Experimental Assessment of the Time-Dependent Protective Effects of Ivermectin Against Atezolizumab-Induced Ovarian Toxicity and Impaired Reproductive Function

Atezolizumab, an immune checkpoint inhibitor, may induce oxidative stress, inflammation, and tissue injury in addition to its antitumor effects. This study investigated the protective effects of ivermectin against atezolizumab-associated ovarian toxicity and their dependence on treatment duration. Four experimental groups comprising six female Wistar albino rats were established: healthy (HG), atezolizumab (ATZ), ivermectin plus atezolizumab for 3 days (IVAZ-3), and ivermectin plus atezolizumab for 6 days (IVAZ-6). Ivermectin was administered orally at 2 mg/kg/day, followed one hour after the final dose by atezolizumab (10 mg/kg, intraperitoneally). Three days after atezolizumab exposure, animals were euthanized with high-dose ketamine. Serum prolactin and anti-Müllerian hormone (AMH) were measured, while ovarian tissues were analyzed for malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β), along with histopathological and immunohistochemical changes. Compared with HG, ATZ increased MDA, TNF-α, and IL-1β and decreased tGSH, SOD, and CAT, with severe ovarian degeneration and increased caspase-3, inducible nitric oxide synthase (iNOS), IL-1β, and microtubule-associated protein-1 light chain 3-beta (LC3B) immunopositivity. IVAZ-3 significantly attenuated these alterations and preserved AMH, whereas most parameters in IVAZ-6 remained comparable to ATZ. Thus, ivermectin exhibited a treatment-duration-dependent protective effect, most pronounced with the 3-day regimen.