Comparative Protective Effects of Melatonin and Apigenin Against Paclitaxel-Induced Testicular Injury in Rats: Oxidative Stress, DNA Damage, Apoptosis, and NF-κB Signaling

Background: Paclitaxel is a widely used chemotherapeutic agent whose clinical efficacy is limited by gonadotoxic side effects. Oxidative stress, apoptosis, and inflammation are key mechanisms underlying paclitaxel-induced testicular injury. This study aimed to comparatively evaluate the protective effects of melatonin and apigenin in a rat model. Methods: Adult male Sprague-Dawley rats were randomly assigned to seven groups: control, solvent control, melatonin, apigenin, paclitaxel, paclitaxel + melatonin, and paclitaxel + apigenin. Testicular malondialdehyde (MDA) and reduced glutathione (GSH) levels were measured, together with apoptotic activity (caspase-3), oxidative DNA damage (8-OHdG), inflammatory signaling (NF-κB/p65, immunoreactivity), and histopathological alterations (Johnsen score). Results: Paclitaxel significantly increased MDA levels and decreased GSH content, accompanied by elevated caspase-3, 8-OHdG, and NF-κB/p65 immunoreactivity, as well as marked degeneration of seminiferous tubules. Melatonin improved redox balance, suppressed apoptotic and inflammatory responses, and preserved testicular architecture. Apigenin reduced lipid peroxidation and improved antioxidant status in paclitaxel-treated rats while decreasing GSH levels under basal conditions without inducing histological damage, suggesting a context-dependent redox-modulating effect. Both agents significantly improved Johnsen scores compared with paclitaxel alone. Conclusions: Paclitaxel-induced testicular injury is mediated by a coordinated interplay of oxidative stress, apoptosis, inflammation, and structural degeneration. Melatonin and apigenin effectively mitigate these processes, with apigenin exhibiting context-dependent antioxidant activity. These findings suggest that melatonin and apigenin may serve as adjunctive strategies for preserving male reproductive function during chemotherapy.