Experimental Assessment of the Time-Dependent Protective Effects of Ivermectin Against Atezolizumab-Induced Ovarian Toxicity and Impaired Reproductive Function.
4 affiliations
- 1Department of Obstetrics and Gynecology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Turkey.
- 2Department of Medical Pharmacology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Turkey.
- 3Department of Biochemistry, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Turkey.
- 4Department of Pathology, Faculty of Veterinary Medicine, Sivas Cumhuriyet University, Sivas 58140, Turkey.
Abstract
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.
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BibTeX
@article{uzun2026experimental,
title = {{Experimental Assessment of the Time-Dependent Protective Effects of Ivermectin Against Atezolizumab-Induced Ovarian Toxicity and Impaired Reproductive Function.}},
author = {Sukran Kozali Uzun and Seval Bulut and Bahadir Suleyman and Renad Mammadov and Taha Abdulkadir Coban and Mustafa Ozkaraca and Halis Suleyman},
journal = {Toxics},
year = {2026},
month = sep,
doi = {10.3390/toxics14100876},
url = {https://europepmc.org/article/MED/42931662},
note = {CC BY},
}
RIS
TY - JOUR
TI - Experimental Assessment of the Time-Dependent Protective Effects of Ivermectin Against Atezolizumab-Induced Ovarian Toxicity and Impaired Reproductive Function.
AU - Sukran Kozali Uzun
AU - Seval Bulut
AU - Bahadir Suleyman
AU - Renad Mammadov
AU - Taha Abdulkadir Coban
AU - Mustafa Ozkaraca
AU - Halis Suleyman
PY - 2026
DA - 2026/09/30
JO - Toxics
DO - 10.3390/toxics14100876
UR - https://europepmc.org/article/MED/42931662
AB - 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.
SN - 2305-6304
ER -