Melatonin and agomelatine alleviate ivermectin-induced mouse spermatogonia apoptosis via suppression of oxidative stress and calcium overload.

Introduction: Drug toxicity poses a significant threat to male fertility, and its mechanism is often associated with redox imbalance and mitochondrial dysfunction. Ivermectin (IVM), an anthelmintic increasingly explored for new therapeutic applications, induces apoptosis and impairs proliferation in spermatogonia via mitochondria-associated cellular injury at high concentrations in vitro. This study evaluated the protective effects of melatonin, agomelatine, and pinoline, as mitochondria-directed cytoprotectants. Methods: Cultured type B spermatogonia were pretreated with 1 μM melatonin, agomelatine, or pinoline for 24 h under low-serum conditions, followed by exposure to 16 μM IVM. Cell proliferation was assessed by cell counting and Ki67 immunocytochemistry. Mechanistic analyses included fluorescence imaging of reactive oxygen species (ROS) using 2',7'-dichlorodihydrofluorescein diacetate, cytosolic Ca Results: Unlike pinoline, melatonin and agomelatine effectively suppressed IVM-induced oxidative stress and Ca Conclusion: Melatonin and agomelatine protect the male reproductive system from drug-induced toxicity by restoring redox homeostasis and mitochondrial function. These findings provide mechanistic insight into melatonin-based therapeutic strategies and the development of fertility preserving agents targeting mitochondria-mediated cellular injury.