Methotrexate is an effective anticancer and immunosuppressive agent. However, nephrotoxicity is one of the complications of its use. On the other hand, curcumin, a naturally occurring polyphenolic compound, is reported to have antioxidant and anti-inflammatory properties. Those two properties are likely to prevent methotrexate-induced nephrotoxicity. The aim of this study is to evaluate the possible protective effect of curcumin against methotrexate-induced nephrotoxicity and delineate various mechanism(s) underlies this effect in rats. Nephrotoxicity was induced in Wistar rats by intraperitoneal administration of methotrexate (7？mg/kg/day) for three consecutive days. Curcumin administration in methotrexate-intoxicated rats resulted in nephroprotective effects as evidenced by the significant decrease in levels of serum creatinine and urea as well as renal malondialdehyde, nitric oxide, and tumor necrosis factor-α with a concurrent increase in renal glutathione peroxidase and superoxide dismutase activities compared to nephrotoxic untreated rats. Additionally, immunohistochemical analysis demonstrated that curcumin treatment markedly reduced cyclooxygenase-2 expression. Histopathological examination confirmed the protective effects of curcumin. In conclusion, curcumin protected rats from methotrexate nephrotoxicity, at least in part, through its antioxidant and anti-inflammatory activities. 1. Introduction Methotrexate, a folic acid antagonist, is widely used in the treatment of various malignancies and inflammatory diseases. However, nephrotoxicity is an important adverse effect of methotrexate therapy [1]. The pathogenesis of methotrexate nephrotoxicity involves multiple pathways, including oxidative stress and inflammation [2, 3]. Several agents have been used, with various degrees of success, to ameliorate or prevent methotrexate nephrotoxicity [2–4]. Curcumin is an active polyphenolic constituent from Curcuma longa with notable antioxidant and anti-inflammatory properties [5, 6] that render it an attractive candidate for protection against methotrexate nephrotoxicity. Curcumin has shown renal protective properties against gentamicin- and cisplatin- induced renal toxicities ([7] and [8], resp.) as well as diabetic nephropathy [9]. The present study therefore was designed to assess the possible renoprotective effect of curcumin and to examine the underlying mechanism(s) responsible for this effect in a rat model of methotrexate-induced nephrotoxicity. The mechanism of renoprotection was evaluated by assessing the oxidative stress (i.e.,
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