Edaravone alleviates methotrexate-induced testicular injury in rats: Implications on inflammation, steroidogenesis, and Akt/p53 signaling

Edaravone (ED) is a neuroprotective drug with beneficial effects against several disorders due to its prominent antioxidant activity. However, its effect against methotrexate (MTX)-induced testicular damage was not previously investigated. Therefore, we aimed to investigate the ability of ED to prevent the oxidative stress, inflammation, and apoptosis induced by MTX on the rat testis and to examine whether ED administration modulated the Akt/p53 signaling and steroidogenesis process. Rats were allocated into; Normal, ED (20 mg/kg, PO, for 10 days), MTX (20 mg/kg, i.p., on the 5^th day), and ED + MTX groups. The results showed that MTX group exhibited higher serum activities of ALT, AST, ALP, and LDH in addition to histopathological alterations in the rat testis, compared to normal group. Furthermore, MTX induced down-regulation of the steroidogenic genes; StAR, CYP11a1, and HSD17B3 and reduced FSH, LH, and testosterone levels. The MTX group also showed higher levels of MDA, NO, MPO, NF-kB, TNF-α, IL-6, IL-1β, Bax, and caspase 3, as well as, lower levels of GSH, GPx, SOD, IL-10, Bcl2 compared to normal rats, p < 0.05. In addition, MTX treatment resulted in increased p53 expression and decreased p-Akt expression. Remarkably, ED administration significantly prevented all the biochemical, genetic, and histological damage induced by MTX. Hence, ED treatment protected the rat testis from apoptosis, oxidative stress, inflammation, and impaired steroidogenesis induced by MTX. This novel protective effect was mediated by decreasing p53 while increasing p-Akt protein expression.