Coreopsis Polyphenols Reverse Stress-Related Depression Signals in Mice

A polyphenol-rich extract from the flowering plant Coreopsis tinctoria reduced several behavioral and biological signs of chronic stress in mice, according to a study in Food Science & Nutrition. Researchers gave the purified extract, known as CCTE, to male mice exposed to six weeks of chronic unpredictable mild stress, or CUMS, and compared their responses with those of untreated stressed animals and a group receiving fluoxetine. The strongest effects occurred at the highest tested dose, 1 gram per kilogram of body weight, suggesting that the plant compound acts through several interconnected pathways rather than a single molecular target. The findings establish a preclinical basis for further investigating the plant’s capitula, the flower heads used in food processing and traditional medicine, as a source of functional ingredients for mood support.

The experiment involved 72 clean-grade ICR mice divided equally among six groups. Except for an unstressed control, each animal was housed alone and exposed to one of 13 unpredictable challenges on a rotating schedule. These included food and water deprivation, wet bedding, cold-water swimming, restraint, tail pinching, disrupted light-dark cycles, heat exposure, noise, shaking and cohabitation with another mouse. The protocol was intended to reproduce several features of chronic stress, including anhedonia, impaired weight gain and behavioral withdrawal. Weekly sucrose-preference and open-field tests tracked motivation, locomotion, exploration and anxiety-like behavior, while fluoxetine at 0.01 gram per kilogram served as the pharmacological positive control.

Stress markedly changed the mice’s behavior, but the deficits were attenuated by CCTE in a broadly dose-dependent manner. At the end of modeling, sucrose preference fell to 30.9% in stressed mice receiving water, compared with 70.6% in controls, indicating loss of interest in a rewarding solution. The extract increased this measure to 45.3%, 48.3% and 52.0% at doses of 0.25, 0.5 and 1 gram per kilogram, respectively; fluoxetine produced a value of 48.1%. High-dose CCTE also restored aspects of open-field behavior, including rearing, crossings of the central area and time spent in that region. No experimental deaths occurred, and the extract also counteracted the stress-related suppression of weight gain.

Molecular measurements showed that CCTE affected both serotonin metabolism and the stress-hormone system. Relative to controls, CUMS lowered serotonin, or 5-HT, in serum by 36.7% and in brain tissue by 27.6%, while increasing its major metabolite, 5-hydroxyindoleacetic acid, by 44.8% in serum and 24.6% in brain tissue. High-dose CCTE substantially restored the brain measures, reducing the deficit in 5-HT to about 15.6% and the excess in its metabolite to about 10.5%. The same dose lowered serum corticotropin-releasing hormone, adrenocorticotropic hormone and corticosterone, indicating reduced hyperactivity of the hypothalamic-pituitary-adrenal axis. These hormonal changes were comparable in magnitude to those caused by fluoxetine.

The extract also shifted biomarkers associated with inflammation and oxidative stress. Chronic stress raised circulating interleukin-1β, interleukin-6, tumor necrosis factor-α and nuclear factor kappa-B, while high-dose CCTE lowered all four relative to stressed controls. In brain tissue, stress reduced superoxide dismutase activity, increased malondialdehyde, a marker of lipid peroxidation, and altered catalase and glutathione levels. High-dose CCTE increased superoxide dismutase by roughly 80% relative to the stressed group, reduced malondialdehyde by about 34%, and normalized the other two indicators. The authors interpret the elevated catalase in stressed animals as a compensatory response to oxidative burden rather than evidence of greater protection, because treatment brought it back toward the control level while strengthening other antioxidant measures.

Protection extended to the hippocampus, a brain region closely linked to learning, memory and stress responses. Histological examination revealed disorganized neurons, shrunken cell bodies, pale cytoplasm, condensed nuclei and neuronal loss in the CA1, CA3 and dentate gyrus regions of stressed mice. Counts of intact neurons in those areas had fallen by approximately 47%, 61% and 67%, respectively. High-dose CCTE increased intact-neuron counts by about 78%, 138% and 172% relative to stressed controls, bringing the values to roughly 90–93% of unstressed levels. Nissl staining, which visualizes structures associated with neuronal health, showed a parallel recovery in staining intensity, cellular alignment and the number of Nissl-positive neurons.

