, Volume 38, Issue 2, pp 476–484 | Cite as

Thalidomide Ameliorates Cisplatin-Induced Nephrotoxicity by Inhibiting Renal Inflammation in an Experimental Model



Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.


cisplatin nephrotoxicity thalidomide cytokines nitric oxide 



This research was supported by a grant from Ardabil University of Medical Sciences.

Conflict of Interest

There are no conflicts of interest.


  1. 1.
    Lebwohl, D., and R. Canetta. 1998. Clinical development of platinum complexes in cancer therapy: an historical perspective and an update. European Journal of Cancer 34: 1522–1534.PubMedCrossRefGoogle Scholar
  2. 2.
    Miller, R.P., R.K. Tadagavadi, G. Ramesh, and W.B. Reeves. 2010. Mechanisms of cisplatin nephrotoxicity. Toxins (Basel) 2: 2490–2518.CrossRefGoogle Scholar
  3. 3.
    Yao, X., K. Panichpisal, N. Kurtzman, and K. Nugent. 2007. Cisplatin nephrotoxicity: a review. American Journal of Medical Sciences 334: 115–124.CrossRefGoogle Scholar
  4. 4.
    Capizzi, R.L. 1999. Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects. Seminars in Oncology 26: 72–81.PubMedGoogle Scholar
  5. 5.
    Koyner, J.L., R. Sher Ali, and P.T. Murray. 2008. Antioxidants. Do they have a place in the prevention or therapy of acute kidney injury. Nephron Experimental Nephrology 109: e109–e117.PubMedCrossRefGoogle Scholar
  6. 6.
    dos Santos, N.A., M.A. Carvalho Rodrigues, N.M. Martins, and A.C. dos Santos. 2012. Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update. Archives of Toxicology 86: 1233–1250.PubMedCrossRefGoogle Scholar
  7. 7.
    Faubel, S., E.C. Lewis, L. Reznikov, D. Ljubanovic, T.S. Hoke, H. Somerset, D.J. Oh, L. Lu, C.L. Klein, C.A. Dinarello, and C.L. Edelstein. 2007. Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney. Journal of Pharmacology and Experimental Therapeutics 322: 8–15.PubMedCrossRefGoogle Scholar
  8. 8.
    Deng, J., Y. Kohda, H. Chiao, Y. Wang, X. Hu, S.M. Hewitt, T. Miyaji, P. McLeroy, B. Nibhanupudy, S. Li, and R.A. Star. 2001. Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney International 60: 2118–2128.PubMedCrossRefGoogle Scholar
  9. 9.
    Tadagavadi, R.K., and W.B. Reeves. 2010. Endogenous IL-10 attenuates cisplatin nephrotoxicity: role of dendritic cells. Journal of Immunology 185: 4904–4911.CrossRefGoogle Scholar
  10. 10.
    Amirshahrokhi, K., M. Ghazi-khansari, A. Mohammadi-Farani, and G. Karimian. 2010. Effect of captopril on TNF-α and IL-10 in the livers of bile duct ligated rats. Iranian Journal of Immunology 7: 247–251.PubMedGoogle Scholar
  11. 11.
    Ramesh, G., and W.B. Reeves. 2002. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. Journal of Clinical Investigation 110: 835–842.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Chirino, Y.I., and J. Pedraza-Chaverri. 2009. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Experimental and Toxicologic Pathology 61: 223–242.PubMedCrossRefGoogle Scholar
  13. 13.
    Ramesh, G., and W.B. Reeves. 2004. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-alpha. Kidney International 65: 490–499.PubMedCrossRefGoogle Scholar
  14. 14.
    Melchert, M., and A. List. 2007. The thalidomide saga. International Journal of Biochemistry & Cell Biology 39: 1489–1499.CrossRefGoogle Scholar
  15. 15.
    Mondello, S., E. Mazzon, R. Di Paola, C. Crisafulli, P. Mondello, M. Buemi, C. Aloisi, and S. Cuzzocrea. 2009. Thalidomide suppresses sclerosing encapsulating peritonitis in a rat experimental model. Shock 32: 332–339.PubMedCrossRefGoogle Scholar
