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Molecular Medicine

, Volume 15, Issue 1–2, pp 43–50 | Cite as

Melatonin: An Established Antioxidant Worthy of Use in Clinical Trials

  • Ahmet Korkmaz
  • Russel J. Reiter
  • Turgut Topal
  • Lucien C. Manchester
  • Sukru Oter
  • Dun-Xian Tan
Review Article

Abstract

Oxidative stress plays a key role in the pathogenesis of aging and many metabolic diseases; therefore, an effective antioxidant therapy would be of great importance in these circumstances. Nutritional, environmental, and chemical factors can induce the overproduction of the superoxide anion radical in both the cytosol and mitochondria. This is the first and key event that leads to the activation of pathways involved in the development of several metabolic diseases that are related to oxidative stress. As oxidation of essential molecules continues, it turns to nitrooxidative stress because of the involvement of nitric oxide in pathogenic processes. Once peroxynitrite forms, it damages via two distinctive mechanisms. First, it has direct toxic effects leading to lipid peroxidation, protein oxidation, and DNA damage. This mechanism involves the induction of several transcription factors leading to cytokine-induced chronic inflammation. Classic antioxidants, including vitamins A, C, and E, have often failed to exhibit beneficial effects in metabolic diseases and aging. Melatonin is a multifunctional indolamine that counteracts virtually all pathophysiologic steps and displays significant beneficial actions against peroxynitrite-induced cellular toxicity. This protection is related to melatonin’s antioxidative and antiinflammatory properties. Melatonin has the capability of scavenging both oxygen- and nitrogen-based reactants, including those formed from peroxynitrite, and blocking transcriptional factors, which induce proinflammatory cytokines. Accumulating evidence suggests that this nontoxic indolamine may be useful either as a sole treatment or in conjunction with other treatments for inhibiting the biohazardous actions of nitrooxidative stress.

