Protective Effect of Melatonine Against Radiation Induced Nephrotoxicity in Rats

  • Kucuktulu, Eda (Dept. of Radiation Oncology, Trabzon Kanuni Training and Research Hospital) ;
  • Yavuz, Aydin Ali (Department of Radiation Oncology, Akdeniz University) ;
  • Cobanoglu, Umit (Department of Pathology, Karadeniz Technical University) ;
  • Yenilmez, Engin (Department of Histology and Embryology, Karadeniz Technical University) ;
  • Eminagaoglu, Selcuk (Department of Biochemistry, Karadeniz Technical University) ;
  • Karahan, Caner (Department of Biochemistry, Karadeniz Technical University) ;
  • Topbas, Murat (Department of Public Health, Karadeniz Technical University) ;
  • Kucuktulu, Uzer (General Surgery, Karadeniz Technical University)
  • Published : 2012.08.31


Purpose: The degree of radiation injury to kidneys which are located within the limits of radiotherapy area is determined by the volume and the dose of radiation to which the organ is exposed. When the tolerance dose of the kidney is exceeded after a latent period of 6 months acute nephritis develops and after 18 months chronic nephritis ensues. Melatonin is known to prevent the oxidative injury of toxins and radiotherapy with its free radical scavenging capacity. Methods and Materials: In this study 8 weeks old 24 Sprague -Dawley rats were allocated into 4 groups: Control group; Radiotherapy group (20 Gy bilaterally in 5 fractions); Melatonin group (10 mg/kg intraperitoneally), and Melatonin+radiotherapy group (20 Gy Radiotherapy in 5 fractions+ melatonin 10 mg/kg intraperitoneally). After a follow-up period of 6 months BUN was determined in all groups. After rats were euthanized the kidneys were removed for histopathological examination under both light and electron microscopes. Results: After 6 months follow-up, both at light and electron microscopy levels, the rats in radiotherapy+melatonin group were significantly protected against the radiation injury comparing to radiotherapy group (p<0.05). Conclusion: It was shown in this experimental model that melatonin has protective effects against radiation injury to kidneys.


