Untargeted metabolomics revealed that quercetin improved adrenal gland metabolism disorders and modulated the HPA axis in perimenopausal depression model rats.

Perimenopausal depression is a psychiatric disorder that occurs around the time of menopause and seriously affects women's health. The pathogenesis of perimenopausal depression is unclear which affects its prevention and treatment. Quercetin is a flavonoid compound with antidepressant and estrogen-like effects. The aim of this research was to investigate the role of quercetin on adrenal gland metabolic disorders in perimenopausal depressed rats based on untargeted metabolomics. Female Wistar rats with no difference in sucrose preference were randomly separated into four groups (n = 12): sham-operated group; perimenopausal depression model group; model + 50 mg/kg.bw quercetin group; model + 0.27 mg/kg.bw 17β-estradiol group. After successful modeling, adrenal gland and hypothalamic samples were collected for metabolomics experiments and detection of related indicators. A total of 22 differential metabolites were identified in the model group, and pathway analysis revealed adrenal gland metabolism abnormalities including steroid hormone biosynthesis, arachidonic acid metabolism, and linoleic acid metabolism. Notably, Spearman's rank correlation analysis between differential metabolites and rat behavioral results showed strong positive or negative correlations (P < 0.01). Meanwhile, the hypothalamus of the model group showed TrkB-BDNF signaling pathway abnormality, and the HPA axis was found to play an important role in perimenopausal depression. Treatment with quercetin or 17β-estradiol restored these abnormal changes. It suggested that quercetin can regulate adrenal metabolic disorders through multiple pathways, thereby ameliorating perimenopausal depression.Further more, quercetin can modulate HPA axis through the TrkB-BDNF signaling pathway. This research provides new ideas for the application of quercetin in the precaution and treatment of perimenopausal depression.