), and purine (uric acid) metabolism induced by CUMS was attenuated by the EA treatment. Furthermore, the correlation analysis indicated that the metabolite changes were strongly correlated with behavioral disorders, BDNF, 5-HT, and inflammatory cytokines levels. This study provided new insights for the antidepressant effects of EA and suggests that EA may be a potential nutraceutical for improving the management of depression.

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