Effects of Flunarizine and Lutein on Atezolizumab-Associated Ovarian Alterations in Rats
7 affiliations
- 1Department of Obstetrics and Gynecology, Konya City Hospital, University of Health Sciences, Konya 42020, Türkiye
- 2Anesthesia Program, Vocational School of Health Services, Erzincan Binali Yıldırım University, Erzincan 24100, Türkiye
- 3Department of Pathological Physiology, Azerbaijan Medical University, Baku AZ 1022, Azerbaijan
- 4Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Türkiye
- 5Department of Pathology, Faculty of Veterinary Medicine, Sivas Cumhuriyet University, Sivas 58140, Türkiye
- 6Laboratory and Veterinary Health Program, Vocational School of Health Services, Osmaniye Korkut Ata University, Osmaniye 80000, Türkiye
- 7Department of Medical Biochemistry, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24100, Türkiye
Abstract
Immune checkpoint inhibitors (ICIs), including atezolizumab, enhance antitumor immune responses by interfering with inhibitory immune checkpoint signaling. Atezolizumab targets programmed death-ligand 1 (PD-L1), thereby disrupting its interaction with programmed death-1 (PD-1). Although ICIs have improved cancer treatment outcomes, their potential associations with ovarian alterations remain insufficiently understood. This study aimed to compare ovarian biochemical, hormonal, histopathological, and immunofluorescence outcomes following the co-administration of flunarizine or lutein with atezolizumab in rats. Twenty-four female Wistar rats were randomly assigned to four groups (n = 6 per group): healthy control (HG), atezolizumab (ATZ), flunarizine plus atezolizumab (FUAZ), and lutein plus atezolizumab (LTAZ). Ovarian oxidative stress markers (MDA, tGSH, SOD, and CAT), inflammatory cytokines (TNF-α and IL-1β), serum anti-Müllerian hormone (AMH) and prolactin levels, histopathological alterations, and immunofluorescence intensities of COX-1, COX-2, IL-1β, and IL-6 were evaluated. Compared with HG, the ATZ group exhibited increased MDA, TNF-α, and IL-1β levels and decreased tGSH, SOD, CAT, and serum AMH levels (p < 0.05). Histopathological examination revealed more pronounced follicular degeneration, parenchymal edema, and hyperemia in the ATZ group, whereas these alterations were milder in the FUAZ group and moderate in the LTAZ group. Immunofluorescence analysis demonstrated reduced COX-1 and increased COX-2, IL-1β, and IL-6 intensities in the ATZ group compared with HG. Both co-administration groups showed higher COX-1 and lower COX-2, IL-1β, and IL-6 intensities than the ATZ group. Several biochemical, histopathological, and immunofluorescence outcomes in the FUAZ group were closer to HG values than those in the LTAZ group. Serum prolactin levels differed significantly only between the ATZ and FUAZ groups in pairwise comparisons. Atezolizumab administration was associated with ovarian oxidative, inflammatory, and histopathological alterations. Co-administration of flunarizine or lutein was associated with differences in several evaluated parameters, with more favorable findings observed in the FUAZ group at the selected doses. However, the absence of appropriate antibody controls and adjunct-only groups limits causal attribution and precludes conclusions regarding independent protective efficacy.
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BibTeX
@article{esenkaya2026effects,
title = {{Effects of Flunarizine and Lutein on Atezolizumab-Associated Ovarian Alterations in Rats}},
author = {Ummugulsum Esenkaya and Esra Tuba Sezgin and Sevinc Haciyeva and Bahadir Suleyman and Mustafa Ozkaraca and Ali Gungor and Taha Abdulkadir Coban and Halis Suleyman},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219862},
url = {https://www.mdpi.com/1422-0067/27/21/9862},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Effects of Flunarizine and Lutein on Atezolizumab-Associated Ovarian Alterations in Rats
AU - Ummugulsum Esenkaya
AU - Esra Tuba Sezgin
AU - Sevinc Haciyeva
AU - Bahadir Suleyman
AU - Mustafa Ozkaraca
AU - Ali Gungor
AU - Taha Abdulkadir Coban
AU - Halis Suleyman
PY - 2026
DA - 2026/11/03
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219862
UR - https://www.mdpi.com/1422-0067/27/21/9862
AB - Immune checkpoint inhibitors (ICIs), including atezolizumab, enhance antitumor immune responses by interfering with inhibitory immune checkpoint signaling. Atezolizumab targets programmed death-ligand 1 (PD-L1), thereby disrupting its interaction with programmed death-1 (PD-1). Although ICIs have improved cancer treatment outcomes, their potential associations with ovarian alterations remain insufficiently understood. This study aimed to compare ovarian biochemical, hormonal, histopathological, and immunofluorescence outcomes following the co-administration of flunarizine or lutein with atezolizumab in rats. Twenty-four female Wistar rats were randomly assigned to four groups (n = 6 per group): healthy control (HG), atezolizumab (ATZ), flunarizine plus atezolizumab (FUAZ), and lutein plus atezolizumab (LTAZ). Ovarian oxidative stress markers (MDA, tGSH, SOD, and CAT), inflammatory cytokines (TNF-α and IL-1β), serum anti-Müllerian hormone (AMH) and prolactin levels, histopathological alterations, and immunofluorescence intensities of COX-1, COX-2, IL-1β, and IL-6 were evaluated. Compared with HG, the ATZ group exhibited increased MDA, TNF-α, and IL-1β levels and decreased tGSH, SOD, CAT, and serum AMH levels (p < 0.05). Histopathological examination revealed more pronounced follicular degeneration, parenchymal edema, and hyperemia in the ATZ group, whereas these alterations were milder in the FUAZ group and moderate in the LTAZ group. Immunofluorescence analysis demonstrated reduced COX-1 and increased COX-2, IL-1β, and IL-6 intensities in the ATZ group compared with HG. Both co-administration groups showed higher COX-1 and lower COX-2, IL-1β, and IL-6 intensities than the ATZ group. Several biochemical, histopathological, and immunofluorescence outcomes in the FUAZ group were closer to HG values than those in the LTAZ group. Serum prolactin levels differed significantly only between the ATZ and FUAZ groups in pairwise comparisons. Atezolizumab administration was associated with ovarian oxidative, inflammatory, and histopathological alterations. Co-administration of flunarizine or lutein was associated with differences in several evaluated parameters, with more favorable findings observed in the FUAZ group at the selected doses. However, the absence of appropriate antibody controls and adjunct-only groups limits causal attribution and precludes conclusions regarding independent protective efficacy.
SN - 1422-0067
ER -