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.