Protective effects of hesperidin against MTX-induced hepatotoxicity in male albino rats

Hesperidin (HD), a bioflavonoid, has been shown to exert hepatoprotective effects. Our aim is to investigate the possible protective effects of HD against methotrexate (MTX) hepatotoxicity in adult male Sprague-Dawley (SD) rats that were divided into four groups (10 rats/each) and were exposed to MTX with or without HD co-administration for consecutive 28 days. The results showed that HD significantly ameliorated MTX-induced increase in liver enzymes and histopathological changes. Hepatic oxidative stress was suppressed by HD, as evidenced by the decrease in malondialdehyde (MDA), with a concomitant increase in total antioxidant activity (TAC), catalase (CAT), and glutathione (GSH) levels. Moreover, co-administration of HD with MTX remarkably upregulated the expression of Nrf2 and HO-1 compared with the MTX group. By the decrease in nuclear factor-kB (NF-kappa B) pathway and tumor necrosis factor alpha (TNF-alpha), HD obviously attenuated inflammatory response in MTX-lesioned livers. Likewise, the downregulation of P53 by HD could explain its antiapoptotic effects as indicated by increase BCl2 and the significant decrease of caspase-9 mRNA expression as compared with the MTX group. Thus, these findings revealed the hepatoprotective nature of HD against MTX hepatotoxicity by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant aptitude.