References

  1. 1.
    Harman D. (2006) Free radical theory of aging, an update: increasing the functional life span. Ann. N. Y. Acad. Sci. 1067:10–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Harman D. (2003) The free radical theory of aging. Antioxid. Redox. Signal. 5:557–61.PubMedCrossRefGoogle Scholar
  3. 3.
    de Grey AD. (2006) Free radicals in aging: causal complexity and its biomedical implications. Free Radic. Res. 40:1244–9.PubMedCrossRefGoogle Scholar
  4. 4.
    O’Keefe JH Jr, Cordain L. (2004) Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer. Mayo Clin. Proc. 79:101–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Diczfalusy E. (2006) Our common future: a rapidly growing and rapidly aging humankind. Aging Male 9:125–34.PubMedCrossRefGoogle Scholar
  6. 6.
    Eisenberg DM, et al. (1998) Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA 280:1569–75.PubMedCrossRefGoogle Scholar
  7. 7.
    Woo JJ. (2007) Adverse event monitoring and multivitamin-multimineral dietary supplements. Am. J. Clin. Nutr. 85:323S–4S.CrossRefGoogle Scholar
  8. 8.
    Muntwyler J, Hennekens CH, Manson JE, Buring JE, Gaziano JM. (2002) Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Arch. Intern. Med. 162:1472–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Ascherio A, et al. (1999) Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Ann. Intern. Med. 130:963–70.PubMedCrossRefGoogle Scholar
  10. 10.
    Lonn E, et al. (2002) Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care 25:1919–27.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Ward NC, et al. (2007) The effect of vitamin E on blood pressure in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. J. Hypertens. 25:227–34.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. (2003) Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 361:2017–23.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Miller ER 3rd, et al. (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann. Intern. Med. 142:37–46.PubMedCrossRefGoogle Scholar
  14. 14.
    Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297:842–57.PubMedCrossRefGoogle Scholar
  15. 15.
    Ceriello A. (2006) Controlling oxidative stress as a novel molecular approach to protecting the vascular wall in diabetes. Curr. Opin. Lipidol. 17:510–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Beckman JS, Koppenol WH. (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am. J. Physiol. 271:C1424–37.Google Scholar
  17. 17.
    Pacher P, Beckman JS, Liaudet L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87:315–424.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Weidig P, McMaster D, Bayraktutan U. (2004) High glucose mediates pro-oxidant and antioxidant enzyme activities in coronary endothelial cells. Diabetes Obes. Metab. 6:432–41.PubMedCrossRefGoogle Scholar
  19. 19.
    Cooke CL, Davidge ST. (2002) Peroxynitrite increases iNOS through NF-kappaB and decreases prostacyclin synthase in endothelial cells. Am. J. Physiol. Cell Physiol. 282:C395–402.CrossRefGoogle Scholar
  20. 20.
    Stockklauser-Farber K, Ballhausen T, Laufer A, Rosen P. (2000) Influence of diabetes on cardiac nitric oxide synthase expression and activity. Biochim. Biophys. Acta 1535:10–20.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Moncada S, Palmer RM, Higgs EA. (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43:109–42.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Dedon PC, Tannenbaum SR. (2004) Reactive nitrogen species in the chemical biology of inflammation. Arch. Biochem. Biophys. 423:12–22.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Joshi MS, et al. (2002) Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions. Proc. Natl. Acad. Sci. U. S. A. 99:10341–6.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Forstermann U, Munzel T. (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113:1708–14.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Demicheli V, Quijano C, Alvarez B, Radi R. (2007) Inactivation and nitration of human superoxide dismutase (SOD) by fluxes of nitric oxide and superoxide. Free Radic. Biol. Med. 42:1359–68.CrossRefGoogle Scholar
  26. 26.
    Alvarez B, Radi R. (2003) Peroxynitrite reactivity with amino acids and proteins. Amino Acids 25:295–311.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Alvarez B, Radi R. (2001) Peroxynitrite decay in the presence of hydrogen peroxide, mannitol and ethanol: a reappraisal. Free Radic. Res. 34:467–75.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Szabo C. (2003) Multiple pathways of peroxynitrite cytotoxicity. Toxicol. Lett. 140–141:105–12.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Okamoto T, et al. (2001) Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation. J. Biol. Chem. 276:29596–602.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Wu J, et al. (2001) Enhanced vascular permeability in solid tumor involving peroxynitrite and matrix metalloproteinases. Jpn. J. Cancer Res.. 92:439–51.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Whang YE, et al. (1998) Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc. Natl. Acad. Sci. U. S. A. 95:5246–50.