Rutin prevents cisplatin-induced ovarian damage via antioxidant activity and regulation of PTEN and FOXO3a phosphorylation in mouse model

• Published in: Reproductive toxicology (Elmsford, N.Y.) Vol. 98; pp. 209 - 217
• Main Authors: Lins, Thae Lanne B.G., Gouveia, Bruna B., Barberino, Ricássio S., Silva, Regina L.S., Monte, Alane P.O., Pinto, Joisyleide G.C., Campinho, Daniela S.P., Palheta Jr, Raimundo C., Matos, Maria H.T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2020
• Subjects: Chemotherapy; Oocyte; Ovarian function; Oxidative stress; PI3K pathway; Oxidative stress; PI3K pathway; Chemotherapy; Ovarian function; Oocyte
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2020.10.001

[Display omitted] •Rutin increased granulosa cell proliferation in mouse ovarian follicles.•Rutin suppressed caspase-3 activity in the ovary of cisplatin-treated mice.•Rutin prevent ovarian oxidative stress and mitochondrial damage induced by CP.•Rutin attenuates CP toxicity through its antioxidant effects and PTEN/FOXO3a. The aims of the present study were to evaluate the protective effects of rutin during cisplatin-induced ovarian toxicity in mice and to verify the possible involvement of the phosphatase and tension homolog (PTEN)/Forkhead box O3a (FOXO3a) pathway in the rutin actions. Mice received saline solution (control, 0.15 M, i.p.) or cisplatin (5 mg/Kg body weight, i.p.) or they were pretreated with N-acetylcysteine (positive control; 150 mg/Kg of body weight [p.o.]) or with rutin (10, 30 or 50 mg/Kg body weight, p.o.) before cisplatin (5 mg/Kg body weight, i.p.) once daily for 3 days. Next, the ovaries were harvested and destined to histological (follicular morphology and activation), immunohistochemical (cell proliferation and apoptosis) and fluorescence (reactive oxygen species [ROS], glutathione [GSH] and mitochondrial activity) analyses. Moreover, the expression of phosphorylated PTEN (p-PTEN) and FOXO3a (p-FOXO3a) were evaluated to investigate a molecular mechanism by which rutin would prevent the cisplatin-induced ovarian damage. The results showed that pretreatment with N-acetylcysteine or 10 mg/Kg rutin before cisplatin preserved the percentage of normal follicles and cell proliferation, reduced apoptosis and ROS levels and increased active mitochondria and GSH levels compared to the cisplatin treatment (P < 0.05). Cisplatin treatment increased p-PTEN and decreased p-FOXO3a expression in follicles, which was prevented by 10 mg/kg rutin. In conclusion, treatment with 10 mg/Kg rutin has the potential to protect the ovarian follicles against cisplatin-induced toxicity through its antioxidant effects and PTEN/FOXO3a pathway.