Agomelatine Protects Cyclophosphamide-Induced Testicular Tissue Damage Despite HPG Axis Suppression in Rats

Abstract This study aimed to evaluate the prophylactic efficacy of agomelatine (Ago), a potent melatonergic agonist and antioxidant, in preserving testicular integrity against cyclophosphamide (CP)-induced acute toxicity. A preconditioning protocol was established in which rats received Ago (40 mg/kg/day) for 14 consecutive days prior to a single toxic dose of CP (200 mg/kg). The parameters assessed included oxidative stress markers (MDA, GSH-px, SOD, and CAT), inflammatory mediators (TNF-α, IL-1β, and NF-κB), histopathological scores, and the endocrine profile (FSH, LH, and testosterone). CP administration elicited severe oxidative stress, inflammation, and histological degeneration. Ago preconditioning significantly attenuated lipid peroxidation and pro-inflammatory cytokine levels while preserving antioxidant enzyme activities. Furthermore, Ago effectively maintained testicular architecture and sperm concentration. Notably, despite this robust structural protection, significant suppression of serum FSH, LH, and testosterone levels was observed in the Ago-treated groups. Our findings demonstrate that Ago preserves testicular morphology and cellular integrity against CP-induced damage through antioxidant and anti-inflammatory mechanisms. However, this structural protection was accompanied by a significant suppression of the HPG axis at the administered dose. These results indicate that Ago-mediated cytoprotection may occur independently of endocrine homeostasis, underscoring the need for future dose–response studies to identify an optimal therapeutic window that balances peripheral protection with hormonal regulation. Graphical Abstract