Evaluation of the Protective Effect of Ramelteon in Methotrexate Induced Nephrotoxicity

Objective: Methotrexate (MTX), which is used as an immunosuppressive and anticancer drug, causes serious toxic side effects in many organs, including the kidney. Activation of apoptotic pathways through oxidative stress is involved in the mechanism of MTX mediated nephrotoxicity. In our study, we investigated the protective effects of ramelteon (RML), an analogue of melatonin, whose antioxidant and antiapoptotic properties are well known, on MTX nephrotoxicity. 
Material and Methods: 32 rats were divided into 4 groups as Control, MTX, MTX+RML and RML. According to the groups, saline or RML (10 mg/kg) was administered by oral gavage for 7 days, and on the 2nd day, 20 mg of MTX or the same volume of saline was administered intraperitoneally according to the groups. At the end of the experiment, the rats were sacrificed and kidney tissues were examined histopathologically with Hematoxylin-Eosin (HE) staining and immunohistochemically (IHC) with caspase-3 and TNF-α staining. In addition, serum BUN, creatinine levels were measured, kidney Total Oxidant and Antioxidant Status (TAS, TOS) levels were studied and Oxidative Stress Index (OSI) was calculated. 
Results: Creatinine, TOS and OSI levels in the MTX group were found to be significantly higher than in the control group. In HE staining, tissue damage was significantly higher in MTX group compared to the control group, and cas-3 and TNF-α staining levels were increased in IHC staining. These findings were found to be reversed in the MTX+RML group. 
Conclusion: We show that RML treatment improves the findings of MTX-induced nephrotoxicity. RML may be a promising drug in MTX nephrotoxicity.