The ovoprotective effect of quercetin against methotrexate-induced injury by targeting Nrf2 signalling in female rats

Abstract

Although methotrexate (MTX) is a widely used anti-cancer drug in chemotherapy, its clinical use is limited due to its toxicity to many organs, including the ovaries. Quercetin (QUE), a natural flavonol, has known antioxidant and anti-inflammatory effects, but QUE's effects on endoplasmic reticulum stress (ERS) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways in MTX-induced ovotoxicity remain unclear. Therefore, this study was designed to investigate the therapeutic effect of QUE in MTX-exposed rats, including the ERS and Nrf2 signalling pathways. Five groups of six rats were formed as follows: control, MTX (20 mg/kg), MTX+low dose QUE (5 mg/kg), MTX+high dose QUE (10 mg/kg) and only high dose QUE (per se). Colourimetric methods were used to determine the levels of reproductive hormones in serum samples, and markers of oxidative stress (OS), inflammation, ERS, Nrf2 pathway and apoptosis in ovarian tissue. MTX administration resulted in dramatic histopathological findings in ovarian tissue and increased OS, inflammation, ERS and apoptosis associated with Nrf2 inhibition. Conversely, QUE treatment reversed the pathological biochemical and histological changes induced by MTX by modulating the Nrf2 pathway. Taken together, the results of this study provide the first evidences that QUE can ameliorate biochemical and histopathological findings in MTX-induced ovotoxicity. This needs to be supported by more comprehensive mechanistic studies before moving to clinical application.