Implication of Wnt/GSK-3β/β-Catenin Signaling in the Pathogenesis of Mood Disturbances Associated with Hyperthyroidism in Rats: Potential Therapeutic Effect of Naringin.

Abstract

Patients with hyperthyroidism are commonly diagnosed with mood disorders. Naringin, (4',5,7-trihydrocyflavanone-7-O-rhamnoglucoside), a natural bioflavonoid, has many neurobehavioral activities including anxiolytic and antidepressant properties. The role of Wingless (Wnt) signaling in psychiatric disorders is considered substantial but debatable. Recently, regulation of Wnt signaling by naringin has been reported in different disorders. Therefore, the present study aimed to investigate the possible role of Wnt/GSK-3β/β-catenin signaling in hyperthyroidism-induced mood disturbances and explore the therapeutic effects of naringin. Hyperthyroidism was induced in rats by intraperitoneal injection of 0.3 mg/kg levothyroxine for 2 weeks. Naringin was orally administered to rats with hyperthyroidism at a dose of 50 or 100 mg/kg for 2 weeks. Hyperthyroidism induced mood alterations as revealed by behavioral tests and histopathological changes including marked necrosis and vacuolation of neurons in the hippocampus and cerebellum. Intriguingly, hyperthyroidism activated Wnt/p-GSK-3β/β-catenin/DICER1/miR-124 signaling pathway in the hippocampus along with an elevation in serotonin, dopamine, and noradrenaline contents and a reduction in brain-derived neurotrophic factor (BDNF) content. Additionally, hyperthyroidism induced upregulation of cyclin D-1 expression, malondialdehyde (MDA) elevation, and glutathione (GSH) reduction. Naringin treatment alleviated behavioral and histopathological alterations and reversed hyperthyroidism-induced biochemical changes. In conclusion, this study revealed, for the first time, that hyperthyroidism could affect mental status by stimulating Wnt/p-GSK-3β/β-catenin signaling in the hippocampus. The observed beneficial effects of naringin could be attributed to increasing hippocampal BDNF, controlling the expression of Wnt/p-GSK-3β/β-catenin signaling as well as its antioxidant properties.