Ramelteon Mitigates Cisplatin-induced Testicular Dysfunction in Rats

Cisplatin is a widely used anti-cancer agent, but it can cause testicular dysfunction, leading to infertility and hypogonadism. Currently, pharmacological agents for preventing testicular dysfunction during chemotherapy are limited. Ramelteon, an insomnia medication that selectively targets melatonin receptor type 1 and type 2, exerts cytoprotective effects across organs via anti-inflammatory and anti-apoptotic mechanisms. Ramelteon has an established safety profile in humans; however, its efficacy against chemotherapy-induced testicular toxicity remains unclear. We therefore examined the protective efficacy of ramelteon against cisplatin-induced testicular dysfunction in a rat model.

Male 8-week-old Jcl:Wistar rats were randomized to control (saline+vehicle), ramelteon (10 mg/kg/day orally on days 1-7), cisplatin (7 mg/kg intraperitoneally once on day 1), or cisplatin+ramelteon (n=8 per group). On day 8, blood, testes, and epididymides were collected. Endpoints included sperm parameters, testicular histopathology, Ki-67 immunostaining, serum testosterone, and testicular quantitative polymerase chain reaction (qPCR) for steroid synthesis-related (Star, Cyp11a1, Cyp17a1, Hsd17b3) and apoptosis- and inflammation-related (Casp3, Il6) transcript levels.

Cisplatin administration induced histological damage to the seminiferous tubules, reduced sperm counts and motility, decreased testosterone levels, increased testicular interstitial Ki-67 positivity, suppressed steroid synthesis-related gene expression, and increased apoptosis-related and inflammation-related gene expression. Co-administration of ramelteon significantly attenuated these changes, resulting in reduced pathological tissue damage in the testes, attenuation of deterioration in sperm parameters and testosterone levels, and improvement in steroid synthesis-related and inflammation-related gene expression.

Ramelteon mitigated acute cisplatin-induced testicular damage in rats by attenuating deterioration in sperm parameters and steroidogenesis-related changes. These findings suggest that ramelteon may be a candidate for further investigation as a strategy to mitigate acute chemotherapy-induced testicular injury.