Coreopsis tinctoria Nutt. Polyphenols Ameliorate CUMS-Induced Depressive Behaviors and Hippocampal Neuronal Damage in Mice

Chronic stress-induced mood disturbances have become a prominent public health concern, and dietary polyphenols are emerging as natural nutritional strategies for mood health management. The capitula of Coreopsis tinctoria Nutt. (CCT) are edible flowers rich in polyphenols, but their mood-supporting efficacy remains unclear. This study investigated the effects, mechanisms, and key bioactive constituents of CCT polyphenol extract (CCTE) in a chronic unpredictable mild stress (CUMS) mouse model. High-dose CCTE (1 g/kg) restored sucrose preference from 30.9% ± 4.1% in CUMS mice to 52.0% ± 5.5%, increased week-6 weight gain from 4.7% ± 2.4% to 38.8% ± 5.9% (p < 0.001), and restored open-field rearing, central-area crossings, and residence time to fluoxetine-comparable levels, indicating dose-dependent attenuation of CUMS-induced depressive-like behaviors. It also ameliorated hippocampal neuronal damage, corrected the CUMS-induced 36.7% reduction in serum 5-HT and 44.8% elevation in 5-HIAA, attenuated hypothalamic-pituitary-adrenal (HPA) hyperactivity, particularly reducing elevated CRH, ACTH, and CORT levels, alleviated oxidative stress, and suppressed NLRP3 inflammasome-driven neuroinflammation via NLRP3/NF-κB downregulation. Three flavonoid aglycones-okanin (OKA), isookanin (ISO), taxifolin (TAX)-crossed the blood-brain barrier (free C max 28.45 ± 10.9, 32.74 ± 27.3, 32.04 ± 6.9 ng/g; T max 20-45 min) and inhibited monoamine oxidase A (MAO-A; IC50 38.66 ± 2.45, 48.23 ± 3.12, 47.28 ± 2.98 μmol/L); their equimolar mixture acted synergistically (IC50 18.79 ± 1.67 μmol/L; pargyline 8.71 ± 1.21 μmol/L, p < 0.001). Thus, CCTE ameliorates stress-induced mood disturbances through multi-target regulation and shows potential as a functional food ingredient.