Investigation of the Effects of Silymarin on Ovarian Ischemia Reperfusion via Nrf‐2/HO‐1/NQO1, Ki‐67 and Wnt Signaling Pathways

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Abstract
Ovarian ischemia is a pathological condition that usually occurs due to ovarian torsion, resulting in the interruption of blood supply to the ovaries and oxygen deficiency. Silymarin (SLM) is a flavonoid complex of plant origin with pharmacological properties such as antioxidant, anti‐inflammatory, and antiapoptotic effects. In this study, we investigated the effects of SLM through different pathways in rats subjected to experimental ovarian ischemia/reperfusion (I/R). Female Wistar rats were divided into five groups: Control, SLM (50 mg/kg), I/R, I/R + SLM25 (25 mg/kg), and I/R + SLM50 (50 mg/kg). SLM was given orally for 7 days, followed by ischemia (2 h) and reperfusion (2 h) on day 8. Biochemical (MDA, GSH, SOD, CAT, GPx) and histological (H&E, Ki‐67 IHC) analyses were performed. Also, molecular (qRT‐PCR) analyses were performed to evaluate oxidative stress, inflammation, apoptosis, and Wnt signaling. I/R increased MDA and NO levels in ovarian tissue while decreasing SOD, CAT, GPx, and GSH. Antioxidant defense genes (Nrf‐2, HO‐1, NQO1) were suppressed, and inflammation markers (NF‐ĸB, IL‐1β, TNF‐α) along with apoptotic markers (Bax, Caspase‐3) were elevated, while Bcl‐2 decreased. The Wnt signaling pathway was inhibited, particularly at Wnt‐3A, LRP5, Dvl‐2, and Cyclin‐1, reducing Ki‐67 protein levels and IHC positivity. Silymarin has shown a therapeutic effect on ovarian ischemia reperfusion injury with its antioxidant, antiapoptotic and anti‐inflammatory effects and cell cycle regulatory activity.

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