Montelukast attenuates diclofenac sodium-induced cardiotoxicity in male rats via targeting Wnt/β-catenin pathway.

Diclofenac sodium (DCFN) is the most often prescribed NSAID, however its prolonged administration is linked to cardiotoxicity mediated by oxidative stress, inflammation, and apoptosis. The role of the Wnt/β-catenin pathway in cardiac injury is well documented; however, it remains unclear whether this pathway is upregulated in the heart during DCFN treatment. This work aims to investigate the cardiac activity of this pathway in DCFN-intoxicated rats and to explore the potential cardioprotective effects of montelukast (MNTL), a leukotriene receptor antagonist. Four groups of male rats were treated as follows for 14 days: control, MNTL control (20 mg/kg, p.o), DCFN (10 mg/kg, i.m), and DCFN+MNTL. Cardiac injury was assessed by serum biomarkers (cardiac troponin-I, creatine kinase-MB, lactate dehydrogenase, and aspartate aminotransferase), oxidative stress markers (malondialdehyde, glutathione, superoxide dismutase), pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6), as well as apoptotic proteins (Bcl-2 and caspase-3). Protein expression of Wnt-1, active β-catenin, and Frizzled-1 (FZD1) was evaluated, and histological analysis of cardiac tissues was performed. DCFN treatment resulted in significant cardiac injury, characterized by elevated serum cardiac biomarkers, increased oxidative stress and inflammatory cytokines, upregulated apoptotic markers, and overexpression of Wnt-1/active β-catenin and FZD-1. Histological examination revealed myocardial degeneration, vascular compression, and marked inflammatory cell infiltration. Co-treatment with MNTL significantly mitigated these biochemical, molecular, and histopathological alterations. In conclusion, the Wnt/β-catenin pathway is activated in the heart during DCFN treatment, suggesting its possible role in its cardiotoxicity. MNTL effectively attenuates this toxicity, highlighting its potential as a cardioprotective agent during NSAID therapy.