Preventive role of mirtazapine in methotrexate induced nephrotoxicity in rats

Methotrexate (MTX) is used in the treatment of rheumatic diseases, psoriasis, and cancer. Since more than 90% of MTX is excreted via the kidneys, nephrotoxicity is one of the most important reasons restricting the use of this drug. In our study, we aimed to evaluate biochemical and histopathological properties to determine whether mirtazapine has a protective effect on MTX-related nephrotoxicity in rats. A group of rats were given a dose of 30 mg/kg of mirtazapine orally through a tube and 1 h after a dose of 5 mg/kg of MTX intraperitoneally. The rats in the control group received MTX alone intraperitoneally. A group of healthy rats was given orally distilled water in equal volume as dissolvent, then distilled water was administered intraperitoneally 1 h later. These procedures were repeated for 7 days. At the end of this period, all animals were sacrificed by giving a high dose of sodium thiopental. The results of biochemical analysis revealed that in the kidney tissues of rats given MTX, malondialdehyde, myeloperoxidase, glutathione, glutathione 5-transferase, and nitric oxide levels were 42.3 +/- 2.4 mu mol/g protein, 31.3 +/- 1.9 U/g, 6.5 +/- 1.0 nmol/g protein, 5.7 +/- 0.8 U/g, and 14.7 +/- 1.2 mu mol/g, respectively; in the mirtazapine group, these values were found to be 24.2 +/- 1.9 pmol/g protein, 19.7 +/- 1.8 U/g, 11.5 +/- 1.3 nmol/g protein, 10.5 +/- 1.1 U/g, and 25.2 +/- 2.7 mu mol/g, respectively. No biomarkers for protein nitrosylation, nitration, or DNA damage were measured. In this study mirtazapine was found to be efficacious to prevent nephrotoxicity due to MTX, suggesting that MTX can be used safely in higher doses and for a longer course in combination with mirtazapine in cancer chemotherapy.