Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice1

Abstract

Cisplatin administration induces DNA damage resulting in germ cell apoptosis and subsequent testicular atrophy. Although 50 percent of male cancer patients receiving cisplatin-based chemotherapy develop long-term secondary infertility, medical treatment to prevent spermatogenic failure after chemotherapy is not available. Under normal conditions, testicular p53 promotes cell cycle arrest, which allows time for DNA repair and reshuffling during meiosis. However, its role in the setting of cisplatin-induced infertility has not been studied. Ghrelin administration ameliorates the spermatogenic failure that follows cisplatin administration in mice, but the mechanisms mediating these effects have not been well established. The aim of the current study was to characterize the mechanisms of ghrelin and p53 action in the testis after cisplatin-induced testicular damage. Here we show that cisplatin induces germ cell damage through inhibition of p53-dependent DNA repair mechanisms involving gamma-H2AX and ataxia telangiectasia mutated protein kinase. As a result, testicular weight and sperm count and motility were decreased with an associated increase in sperm DNA damage. Ghrelin administration prevented these sequelae by restoring the normal expression of gamma-H2AX, ataxia telangiectasia mutated, and p53, which in turn allows repair of DNA double stranded breaks. In conclusion, these findings indicate that ghrelin has the potential to prevent or diminish infertility caused by cisplatin and other chemotherapeutic agents by restoring p53-dependent DNA repair mechanisms.

Effect of ghrelin on total antioxidant capacity, lipid peroxidation, sperm parameters and fertility in mice against oxidative damage caused by cyclophosphamide

“…However, administration of ghrelin in mice treated with CP indicated that the ghrelin prevents the reduction in body weight and epididymis. In support of our findings, Garcia et al reported that ghrelin prevents decreased body weight and sexual organs of mice treated with cisplatin (Garcia et al, 2015). This protective effect of ghrelin could be attributed to the antioxidant activity of ghrelin under oxidative stress conditions.…”

Synergistic effect of melatonin and ghrelin in preventing cisplatin‐induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27Kip1 promoter in primordial follicles

“…Our research focuses on developing adjuvants to preserve fertility in female cancer patients. Studies have shown that melatonin and ghrelin provide partial protection against cisplatin‐induced damage to the ovaries and testes . However, the administration of either drug alone does not provide adequate protection against cisplatin‐induced infertility and the effect of ghrelin on the ovaries remains uncharacterized.…”

Rutin ameliorates cisplatin-induced reproductive damage via suppression of oxidative stress and apoptosis in adult male rats

“…Our results showed that CP treatment caused significant decrease in TTW, sperm motility, dead sperm rate, mid‐sperm abnormality, tail sperm abnormality and total sperm abnormality while only a numerical decrease in sperm cell density was observed when compared to control group. Our results were compatible with findings of several researchers (Ateşşahin et al ., ; Turk et al ., ; Rezvanfar et al ., ; Aksu et al ., ; Garcia et al ., ; Kaya et al ., ) and ratified the spermiotoxic effects of CP. RUT treatment mitigated some of mentioned spermatological parameters including sperm motility, dead sperm rate, mid‐sperm abnormality, tail sperm abnormality and total sperm abnormality.…”

“…To reduce side effects of the drug, usage of antioxidant compounds may be beneficial and important strategy for protecting of male fertility along chemotherapy period. CP treatment causes decrease in testis weight, sperm density, sperm motility, live sperm rate (Ateşşahin et al ., ; Turk et al ., ; Rezvanfar et al ., ; Aksu et al ., ; Garcia et al ., ), enzymatic or nonenzymatic antioxidant levels in testes (Ateşşahin et al ., ; Turk et al ., ; Rezvanfar et al ., ; Kaya et al ., ; Saral et al ., ) and degenerations in testicular tissue (Ateşşahin et al ., ; Turk et al ., ; Kaya et al ., ; Saral et al ., ). Although above‐mentioned researchers preferred different treatment procedures (as pre‐treatment, post‐treatment or combined treatment), we preferred pre‐treatment for 10 days and post‐treatment for 4 days with RUT from CP injection to avoid time‐dependent healing in studied parameters.…”