Harmine Has Nephroprotective Effect against Methotrexate-Induced Injury in Mice via Inhibition of Oxidative Stress

Background and objectives: Despite clinical use, the efficacy of methotrexate is often limited by some adverse effects, mainly nephrotoxicity. The most common mechanism of methotrexate-induced kidney damages is oxidative stress. Harmine as a plant-derived compound has antioxidant and anti-inflammatory properties, The aim of this study was to evaluate the therapeutic effect of harmine, against methotrexate -induced nephrotoxicity. Methods: The mice were divided into six groups: control (saline only); 20 mg/kg methotrexate; 20 mg/kg harmine, and 20 mg/kg methotrexate + harmine at three doses of 5, 10, or 20 mg/kg. Administrations were intraperitoneally and the treatment period was a 14-days. After this time, the sera and kidneys were collected from each group for the following analyses. Samples were analyzed by hematoxylin-eosin (H&E) staining, qRT-PCR, and biochemical assays. Results: The mice that received methotrexate showed significant increase in creatinine and blood urea nitrogen levels, and 10, or 20 mg/kg harmine mitigated these results. The number and diameter of glomeruli were improved by harmine in methotrexate -treated groups. Moreover, malondialdehyde and nitric oxide levels showed significant increase in the kidney of the mice that received methotrexate, while total antioxidant capacity and superoxide dismutase were diminished. Harmine treatment suppressed oxidative stress markers and also enhanced antioxidant defense parameters. Harmine inhibited methotrexate-induced oxidative stress as shown by the decreased expression of Nqo1, Ho-1, Trx1 and Nrf2 at mRNA level. Harmine also ameliorated histological alterations induced by methotrexate. Conclusion: Our results suggested that harmine has the potential to protect against methotrexate-induced nephrotoxicity.