  16. 16.
    Majumder, S., M. Rajaram, A. Muley, H.S. Reddy, K.P. Tamilarasan, G.K. Kolluru, S. Sinha, J.H. Siamwala, R. Gupta, R. Ilavarasan, S. Venkataraman, K.C. Sivakumar, S. Anishetty, P.G. Kumar, and S. Chatterjee. 2009. Thalidomide attenuates nitric oxide-driven angiogenesis by interacting with soluble guanylyl cyclase. British Journal of Pharmacology 158: 1720–1734.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Amirshahrokhi, K., and M. Ghazi-Khansari. 2012. Thalidomide attenuates multiple low-dose streptozotocin-induced diabetes in mice by inhibition of proinflammatory cytokines. Cytokine 60: 522–527.PubMedCrossRefGoogle Scholar
  18. 18.
    Amirshahrokhi, K. 2013. Anti-inflammatory effect of thalidomide in paraquat-induced pulmonary injury in mice. International Immunopharmacology 17: 210–215.PubMedCrossRefGoogle Scholar
  19. 19.
    El-Naga, R.N. 2014. Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: impact on NOX-1, inflammation and apoptosis. Toxicology and Applied Pharmacology 274: 87–95.PubMedCrossRefGoogle Scholar
  20. 20.
    Pabla, N., and Z. Dong. 2008. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney International 73: 994–1007.PubMedCrossRefGoogle Scholar
  21. 21.
    Ueki, M., M. Ueno, J. Morishita, and N. Maekawa. 2013. D-ribose ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice. Tohoku Journal of Experimental Medicine 229: 195–201.PubMedCrossRefGoogle Scholar
  22. 22.
    Chirino, Y.I., J. Trujillo, D.J. Sánchez-González, C.M. Martínez-Martínez, C. Cruz, N.A. Bobadilla, and J. Pedraza-Chaverri. 2008. Selective iNOS inhibition reduces renal damage induced by cisplatin. Toxicology Letters 176: 48–57.PubMedCrossRefGoogle Scholar
  23. 23.
    Tabata, C., R. Tabata, Y. Kadokawa, S. Hisamori, M. Takahashi, M. Mishima, T. Nakano, and H. Kubo. 2007. Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice. Journal of Immunology 179: 708–714.CrossRefGoogle Scholar
  24. 24.
    Chirino, Y.I., R. Hernandez-Pando, and J. Pedraza-Chaverri. 2004. Peroxynitrite decomposition catalyst ameliorates renal damage and protein nitration in cisplatin-induced nephrotoxicity in rats. BMC Pharmacology 4: 20.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Shimazawa, R., H. Sano, A. Tanatani, H. Miyachi, and Y. Hashimoto. 2004. Thalidomide as a nitric oxide synthase inhibitor and its structural development. Chemical & Pharmaceutical Bulletin (Tokyo) 52: 498–499.CrossRefGoogle Scholar
  26. 26.
    Taliyan, R., and P.L. Sharma. 2012. Possible mechanism of protective effect of thalidomide in STZ-induced-neuropathic pain behavior in rats. Inflammopharmacology 20: 89–97.PubMedCrossRefGoogle Scholar
  27. 27.
    Sahu, B.D., M. Kuncha, G.J. Sindhura, and R. Sistla. 2013. Hesperidin attenuates cisplatin-induced acute renal injury by decreasing oxidative stress, inflammation and DNA damage. Phytomedicine 20: 453–560.PubMedCrossRefGoogle Scholar
  28. 28.
    Gulec, M., M. Iraz, H.R. Yilmaz, H. Ozyurt, and I. Temel. 2006. The effects of ginkgo biloba extract on tissue adenosine deaminase, xanthine oxidase, myeloperoxidase, malondialdehyde, and nitric oxide in cisplatin-induced nephrotoxicity. Toxicology and Industrial Health 22: 125–130.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Pharmacology, School of PharmacyArdabil University of Medical SciencesArdabilIran
  2. 2.Division of Pathology, Imam HospitalArdabil University of Medical SciencesArdabilIran

Personalised recommendations