Synergistic benefits of melatonin and therapeutic exercise as a unified strategy for managing stroke and doxorubicin-induced cardiotoxicity

Sookyoung ParkZeeshan Ahmad KhanYunkyung HongJinhee ShinTserentogtokh LkhagvasurenSeunghoon LeeYonggeun Hong^*

• Inje University, Gimhae, Republic of Korea

Introduction: Epidemiological studies highlight a significant occurrence of ischemic strokes in cancer patients, particularly in the elderly, where stroke and systemic cancer are the leading causes of death. This comprehensive study investigates the combined effect of melatonin (MT) and exercise (Ex) against stroke, and a chemotherapeutic drug doxorubicin (Dox)-induced cardiotoxicity (DIC). Method: This study employs two models—middle cerebral artery occlusion (MCAo) and DIC—to evaluate the synergistic effects of MT+Ex. For both models, rats were assigned to the same treatment groups (n=5 per group): control, vehicle, MT (10 mg/kg, twice daily), Ex (10 m/min for 30 min/day), and combined MT+Ex after either MCAo or DIC. The treatments were administered for 4 weeks. Significance was determined using one-way ANOVA. Results: In the MCAo model, the MT+Ex group showed a significant reduction in brain infarct volume and neurological deficits compared to control animals (p<0.01). Western blot analysis revealed downregulation of molecular markers associated with neuronal damage and enhanced neuronal growth in the treatment group (p<0.01). Additionally, the MT+Ex group exhibited a higher density of dendritic spines and a progressive increase in neurite crossing at days 14 and 28, compared to both MT and Ex groups (p<0.01). In the DIC model, both MT and Ex treatments provided cardioprotection, while the combined MT+Ex group demonstrated a significantly greater protective effect against heart weight loss and histopathological damage compared to controls (p<0.01). Also, pretreatment of MT significantly improves the cell viability compared to both Veh and resveratrol but its effect on beating frequency of cardiomyocytes was similar to resveratrol. Conclusion: MT+Ex reduced brain infarct volume and neurological deficits, enhanced neuronal growth, and provided superior cardioprotection, preventing heart weight loss and histopathological damage. This study is the first to show synergistic protective action of MT and Ex against stroke and DIC, contributing key insights into an interplay between neurological and cardiovascular health and addressing multifaceted challenges posed by stroke, and anticancer interventions.