Resveratrol Ameliorates the Anxiety- and Depression-Like Behavior of Subclinical Hypothyroidism Rat: Possible Involvement of the HPT Axis, HPA Axis, and Wnt/β-Catenin Pathway

Abstract

Metabolic disease subclinical hypothyroidism (SCH) is closely associated with depression-like behavior both in human and animal studies, and our previous studies have identified the antidepressant effect of resveratrol (RES) in stressed rat model. The aim of this study was to investigate whether RES would manifest an antidepressant effect in SCH rat model and explore the possible mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization, after which the model rats in the RES and LT4 groups received a daily intragastric injection of RES at the dose of 15 mg/kg or LT4 at the dose of 60 μg/kg for 16 days. The rats’ plasma concentrations of thyroid hormones were measured. Behavioral performance and hypothalamic–pituitary–adrenal (HPA) activity were evaluated. The protein expression levels of the Wnt/β-catenin in the hippocampus were detected by western blot. The results showed that RES treatment downregulated the elevated plasma thyroid-stimulating hormone concentration and the hypothalamic mRNA expression of thyrotropin-releasing hormone in the SCH rats. RES-treated rats showed increased rearing frequency and distance in the open-field test, increased sucrose preference in the sucrose preference test, and decreased immobility in the forced swimming test compared with SCH rats. The ratio of the adrenal gland weight to body weight, the plasma corticosterone levels, and the hypothalamic corticotrophin-releasing hormone mRNA expression were reduced in the RES-treated rats. Moreover, RES treatment upregulated the relative ratio of phosphorylated-GSK3β (p-GSK3β)/GSK3β and protein levels of p-GSK3β, cyclin D1, and c-myc, while downregulating the relative ratio of phosphorylated-β-catenin (p-β-catenin)/β-catenin and expression of GSK3β in the hippocampus. These findings suggest that RES exerts anxiolytic- and antidepressant-like effect in SCH rats by downregulating hyperactivity of the HPA axis and regulating both the HPT axis and the Wnt/β-catenin pathway.

Effect of resveratrol on growth performance, rectal temperature and serum parameters of yellow‐feather broilers under heat stress

“…() reported that supplementation with resveratrol at 400 mg/kg decreased serum COR and beneficially protects broilers against heat stress. Previous study has identified the antidepressant effect of resveratrol in stressed rat model, and results showed that resveratrol downregulates hyperactivity of the HPA axis and regulates hypothalamic–pituitary–thyroid (HPT) axis (Ge, Xu, Qin, Cheng, & Chen, ). Additionally, Supornsilchai, Svechnikov, Seidlova‐Wuttke, Wuttke, and Soder () demonstrated that resveratrol suppresses COR produced and secreted by inhibiting cytochrome P450 c21 hydroxylase researched on primary rat adrenocortical cell cultures in vitro and ex vivo.…”

Brain Beta-Catenin Signalling During Stress and Depression

“…While constant overexpression of beta-catenin is characteristic in cancer [79], changes in beta-catenin levels under depression is dependent upon the region of the brain [16, 17, 29, 46, 69] and not as easily definable as its role in cancer; as such, beta-catenin in depression requires a more varied approach to its investigation. Furthermore, beta-catenin in cancer is closely linked to the mutation of p53 [80, 81], whereas in depression, alterations in beta-catenin levels appears to be more associated with changes in the phosphorylation state of GSK3β and the serotonergic system [16, 17, 62-64].…”

“…However, the exact mechanism by which venlafaxine acts to induce the Wnt signalling pathway is yet unclear [68]. The anti-depressant resveratrol was also shown to downregulate hyperactivity of the HPA axis and upregulate the activity of beta-catenin in the hippocampus of rats suffering from subclinical hypothyroidism [69]. …”

Resveratrol targeting the Wnt signaling pathway: A focus on therapeutic activities

“…This effect may result in the amelioration of inflammation. Overall, Res is capable of modulation of the Wnt signaling pathway to reduce anxiety and depression (Ge et al, ).…”