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.

Jin-Fang Ge,Ya-Yun Xu,Gan Qin,Fei-Hu Chen,Jiang-Qun Cheng

doi:10.3389/fendo.2016.00044

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.

Highlights

Imbalances in thyroid hormone homeostasis are associated with both functional and structural brain alterations, resulting in neurobehavioral alterations, including depression [1, 2]
We explored the antidepressant effects of RES in Subclinical hypothyroidism (SCH) rats
The results showed that RES treatment could alleviate anxiety- and depression-like behavior in SCH rats, as indicated by their increased rearing frequency and moving distance in the open-field test (OFT), their elevated sucrose preference index, and their decreased immobility in the forced swimming test (FST)

Summary

Introduction

Imbalances in thyroid hormone homeostasis are associated with both functional and structural brain alterations, resulting in neurobehavioral alterations, including depression [1, 2]. Subclinical hypothyroidism (SCH) is defined as an elevated plasma thyroid-stimulating hormone (TSH) level associated with normal total or free thyroxine (fT4) and triiodothyronine (T3) levels. The hypometabolism symptoms, including fatigue, weakness, and cold intolerance, are dormant and nonspecific in SCH patients, increasing evidence suggests that SCH is associated with neuropsychiatric disorders such as cognitive dysfunction [2] and depression [3, 4]. Clinical studies have demonstrated that treatment with levothyroxine (LT4) improves mood and normalizes the elevated relative cerebral glucose metabolism in several brain areas of depression patients [7, 8]. The unpredictable clinical effects of the currently available antidepressants, including poor efficacy and adverse reactions, make the development of new drugs to alleviate depression in SCH patients an urgent clinical need

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