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Juedes MJ, Wogan GN. (1996) Peroxynitrite-induced mutation spectra of pSP189 following replication in bacteria and in human cells. Mutat. Res. 349:51–61.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Masuda M, Nishino H, Ohshima H. (2002) Formation of 8-nitroguanosine in cellular RNA as a biomarker of exposure to reactive nitrogen species. Chem. Biol. Interact. 139:187–97.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Tamir S, deRojas-Walker T, Wishnok JS, Tannenbaum SR. (1996) DNA damage and genotoxicity by nitric oxide. Methods Enzymol. 269:230–43.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Yoshie Y, Ohshima H. (1997) Nitric oxide syner-gistically enhances DNA strand breakage induced by polyhydroxyaromatic compounds, but inhibits that induced by the Fenton reaction. Arch. Biochem. Biophys. 342:13–21.PubMedCrossRefGoogle Scholar
  36. 36.
    Chaturvedi N, et al. (1998) Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 351:28–31.PubMedCrossRefGoogle Scholar
  37. 37.
    Yermilov V, Yoshie Y, Rubio J, Ohshima H. (1996) Effects of carbon dioxide/bicarbonate on induction of DNA single-strand breaks and formation of 8-nitroguanine, 8-oxoguanine and base-propenal mediated by peroxynitrite. FEBS Lett. 399:67–70.PubMedCrossRefGoogle Scholar
  38. 38.
    Chien YH, Bau DT, Jan KY. (2004) Nitric oxide inhibits DNA-adduct excision in nucleotide excision repair. Free Radic. Biol. Med. 36:1011–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Virag L, Szabo E, Gergely P, Szabo C. (2003) Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol. Lett. 140–141:113–24.PubMedCrossRefGoogle Scholar
  40. 40.
    Szabo C. (2006) Poly(ADP-ribose) polymerase activation by reactive nitrogen species—relevance for the pathogenesis of inflammation. Nitric Oxide 14:169–79.PubMedCrossRefGoogle Scholar
  41. 41.
    Korkmaz A, Yaren H, Topal T, Oter S. (2006) Molecular targets against mustard toxicity: implication of cell surface receptors, peroxynitrite production, and PARP activation. Arch. Toxicol. 80:662–70.PubMedCrossRefGoogle Scholar
  42. 42.
    Korkmaz A, Topal T, Oter S. (2007) Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol. Toxicol. 23:303–12.PubMedCrossRefGoogle Scholar
  43. 43.
    Yaren H, et al. (2007) Lung toxicity of nitrogen mustard may be mediated by nitric oxide and peroxynitrite in rats. Res. Vet. Sci. 83:116–22.PubMedCrossRefGoogle Scholar
  44. 44.
    Korkmaz A, et al. (2005) Peroxynitrite may be involved in bladder damage caused by cyclophosphamide in rats. J. Urol. 173:1793–6.PubMedCrossRefGoogle Scholar
  45. 45.
    de la Lastra CA, Villegas I, Sanchez-Fidalgo S. (2007) Poly(ADP-ribose) polymerase inhibitors: new pharmacological functions and potential clinical implications. Curr. Pharm. Des. 13:933–62.PubMedCrossRefGoogle Scholar
  46. 46.
    Korkmaz A, et al. (2008) Effects of poly(ADP-ribose) polymerase inhibition in bladder damage caused by cyclophosphamide in rats. Exp. Biol. Med. (Maywood) 233:338–43.CrossRefGoogle Scholar
  47. 47.
    Tan DX, et al. (2003) Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J. Pineal Res. 34:75–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Reiter RJ, et al. (2007) Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv. Med. Sci. 52:11–28.PubMedGoogle Scholar
  49. 49.
    Reiter RJ, Tan DX, Burkhardt S. (2002) Reactive oxygen and nitrogen species and cellular and organismal decline: amelioration with melatonin. Mech. Ageing Dev. 123:1007–19.PubMedCrossRefGoogle Scholar
  50. 50.
    Reiter RJ, Tan DX, Allegra M. (2002) Melatonin: reducing molecular pathology and dysfunction due to free radicals and associated reactants. Neuro. Endocrinol. Lett. 23(Suppl 1):3–8.PubMedGoogle Scholar
  51. 51.
    Reiter RJ, et al. (2003) Melatonin: detoxification of oxygen and nitrogen-based toxic reactants. Adv. Exp. Med. Biol. 527:539–48.PubMedCrossRefGoogle Scholar
  52. 52.
    Lopez-Burillo S, Tan DX, Mayo JC, Sainz RM, Manchester LC, Reiter RJ. (2003) Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and alpha-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: a study of their individual and synergistic actions. J. Pineal Res. 34:269–77.PubMedCrossRefGoogle Scholar
  53. 53.
    Sudnikovich EJ, et al. (2007) Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats. Eur. J. Pharmacol. 569:180–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Gilad E, Cuzzocrea S, Zingarelli B, Salzman AL, Szabo C. (1997) Melatonin is a scavenger of peroxynitrite. Life Sci. 60:PL169–74.PubMedCrossRefGoogle Scholar
  55. 55.
    Ucar M, et al. (2007) Melatonin alleviates lung damage induced by the chemical warfare agent nitrogen mustard. Toxicol. Lett. 173:124–31.PubMedCrossRefGoogle Scholar
  56. 56.
    Topal T, et al. (2005) Melatonin ameliorates bladder damage induced by cyclophosphamide in rats. J. Pineal Res. 38:272–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. (2007) One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J. Pineal Res. 42:28–42.CrossRefGoogle Scholar
  58. 58.
    Reiter RJ, Tan DX, Terron MP, Flores LJ, Czarnocki Z. (2007) Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions. Acta. Biochim. Pol. 54:1–9.PubMedGoogle Scholar
