Abstract / Summary
Background: Glucocorticoid-induced metabolic dysfunction and insulin resistance-related abnormalities are important complications associated with dexamethasone (DEX) exposure. This study investigated the protective effects of montelukast (MNT) against DEX-induced metabolic and hepatic disturbances and characterized associated oxidative, inflammatory, leukotriene-related, and insulin-signaling changes in rats. Methods: Male Wistar rats were allocated to five groups receiving vehicle, MNT (20 mg/kg), DEX (8 mg/kg), or DEX combined with MNT (10 or 20 mg/kg). Glycemic parameters, oral glucose tolerance, lipid profile, liver function biomarkers, oxidative stress indices, inflammatory mediators, leukotriene-related markers, and hepatic histopathological and ultrastructural changes were assessed. Selected insulin-signaling and metabolic markers were evaluated using immunohistochemistry, ELISA-based assays, and Western blotting. Results: DEX administration induced hyperglycemia, hyperinsulinemia, impaired glucose tolerance, increased HOMA2-IR, dyslipidemia, hepatic dysfunction, and histopathological and ultrastructural alterations. These abnormalities were accompanied by oxidative stress and changes in selected molecular markers, including SGK1, AKT, JNK, IRS1, GLUT4, PI3K/FOXO3/PPARγ, GS/PEPCK/GSK, NF-κB/IL-6, NLRP3 abundance, and leukotriene-related markers, including LTD4 and CysLT2, together with alterations in phosphorylation-associated AMPK, PI3K, and ERK1/2 signaling markers. MNT attenuated several DEX-associated metabolic, oxidative, inflammatory, and hepatic abnormalities and modulated these molecular markers. Conclusions: MNT attenuated DEX-associated metabolic and hepatic disturbances in rats, accompanied by modulation of selected SGK1-associated insulin-signaling, metabolic, oxidative, inflammatory, and leukotriene-related markers. These findings support further investigation of MNT in experimental glucocorticoid-associated metabolic dysfunction. However, the molecular findings represent associated alterations rather than definitive evidence of direct pathway activation, target engagement, or causal mechanisms.