Dieta suplementada com disseleneto de difenila atenua as alterações bioquímicas e comportamentais no modelo de hipotireoidismo induzido por metimazol

Abstract

Hypothyroidism is a syndrome resulting from decreased production and secretion of triiothyronine (T3) and thyroxine (T4) hormones, frequently diagnosed in women. Clinical and experimental evidence support the association between reduction in thyroid hormones, neuropsychiatric disorders and oxidative stress. Selenium (Se) is a trace element essential to thyroid functions. The present study investigated the effect of diphenyl diselenide supplementation in a model of methimazole-induced hypothyroidism in female rats. We evaluated behavioral parameters related to memory and spatial learning (Article 1) and depressive-like behavior (Manuscript 1). Biochemical parameters were also investigated in relation to oxidative stress, MAO activity and the expression of antioxidant enzymes genes (Manuscripts 1 and 2). In Article 1, we observed a significant effect of diet supplemented with diphenyl diselenide in improving memory and spatial learning deficits in hypothyroid animals undergoing the task of Morris Water Maze. In Manuscript 1 we observed that methimazole-induced hypothyroidism caused a depressive-like behavior assessed in the forced swimming test and that supplementation with diphenyl diselenide caused a reversal of this effect. Furthermore, animals supplemented with diphenyl diselenide performed better in evaluating the antidepressant-like effect. In both (Article 1 and Manuscript 1), there were no motor and/or anxiety alterations, which could interfere with the results. Biochemical parameters in Manuscript 1 and 2 demonstrated that diphenyl diselenide improved analyzes related to oxidative stress (TBARS, ROS and NP-SH) in brain structures and restored the activity of MAO-B (Manuscript 1). In addition, Manuscript 2 evaluated the effects of hypothyroidism and supplementation with diphenyl diselenide on gene expression of antioxidant enzymes and transcription factor NRF-2. The results showed that hypothyroidism caused a significant increase in the expression of antioxidant enzymes, positively correlated to the transcription factor NRF-2. This effect was observed predominantly in the cerebral cortex and hippocampus, whereas supplementation with diphenyl diselenide was effective in normalizing the levels of antioxidant gene expression. Although hypothyroidism has caused a significant increase in gene expression levels of SOD, CAT and GPx were not observed changes in enzyme activity. Finally, the results of this study indicate through different experimental protocols that methimazole-induced hypothyroidism caused a deficit in spatial learning and memory, and depressive-like behavior. In addition, there were changes related to oxidative stress and the regulation of gene expression related to the antioxidant defense system. Diphenyl diselenide presented significant effects in promoting the reversal of behavioral effects and restore the biochemical parameters, and its role in regulating the expression of genes related to antioxidant defense system, adding a new interpretation to its pharmacological effects and demonstrates its potential to treat the complications caused by hypothyroidism.