  59. 59.
    Reiter RJ, et al. (2008) Biogenic amines in the reduction of oxidative stress: melatonin and its metabolites. Neuro Endocrinol. Lett. 29:391–8.PubMedGoogle Scholar
  60. 60.
    Peyrot F, Houee-Levin C, Ducrocq C. (2006) Melatonin nitrosation promoted by NO*2; comparison with the peroxynitrite reaction. Free Radic. Res. 40:910–20.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang H, Squadrito GL, Uppu R, Pryor WA. (1999) Reaction of peroxynitrite with melatonin: a mechanistic study. Chem. Res. Toxicol. 12:526–34.PubMedCrossRefGoogle Scholar
  62. 62.
    Soung DY, et al. (2004) Peroxynitrite scavenging activity of indole derivatives: interaction of indoles with peroxynitrite. J. Med. Food 7:84–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Rodriguez C, et al. (2004) Regulation of antioxidant enzymes: a significant role for melatonin. J. Pineal Res. 36:1–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Reiter RJ, Tan DX, Maldonado MD. (2005) Melatonin as an antioxidant: physiology versus pharmacology. J. Pineal Res. 39:215–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Winiarska K, Fraczyk T, Malinska D, Drozak J, Bryla J. (2006) Melatonin attenuates diabetes-induced oxidative stress in rabbits. J. Pineal Res. 40:168–76.PubMedCrossRefGoogle Scholar
  66. 66.
    Baydas G, Canatan H, Turkoglu A. (2002) Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin-induced diabetes mellitus. J. Pineal Res. 32:225–30.PubMedCrossRefGoogle Scholar
  67. 67.
    Wahab MH, Akoul ES, Abdel-Aziz AA. (2000) Modulatory effects of melatonin and vitamin E on doxorubicin-induced cardiotoxicity in Ehrlich ascites carcinoma-bearing mice. Tumori 86:157–62.PubMedCrossRefGoogle Scholar
  68. 68.
    Montilla P, et al. (2001) Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats. J. Pineal Res. 31:138–44.PubMedCrossRefGoogle Scholar
  69. 69.
    Hsu C, Han B, Liu M, Yeh C, Casida JE. (2000) Phosphine-induced oxidative damage in rats: attenuation by melatonin. Free Radic. Biol. Med. 28:636–42.PubMedCrossRefGoogle Scholar
  70. 70.
    Gultekin F, Delibas N, Yasar S, Kilinc I. (2001) In vivo changes in antioxidant systems and protective role of melatonin and a combination of vitamin C and vitamin E on oxidative damage in erythrocytes induced by chlorpyrifos-ethyl in rats. Arch. Toxicol. 75:88–96.PubMedCrossRefGoogle Scholar
  71. 71.
    Rosales-Corral S, et al. (2003) Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-beta pep-tide in rat brain: a comparative, in vivo study versus vitamin C and E. J. Pineal Res. 35:80–4.PubMedCrossRefGoogle Scholar
  72. 72.
    Anwar MM, Meki AR. (2003) Oxidative stress in streptozotocin-induced diabetic rats: effects of garlic oil and melatonin. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 135:539–47.PubMedCrossRefGoogle Scholar
  73. 73.
    Forrest CM, Mackay GM, Stoy N, Stone TW, Darlington LG. (2007) Inflammatory status and kynure-nine metabolism in rheumatoid arthritis treated with melatonin. Br. J. Clin. Pharmacol. 64:517–26.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Kedziora-Kornatowska K, et al. (2008) Antioxidative effects of melatonin administration in elderly primary essential hypertension patients. J. Pineal Res. 45:312–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Tamura H, et al. (2008) Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J. Pineal Res. 44:280–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Tomas-Zapico C, Coto-Montes A. (2005) A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J. Pineal Res. 39:99–104.PubMedCrossRefGoogle Scholar
  77. 77.
    Korkmaz A, Reiter RJ. (2008) Epigenetic regulation: a new research area for melatonin? J. Pineal Res. 44:41–4.PubMedGoogle Scholar
  78. 78.
    Korkmaz A, Sanchez-Barcelo EJ, Tan DX, Reiter RJ. (2008) Role of melatonin in the epigenetic regulation of breast cancer. Breast Cancer Res. Treat. 2008, Jul 1 [Epub ahead of print].Google Scholar
  79. 79.
    Brown GC. (1992) Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochem. J. 284(Pt 1):1–13.CrossRefGoogle Scholar
  80. 80.
    Reiter RJ, Paredes SD, Korkmaz A, Jou MJ, Tan DX. (2008) Melatonin combats molecular terrorism at the mitochondrial level. Interdisc. Toxicol. 1:137–49.CrossRefGoogle Scholar
  81. 81.
    Leon J, Acuna-Castroviejo D, Escames G, Tan DX, Reiter RJ. (2005) Melatonin mitigates mitochondrial malfunction. J. Pineal Res. 38:1–9.CrossRefGoogle Scholar
  82. 82.
    Gilad E, et al. (1998) Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: role of inhibition of NFkappaB activation. FASEB J. 12:685–93.PubMedCrossRefGoogle Scholar
  83. 83.
    Crespo E, et al. (1999) Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysac-charide-induced multiple organ dysfunction syndrome in rats. FASEB J. 13:1537–46.PubMedCrossRefGoogle Scholar
  84. 84.
    Dong WG, et al. (2003) Effects of melatonin on the expression of iNOS and COX-2 in rat models of colitis. World J. Gastroenterol. 9:1307–11.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Rodriguez MI, et al. (2007) Chronic melatonin treatment prevents age-dependent cardiac mito-chondrial dysfunction in senescence-accelerated mice. Free Radic. Res. 41:15–24.PubMedCrossRefGoogle Scholar
