The potential protective effect of Empagliflozin against Cisplatin-induced ovarian damage via upregulation of SIRT1/Nrf2 and amelioration ER Stress

Cisplatin (Cis) is a chemotherapeutic agent used for several types of malignant tumors. Though, its use causes several adverse effects as ovarian toxicity through its effect on unbalancing antioxidant and oxidants causing oxidative stress and inflammation. The present study aimed to examine the potential protective effect of Empagliflozin (EMPA) on Cisplatin-induced ovarian damage. Forty-four adult female albino rats were divided into four groups: control group, EMPA group (EMPA 10 mg/kg/day, P.O) for 17 days, CIS group (CIS 7 mg/kg, I.P) on day 14, Cis + EMPA group, EMPA (10 mg/kg/day, P.O) for 17 days with CIS (7 mg/kg) on day 14. Oxidative stress markers, inflammatory markers and endoplasmic reticulum stress markers of ovarian tissues, and ovarian SIRTuin-1 (SIRT-1) were analyzed. Histopathological examination of ovaries and capase-9 immunohistochemical staining were also evaluated. CIS significantly increased ovarian oxidative stress markers, ER stress markers and reduced both AMH levels and SIRT-1 expression. Histopathological findings showed ovarian toxicity, necrosis and positive capase-9 immuno-expression. EMPA significantly decreased both oxidative stress and ER stress biomarkers with a significant improvement in the histopathological findings and a decrease in caspase-9 immuno-expression.Accordingly, EMPA protected against CIS-induced ovarian damage by activating both the SIRT-1/NRF2 /caspase-9 pathway and reducing ER stress.