Berberine ameliorates methotrexate-induced liver injury by activating Nrf2/HO-1 pathway and PPARγ, and suppressing oxidative stress and apoptosis in rats

Berberine (BBR) is a natural isoquinoline alkaloid with very impressive health benefits. It is one of the most effective natural supplements available; however, its ameliorative mechanism against methotrexate (MTX)-induced liver injury is not well defined. This study investigated the protective effect of BBR against MTX hepatotoxicity, focusing on its ability to attenuate oxidative stress and apoptosis and to activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and peroxisome proliferator activated receptor gamma (PPAR gamma). Rats received BBR (25 and 50 mg/kg) orally for 7 days before MTX injection. Other groups received MTX followed by BBR (25 and 50 mg/kg) orally for 7 days. MTX-induced rats showed significant body weight loss, increased serum liver function marker enzymes, bilirubin and tumor necrosis factor alpha (TNF-alpha). Liver lipid peroxidation, nitric oxide (NO) and caspase-3 were significantly increased following MTX administration. BBR supplemented either before or after MTX significantly ameliorated body weight, liver function markers, TNF-alpha, lipid peroxidation, NO and caspase-3. BBR increased serum albumin and liver antioxidant defenses in MTX-induced rats. Histological and immunohistochemical examination showed improved histological structure and decreased expression of Bax in liver of MTX-induced rats treated with BBR. In addition, BBR up-regulated Nrf2, HO-1 and PPAR gamma expression in the liver of MTX-induced rats. In conclusion, BBR attenuated MTX-induced oxidative stress and apoptosis, possibly through up-regulating Nrf2/HO-1 pathway and PPAR gamma. Therefore, BBR can protect against MTX-induced liver injury. (C) 2017 Elsevier Masson SAS. All rights reserved.