The beneficial effects of l‐carnitine and infliximab in methotrexate‐induced hepatotoxicity: Emphasis on Notch1/Hes‐1 signaling

Abstract

Methotrexate (MTX)‐induced hepatotoxicity is a serious adverse effect that may limit its use. Therefore, eligible drugs to ameliorate MTX‐induced hepatotoxicity are required. l‐Carnitine (LC) is a natural molecule with beneficial metabolic effects and infliximab (INF) is an anti‐inflammatory monoclonal antibody against tumor necrosis factor‐alpha (TNF‐α). Recently, Notch1/Hes‐1 signaling was found to play a key role in the pathogenesis of liver injury. However, its role in MTX‐induced hepatotoxicity is unclear. This study aimed to evaluate the modulatory effects of LC or INF on MTX‐induced hepatotoxicity and to explore the underlying mechanism with emphasis on the Notch1/Hes‐1 signaling pathway. Sixty rats were randomized into six groups (n = 10): (1) control (saline); (2) MTX (20 mg/kg MTX, intraperitoneal [ip], once); (3) LC group (500 mg/kg ip, 5 days); (4) INF (7 mg/kg INF ip, once); (5) MTX+LC (20 mg/kg ip, once, 500 mg/kg ip, 5 days, respectively); (6) MTX+INF (20 mg/kg ip, once, 7 mg/kg INF ip, once, respectively). Oxidative stress, inflammatory markers, and Notch1/Hes‐1 were investigated. MTX induced the expression of Notch1 and Hes‐1 proteins and increased the levels of TNF‐α, interleukin (IL)‐6, and IL‐1β in the liver. Cotreatment with LC or INF showed apparent antioxidant and anti‐inflammatory effects. Interestingly, the downregulation of Notch1 and Hes‐1 expression was more prominent in LC cotreatment as compared with INF. In conclusion, LC or INF attenuates MTX‐induced hepatotoxicity through modulation of Notch1/Hes‐1 signaling. The LC ameliorative effect against MTX‐induced hepatotoxicity is significantly better than that of INF. Therefore, LC cotreatment may present a safe and therapeutically effective therapy in alleviating MTX‐induced hepatotoxicity.