Investigation of the ovarian damage induced by niraparib and the protective effects of N-acetylcysteine in rats

Poly-ADP-ribose polymerase (PARP) plays a critical role in the repair of damaged DNA. Niraparib, a PARP inhibitor, is an antineoplastic and immunomodulatory agent that selectively induces apoptosis in tumor tissues through PARP inhibition. While it has been approved for maintenance therapy in ovarian cancer and for the treatment of breast cancer in Phase III clinical trials, there is limited literature specifically addressing the extent and nature of ovarian damage caused by niraparib. N-acetylcysteine (NAC), a thiol-containing antioxidant and mucolytic agent, has been safely used in clinical settings since the 1970s. It has also shown efficacy in preserving ovarian function and maintaining circulating hormone levels. This study aimed to experimentally investigate the potential toxic effects of niraparib, a PARP inhibitor, on rat ovarian tissue, and the protective role of NAC against such effects. A total of 30 female rats, obtained from the Experimental Medicine Application and Research Center of Selçuk University, were randomly divided into five groups. Body weights were recorded before and after treatment. Blood samples were collected to assess serum Anti-Müllerian Hormone (AMH) levels. Apoptosis and necrosis in ovarian tissues were analyzed using flow cytometry following Annexin V/PI staining. Additionally, ovarian tissues were examined histopathologically and immunohistochemically. Follicles at six developmental stages (primordial, primary, secondary, preovulatory, antral, and atretic) and corpus luteum structures were evaluated through PCNA immunostaining. VEGF-A expression levels were assessed using VEGF-A antibodies. In conclusion, niraparib did not significantly affect AMH levels, apoptosis or necrosis rates, or the counts of various follicular stages and corpus luteum in rat ovaries. However, VEGF-A expression was found to be decreased in the low-dose niraparib group and increased in the high-dose group. Since niraparib did not impair ovarian reserve or increase apoptotic and necrotic cell death, it may be inappropriate to attribute a definitive protective role to NAC in these contexts. Nevertheless, NAC appeared to mitigate congestion and edema induced by low-dose niraparib, as well as follicular cell degeneration observed with high-dose niraparib.