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Mediators of Inflammation
Volume 2015, Article ID 859383, 12 pages
Research Article

Mechanisms of Thymoquinone Hepatorenal Protection in Methotrexate-Induced Toxicity in Rats

1Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
2Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
3Department of Biochemistry, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
4Department of Histology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt

Received 9 January 2015; Revised 5 May 2015; Accepted 13 May 2015

Academic Editor: Giuseppe Valacchi

Copyright © 2015 Azza A. K. El-Sheikh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


To investigate mechanisms by which thymoquinone (TQ) can prevent methotrexate- (MTX-) induced hepatorenal toxicity, TQ (10 mg/kg) was administered orally for 10 days. In independent rat groups, MTX hepatorenal toxicity was induced via 20 mg/kg i.p. at the end of day 3 of experiment, with or without TQ. MTX caused deterioration in kidney and liver function, namely, blood urea nitrogen, creatinine, alanine aminotransferase, and aspartate aminotransferase. MTX also caused distortion in renal and hepatic histology, with significant oxidative stress, manifested by decrease in reduced glutathione and catalase, as well as increase in malondialdehyde levels. In addition, MTX caused nitrosative stress manifested by increased nitric oxide, with upregulation of inducible nitric oxide synthase. Furthermore, MTX caused hepatorenal inflammatory effects as shown by increased tumor necrosis factor-α, besides upregulation of necrosis factor-κB and cyclooxygenase-2 expressions. MTX also caused apoptotic effect, as it upregulated caspase 3 in liver and kidney. Using TQ concurrently with MTX restored kidney and liver functions, as well as their normal histology. TQ also reversed oxidative and nitrosative stress, as well as inflammatory and apoptotic signs caused by MTX alone. Thus, TQ may be beneficial adjuvant that confers hepatorenal protection to MTX toxicity via antioxidant, antinitrosative, anti-inflammatory, and antiapoptotic mechanisms.