Untargeted metabolomics revealed that quercetin improved metabolism dysregulation in the prefrontal cortex of perimenopausal depression rat model

Perimenopausal depression is a subtype of depression and its pathogenesis is still unclear, which affects its prevention and treatment to a certain extent. Prefrontal cortex (PFC) is an advanced center for cognitive and emotional integration, which is intimately connected to the development of perimenopausal depression. Using an untargeted metabolomic analysis, the study attempts to explore whether quercetin can have a protective effect on perimenopausal depression. Female Wistar rats were randomly divided into 4 experimental groups (n=12): the sham group, the model group, the model+17β-estradiol (E 2 ) intervention group (0.27 mg/kg.bw), the model+quercetin intervention group (50 mg/kg.bw). Subsequently, perimenopausal depression rat model was established using ovariectomy (OVX) combined with chronic unpredictable mild stress (CUMS). After the experiment, tissues from PFC were collected for subsequent metabolomic analyses as well as the detection of phospholipase A 2 (PLA2), arachidonate 5-lipoxygenase (ALOX5) and malondialdehyde (MDA). A total of 13 differential metabolites were identified in the model group, and a pathway enrichment analysis indicated that the metabolism disorders of PFC were mainly related to lipid metabolism, amino acid metabolism, and carnitine synthesis. Notably, this study further discovered that lipid metabolism disorders might cause ferroptosis in PFC of rat model with perimenopausal depression. These changes in differential metabolites were normalized after an intervention with quercetin and E 2 , suggesting that quercetin could regulate the metabolic disorders of PFC in perimenopausal depression rat model via exerting the estrogen-like and neuroprotective effect. Quercetin may be a potential adjuvant for perimenopausal depression.