Biochemical, Immunohistochemical and Behavioral Effects of Spexin in a Methimazole-Induced Hypothyroidism Rat Model

Hypothyroidism is associated with metabolic, neurobehavioral, and reproductive alterations that may involve neuroendocrine regulatory peptides. Spexin, a neuropeptide implicated in energy homeostasis, has recently attracted attention for its possible role in thyroid and reproductive axis regulation. Therefore, this study aimed to investigate the effects of spexin on neurobehavioral responses and the tissue-specific expression of irisin and KISS-1 in the cerebral cortex and testis under hypothyroid conditions. Thirty-two male Wistar albino rats were randomly divided into four groups: Control, Hypothyroid (methimazole, 0.03% in drinking water for 35 days), Hypothyroid + Spexin (methimazole plus spexin, 25 µg/kg, intraperitoneally), and Spexin (25 µg/kg, intraperitoneally). Behavioral assessments were performed using the Open Field Test and Forced Swim Test. Serum thyroid hormone levels were analyzed, and brain and testis tissues were evaluated immunohistochemically for irisin and KISS-1 expression. Hypothyroid rats showed increased thyroid-stimulating hormone levels, decreased thyroxine concentrations. Spexin administration significantly reduced TSH levels and increased T4 concentrations. Spexin treatment reduced thigmotaxis compared to controls. No significant differences were found among groups in overall locomotor activity, time spent in the central zone, or FST parameters. Immunohistochemical analyses demonstrated reduced irisin and KISS-1 expression in hypothyroid rats, which was restored following spexin treatment. In conclusion, spexin exerted TSH-suppressive and T4-enhancing effects in experimental hypothyroidism. Its effects on irisin and KISS-1 expression suggest potential involvement in neuroendocrine and reproductive axis regulation.