Agmatine Attenuates Methotrexate-Induced Hepatotoxicity: Targeting Oxidative Stress, Inflammation, and Apoptotic...

Drug-induced hepatic insult is the most frequent antecedent of liver dysfunction. The folic acid antagonist, Methotrexate (MTRX), has tremendous applications in the treatment of various tumors, autoimmune disorders, and inflammatory diseases, but hepatotoxicity limits its clinical use. This study aimed to investigate the role of AGM against MTRX-induced hepatotoxicity and its possible underlying mechanistic pathways. Mice were pre-treated with AGM (14 mg/kg, orally) and administered a single injection of MTRX (20 mg/kg, i.p.) on Day 6. MTRX-induced hepatic injury was evidenced by marked increase in serum hepatotoxicity markers, decreased hepatic reduced glutathione (GSH) level and superoxide dismutase (SOD) activity, and hepatic interleukin (IL)-10 content, besides increased levels of malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), IL-6, c-Jun N-terminal kinase (JNK), BCL2-associated X protein (BAX), and Caspase-3. Moreover, MTRX increased hepatic expression of nuclear factor kappa-B (NF-κB), and inducible nitric oxide synthase (iNOS), AGM pretreated group revealed a substantial elevation in hepatic antioxidant markers, besides marked reduction in the serum levels of hepatotoxicity markers and hepatic content of MDA, NO, NF-κB, TNF-α, IL-6, iNOS, JNK, BAX, and Caspase-3. Furthermore, the protective effect of AGM was affirmed by liver histological examination. Therefore, AGM attenuates MTRX's liver injury by mitigating oxidative stress, inflammation, and apoptosis. These findings suggest that AGM could be considered as a potential adjuvant in MTRX-induced toxicity.