At the molecular level, the treatment appeared to restrain two linked inflammatory systems in hippocampal tissue. CUMS increased expression of the NLRP3 inflammasome components NLRP3, apoptosis-associated speck-like protein containing a CARD, caspase-1 and interleukin-1β. High-dose CCTE reduced their immunoreactivity by approximately 31% to 57% compared with stressed animals, with an overall effect similar to fluoxetine. It also suppressed phosphorylated nuclear factor kappa-B p65, phosphorylated inhibitor kappa-B-alpha and cleaved caspase-3, a marker of apoptosis. The combined pattern is consistent with a coordinated interruption of NF-κB-driven inflammatory priming, NLRP3 inflammasome activation and neuronal cell-death signaling, although the experiments did not directly manipulate these targets to prove that each was necessary for the behavioral effect.

LC-MS/MS analysis offered a more specific explanation for how CCTE might influence the brain. After oral administration, only three of the extract’s 11 major polyphenols were detected in brain tissue: the flavonoid aglycones okanin, isookanin and taxifolin. Five flavonoid glycosides and three phenolic acids were not detected, a pattern consistent with their greater polarity and molecular weight restricting passage across the blood-brain barrier. Okanin and isookanin reached peak brain concentrations after about 45 minutes, while taxifolin peaked after 20 minutes. Enzymatic treatment revealed that the compounds were present largely as glucuronide or sulfate conjugates, and measurable levels of okanin and isookanin remained at 240 minutes. The aglycones may also be generated when intestinal enzymes remove sugar groups from larger glycosides before absorption.

All three brain-accessible compounds inhibited monoamine oxidase A, the enzyme responsible for oxidative deamination of serotonin, in laboratory assays. Their half-maximal inhibitory concentrations were 38.66 micromolar for okanin, 48.23 micromolar for isookanin and 47.28 micromolar for taxifolin. An equimolar mixture was more potent than any compound alone, with a half-maximal inhibitory concentration of 18.79 micromolar, indicating a supra-additive interaction in the test system. The mechanism-specific reference inhibitor pargyline was more potent, at 8.71 micromolar. Because whole-brain concentrations were below the individual assay thresholds, the researchers cautioned that local accumulation in mitochondria-rich presynaptic terminals, along with synergy and the extract’s anti-inflammatory and antioxidant effects, may be important in vivo. The study therefore supports a multi-target model, but it does not establish CCTE as a treatment for human depression or establish a safe and effective dietary dose.

Several limitations constrain translation. The CUMS model reproduces selected features of stress-related mood disturbance but cannot capture the full heterogeneity of human depression. Most mechanistic analysis focused on the hippocampus, and the findings were largely correlational rather than based on genetic or cell-specific tests of causality. The extract is also a complex mixture whose other components may act through peripheral routes or contribute indirectly to central effects. Before CCTE could be positioned as a functional food ingredient, researchers would need to assess raw-material safety, digestion and bioavailability, determine an appropriate human dietary equivalent, and conduct clinical studies. The immediate advance is mechanistic rather than clinical: the study connects a chemically defined plant extract to measurable improvements in stress-exposed mice and identifies brain-penetrant compounds whose combined effects may help explain those improvements.

Subject of Research: Effects of Coreopsis tinctoria polyphenols on stress-related mood and hippocampal injury in mice

Article Title: Coreopsis tinctoria Nutt. Polyphenols Ameliorate CUMS‐Induced Depressive Behaviors and Hippocampal Neuronal Damage in Mice

Article References: Han, H., Feng, Y., Wang, Z., Ma, R., Sun, J., Yang, X., Cui, Y., Wang, J., & Jia, M. (2026). Coreopsis tinctoria Nutt. Polyphenols Ameliorate CUMS ‐Induced Depressive Behaviors and Hippocampal Neuronal Damage in Mice. Food Science & Nutrition, 14(10), Article e72480. https://doi.org/10.1002/fsn3.72480

Image Credits: AI Generated

DOI: 10.1002/fsn3.72480

Keywords: Coreopsis tinctoria, polyphenols, depression, chronic stress, hippocampus, serotonin, MAO-A, neuroinflammation, oxidative stress, mouse model, Coreopsis, tinctoria