  86. 86.
    Lopez LC, et al. (2006) Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic mice: its relation with mitochondrial dysfunction and prevention by melatonin. Int. J. Biochem. Cell Biol. 38:267–78.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Teixeira A, et al. (2003) Melatonin protects against pro-oxidant enzymes and reduces lipid peroxidation in distinct membranes induced by the hydroxyl and ascorbyl radicals and by peroxynitrite. J. Pineal Res. 35:262–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Mayo JC, et al. (2005) Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J. Neuroimmunol. 165:139–49.PubMedCrossRefGoogle Scholar
  89. 89.
    Rao VS, Santos FA, Silva RM, Teixiera MG. (2002) Effects of nitric oxide synthase inhibitors and melatonin on the hyperglycemic response to streptozotocin in rats. Vascul. Pharmacol. 38:127–30.PubMedCrossRefGoogle Scholar
  90. 90.
    Montilla PL, et al. (1998) Oxidative stress in diabetic rats induced by streptozotocin: protective effects of melatonin. J. Pineal Res. 25:94–100.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Korkmaz A, Topal T, Oter S, Tan DX, Reiter RJ. (2008) Hyperglycemia-related pathophysiologic mechanisms and potential beneficial actions of melatonin. Mini Rev. Med. Chem. 8:1144–53.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Sadir S, Deveci S, Korkmaz A, Oter S. (2007) Alpha-tocopherol, beta-carotene and melatonin administration protects cyclophosphamide-induced oxidative damage to bladder tissue in rats. Cell Biochem. Funct. 25:521–6.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Yildirim I, Korkmaz A, Oter S, Ozcan A, Oztas E. (2004) Contribution of antioxidants to preventive effect of mesna in cyclophosphamide-induced hemorrhagic cystitis in rats. Cancer Chemother. Pharmacol. 54:469–73.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Li JH, et al. (2005) Melatonin reduces inflammatory injury through inhibiting NF-kappaB activation in rats with colitis. Mediators Inflamm. 2005:185–93.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Reiter RJ. (2003) Melatonin: clinical relevance. Best Pract. Res. Clin. Endocrinol. Metab. 17:273–85.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Dugo L, et al. (2001) Effect of melatonin on cellular energy depletion mediated by peroxynitrite and poly (ADP-ribose) synthetase activation in an acute model of inflammation. J. Pineal Res. 31:76–84.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Tan DX, et al. (2005) Interactions between melatonin and nicotinamide nucleotide: NADH preservation in cells and in cell-free systems by melatonin. J. Pineal Res. 39:185–94.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Lopez LC, Escames G, Ortiz F, Ros E, Acuna-Castroviejo D. (2006) Melatonin restores the mitochondrial production of ATP in septic mice. Neuro. Endocrinol. Lett. 27:23–630.Google Scholar
  99. 99.
    Tan DX, et al. (1993) The pineal hormone melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in vivo. Cancer Lett. 70:65–71.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Mollace V, Muscoli C, Masini E, Cuzzocrea S, Salvemini D. (2005) Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol. Rev. 57:217–52.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Landino LM, Crews BC, Timmons MD, Morrow JD, Marnett LJ. (1996) Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis. Proc. Natl. Acad. Sci. U. S. A. 93:15069–74.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Deng WG, Tang ST, Tseng HP, Wu KK. (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood 108:518–24.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Regoli F, Winston GW. (1999) Quantification of total oxidant scavenging capacity of antioxidants for peroxynitrite, peroxyl radicals, and hydroxyl radicals. Toxicol. Appl. Pharmacol. 156:96–105.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Tan DX, et al. (2002) Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr. Top. Med. Chem. 2:181–97.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Seabra ML, Bignotto M, Pinto LR Jr, Tufik S. (2000) Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J. Pineal Res. 29:193–200.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Jahnke G, et al. (1999) Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicol. Sci. 50:271–9.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Reiter R, Gultekin F, Flores LJ, Terron MP, Tan DX. (2006) Melatonin: potential utility for improving public health. TAF Prev. Med. Bull. 5:131–58.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2009

Authors and Affiliations

  • Ahmet Korkmaz
    • 1
    • 2
  • Russel J. Reiter
    • 2
  • Turgut Topal
    • 1
  • Lucien C. Manchester
    • 2
  • Sukru Oter
    • 1
  • Dun-Xian Tan
    • 2
  1. 1.Department of Physiology, School of MedicineGulhane Military Medical AcademyAnkaraTurkey
  2. 2.Department of Cellular and Structural BiologyThe University of Texas Health Science Center at San AntonioSan AntonioUSA

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