  1. Andreassen CN, Grau C, Lindegoard JC (2003). Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy. Seminars in Radiation Oncology, 13, 62-72.
  2. Blask DE, Sauer LA, Dauchy RT (2002). Melatonin as a chronobiotic/anticancer agent: cellular, biochemical and molecular mechanisms of action and their implications for circadian-based cancer therapy. Current Topics in Medicinal Chemistry, 2, 113-32.
  3. Blickenstaff RT, Brandstadter SM, Reedy S (1994). Potential radioprotective agents: 1. homologs of melatonin. J Pharm Sci, 83, 216-8.
  4. Bohle A, Mackensen-Haen S, Gise H (1990). The consequences of tubulo-interstitial changes for renal function in glomerulopathies. Pathol Res Pract, 186, 135-44.
  5. Bornman MS, Oosthuizen JMC, Barnard HC (1989). Melatonin and sperm motility. Andrologia, 21, 483-5.
  6. Brzenzinski A, Seibel MM, Lynch HJ (1987). Melatonin in human preovulatory folicular fluid. J Clin Endocrinal, 64, 865-7.
  7. Casado-Zapico S, Rodringuez-Blanco J, Garcia-Santos G (2010). Synergistic antitumor effect of melatonin with several chemotherapeutic drugs on human ewing sarcoma cancer cells: potentiation of the extrinsic apoptotic pathway. J Pineal Res, 48, 72-80.
  8. Claustrat B, Geoffriau M, Brun J (1995). Melatonin in humans: a biochemical marker of the circadian clock and an endogenous synchronizer. Neurophysiol Clin Sci, 2, 351-9.
  9. Cohen EP, Robbins EC (2003). Radiation nephropathy. Seminars in Nephrology, 23, 486-99.
  10. Cos S, Mediavilla MD, Fernandez R (2002). Melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro. J Pineal Res, 32, 90-4.
  11. Edwards JC, Chapman D, Cramp WA (1984). The effects of ionizing radiation on biomembrane structure and function. Prog Biophys Mol Biol, 43, 71-93.
  12. Glatstein E, Fajanda LF, Brown JM (1977). Radiation injury in the mouse kidney-I sequential light microscopic study. Int J Radiat Oncol Biol Phys, 2, 933-43.
  13. Hara M, Yoshida M, Nishijima H (2001). Melatonin: a pineal secretory product with antioxidant properties, protects against cisplatin-induced nephrotoxicity in rats. J Pineal Res, 30, 129-38.
  14. Hedlund L, Lischko MM, Rollag MD (1976). Melatonin cycle in plasma and cerebrospinal fluid of calves. Science, 195, 686-7.
  15. Jongejan HTM, Van Der Kogel AJ, Provoost AP (1987). Radiation Nephropathy in Young and Adult Rats. Int J Radiat Oncol Biol Phys, 13, 225-32.
  16. Kennaway DJ, Voultsios A (1998). Circadian rhythm of free melatonin in human plasma. J Clin Endocrinol Metab, 83, 1013-5.
  17. Kunkler PB, Farr RF, Luxton RW (1952). The limit of renal tolerance to X rays. Br J Radiol, 25, 190-201.
  18. Luxton, Kunkler (1964). Radiation nephritis. Acta Radiol, 2, 169-78.
  19. Madrazo AA, Churg J (1976). Radiation nephritis. Chronic changes following moderate doses of radiation. Lab Invest, 34, 283-90.
  20. Majsterek I, Gloc E, Blasiak J (2005). A comparison of the action of amifostine and melatonin on DNA damaging effects and apoptosis induced by idarubicin in normal and cancer cells. J Pineal Res, 38, 254-63.
  21. Manda K, Bhatia AL (2003). Melatonin-induced reduction in age-related accumulation of oxidative damage in mice. Biogerontology, 4, 133-9.
  22. Martinez-Cayuela M (1955). Oxygen free radicals and human disease. Biochimie, 77, 147-61.
  23. Nair CKK, Parida DK, Nomura T (2001). Radioprotectors in Radiotherapy. J Radiat Res, 42, 21-37.
  24. Nowak R, McMillen JC, Redman J (1987). The correlation between serum and salivary melatonin concentrations and urinary 6-hydroxymelatonin sulphate excretion rates: Two non-invasive techniques for monitoring human circadian rhythmicity. Clin Endocrinol, 27, 445-52.
  25. Ong ACM, Fine LG (1994). Tubular-derived growth factors and cytokines in the pathogenesis of tubulointerstitial firosis : Implications for human renal disease progression. Am J Kidney, 23, 205-9.
  26. Pardridge WM, Meitus LJ (1980). Transport of albumin-bound melatonin through the blood-brain barrier. J Neurochem, 34, 1761-3.
  27. Perez CA, Halperin EC (2008). Principles and Practice of Radiation Oncology, ed 5. Lippincott Williams and Wilkins; Philadelphia.
  28. Reiter RJ (1986). Normal patterns of melatonin levels in thepineal gland and body fluids of humans and experimental animals. J Neural Transm, 21, 35-54.
  29. Reiter RJ, Tan DX, Manchester LC (2001). Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: A review of the evidence. Cell Biochem Biophys, 34, 237-56.
  30. Robbins MEC, Stephens LC, Thames HD (1994). Radiation response of the monkey kidney following controlateral nephrectomy. Int J Radiat Oncol Biol Phys, 30, 347-54.
  31. Robbins MEC, Wooldridge MJA, Jaenke RS (1991). A morphological study of radiation nephropathy in the pig. Radiat Res, 126, 317-27.
  32. Rodriguez C, Mayo JC, Sainz RM (2004). Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res, 36, 1-9.
  33. Rodringuez-Garcia A, Mayo JC, Hevia D (2012). Phenotypic changes caused by melatonin increased sensitivity of prostate cancer cells to cytokine-induced apoptosis. J Pineal Res, 31.
  34. Rousseau A, Petren S, Planntin J (1999). Serum and cerebrospinal fluid concentrations of melatonin : a pilot study in healthy male volunteers. J Neural Transm, 106, 883-8.
  35. Russcher M, Koch B, Nagtegaal E (2012). The role of melatonin treatment in chronic kidney disease. Front Biosci, 17, 2644-56.
  36. Shaw PF, Kennaway DJ, Seamark RF (1989). Evidence of high concentrations of melatonin in lateral ventricular cerebrospinal fluid of sheep. J Pineal Res, 6, 201-8.
  37. Shirazi A, Ghobadi G, Ghazi-Khansari M (2007). A radiobiological review on melatonin: a novel radioprotector. J Radiat Res, 48, 263-72.
  38. Snyder SH, Axelrod J (1967). Circadianrhythm in the serotonin content in the pineal gland: Regulating factors. J Pharmacol Exp Ther, 158, 206-13.
  39. Stephens LC, Robbins MEC, Thames HD (1995). Radiation nephropathy in the rhesus monkey: morphometric analysis of glomerular and tubular alterations. Int J Radiat Oncol Biol Phys, 31, 865-73.
  40. Tan DX, Manchester LC, Reiter J (1999). High physiological levels of melatonin in bile of mammals. Life Sci, 65, 523-9.
  41. Vakkuri O (1985). Diurnal rhythm of melatonin in human saliva. Acta Physiol Scand, 124, 409-12.
  42. Verma SP, Sonwalker N (1991). Structural changes in plasma membranes prepared from irradiated Chinese hamster V79 cells as revealed by raman spectroscopy. Radiat Res, 126, 27-35.
  43. Vijayalaxmi ML, Reiter RJ, Herman TS (1999). Melatonin and Protection from Genetic Damage in Blood and Bone Marrow: Whole Body Irradiation Studies in Mice. J Pineal Res, 27, 221-5.
  44. Vijayalaxmi ML, Reiter RJ, Sewerynek E (1995). Marked Reduction of Radiation Induced Micronuclei in Human Blood Lymphocytes Pre-treated with Melatonin. Radiat Res, 143, 102-6.
  45. Vijayalaxmi ML, Reiter RJ, Tan DX (2004). Melatonin as a radioprotective agent: a review. Int J Radiation Oncology Biol Phys, 59, 639-53.
  46. Wang YM, Jin BZ, Ai F (2012). The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol, 69, 1213-20.
  47. Zaki EL, Springate JE, Taub M (2003). Comparative toxicity of ifosfamide metabolites and protective effects of mesna and amifostine in cultured renal tubular cells. Toxicology in Vitro, 17, 397-402.
  48. Zhang B, Su Y, Wang Y (2005). Involvement of Peroxiredoxin I in Protecting Cells from Radiation-Induced Death. J Radiation Res, 46, 305-12.

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