Protective effects of melatonin against 5-fluorouracil-induced cardiotoxicity in rats: A comprehensive evaluation of oxidative, inflammatory, and apoptotic pathways

Background: Cardiotoxicity is a serious adverse effect of 5-fluorouracil (5-FU) a common chemotherapeutic agent. This study aimed to evaluate the protective effects of melatonin (MLT) against 5-fluorouracil (5-FU)-induced cardiotoxicity in rats, focusing on oxidative stress, inflammatory pathways, gene expression, electrocardiographic and histopathological changes. Materials and methods: Twenty-five male Wistar rats were divided into five groups. The animals received either MLT at doses of 2.5, 5, or 10 mg/kg/day, 5-FU at 50 mg/kg (i.p.), or a combination of both treatments. Cardiotoxicity was assessed through electrocardiography, cardiac enzymes, oxidative stress markers, and histopathology. Results: 5-FU treatment significantly increased oxidative stress markers and inflammatory mediators while causing histopathological damage in heart tissues. Co-administration of MLT with 5-FU significantly mitigated these effects by reducing oxidative damage, as evidenced by lower levels of malondialdehyde (MDA), nitric oxide (NO), and myeloperoxidase (MPO). Additionally, MLT enhanced antioxidant activity, as reflected by increased levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in heart tissues. Gene expression analysis further confirmed that MLT treatment reduced the elevated levels of COX-2 and VEGF, which are critical players in the inflammatory process. Histopathological examination demonstrated that MLT preserved the structural integrity of myocardial tissues, reducing 5-FU-induced damage score in a dose-dependent manner. Furthermore, MLT co-administration significantly attenuated the rise in cardiac biomarkers, including LDH, AST, and CK-MB, associated with 5-FU-induced cardiotoxicity. Conclusion: These findings highlight that MLT, through its antioxidant and anti-inflammatory properties, exerts a protective effect against 5-FU-induced toxicity, suggesting its therapeutic potential for improving cardiovascular health during chemotherapy.