Advertisement

Journal of Endocrinological Investigation

, Volume 29, Issue 3, pp 281–287 | Cite as

Melatonin and nitric oxide

  • S. AydoganEmail author
  • M. Betul Yerer
  • A. Goktas
Review Article

Abstract

Melatonin is a product of the amino acid tryptophan in the pineal gland. Once synthesized, the specific mechanisms governing the release of melatonin from the pineal gland and its functions are largely unknown. Besides its regulatory role in circadian rhythms in mammals, because of its widespread subcellular distribution, melatonin contributes to the reduction of oxidative damage in both the lipid and the aqueous environments of the cell. This postulate is widely supported by the experimental observations showing that melatonin protects lipids in membranes, proteins in the cytosol, and DNA in the nucleus and mitochondria from free radical damage. Melatonin thus reduces the severity of disease conditions where free radicals are implicated. The direct free radical scavenging effects of melatonin are receptor independent. It has recently been shown that it has an ability to scavenge free radicals, including hydroxyl radicals, hydrogen peroxide, peroxyl radicals, singlet oxygen and nitric oxide (NO) and peroxynitrite anion. An excessive amount of NO, a free radical which is generated by the inducible form of NO synthase, is known to cause cytotoxic changes in cells. Hence, NO synthase is considered a pro-oxidative enzyme, and any factor that reduces its activity would be considered an antioxidant. Recent studies have shown that melatonin inhibits the activity of NO synthase, beside its NO and peroxynitrite scavenging activity. Thus, inhibition of NO production may be another means whereby melatonin reduces oxidative damage under conditions, such as ischemia-reperfusion, sepsis, etc, where NO seems to be important in terms of the resulting damage. (J. Endocrinol. Invest. 28: 281–287, 2005)

Key Words

Melatonin nitric oxide peroxynitrite nitric oxide synthase antioxidant 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiologyand pharmachology. Pharmacol Rev 1991, 43: 109–42.PubMedGoogle Scholar
  2. 2.
    Lipton SA, Choi YB, Pan ZH, et al. A redox based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso compounds. Nature 1993, 364: 626–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Yerer MB, Yapislar H, Aydogan S, Yalcin O, Baskurt OK. Lipid peroxidation and deformability of red blood cells in experimental sepsis in rats: the protective effects of melatonin. Clin Hemorheol Microcirc 2004, 30: 77–82.PubMedGoogle Scholar
  4. 4.
    Reiter RJ. Melatonin: the chemical expression of darkness. Mol Cell Endocrinol 1991, 79: 153–8.CrossRefGoogle Scholar
  5. 5.
    Turjanski AG, Saenz DA, Doctorovic F, Estrin DA, Rosenstein RE. Nitrosation of melatonin by nitric oxide: a computational study. J Pineal Res 2001, 31: 97–101.PubMedCrossRefGoogle Scholar
  6. 6.
    Armstrong SM, Redman JR. Melatonin: A chronobiotic with antiaging properties. Med Hypotheses 1991, 34: 300–9.PubMedCrossRefGoogle Scholar
  7. 7.
    McCann SM, Licinio J, Wong ML, Yu WH, Karanth S, Rettori V. The nitric oxide hypothesis of aging. Exp Gerontol 1998, 33: 813–26.PubMedCrossRefGoogle Scholar
  8. 8.
    Koppal T, Drake J, Yatin S, et al. Peroxynitrite-induced alterations in synaptosomal membrane proteins: insight into oxidative stress in Alzheimer’s disease. J Neurochem 1999, 72: 310–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Crow JP, Beckman JS. The role of peroxynitrite in nitric oxide-mediated toxicity. Curr Top Microbiol Immunol 1995, 196: 57–73.PubMedGoogle Scholar
  10. 10.
    Dawson D, Encel N. Melatonin and sleep in humans J Pineal Res 1993, 15: 1–12.PubMedCrossRefGoogle Scholar
  11. 11.
    McArthur AJ, Gilette MV, Prosser RA. Melatonin directly resets the rat suprachiasmatic circadian clock in vitro. Brain Res 1991, 565: 158–61.PubMedCrossRefGoogle Scholar
  12. 12.
    Curoleo MC, Frasca D, Nistico G, Doria G. Melatonin as immunomodulator in immunodeficient mice. Immunopharmachology 1992, 23: 81–9.CrossRefGoogle Scholar
  13. 13.
    Reiter RJ, Carneiro RG, Oh S. Melatonin in relation to cellular antioxidative defense mechanisms. Horm Metab Res 1997, 29: 363–72.PubMedCrossRefGoogle Scholar
  14. 14.
    Marshall KA, Reiter RJ, Poeggeler B. Evaluation of the anti-oxidant activity of melatonin in vivo. Free Radic Biol Med 1996, 21: 307–15.PubMedCrossRefGoogle Scholar
  15. 15.
    Reiter RJ, Tan DX, Manchester LC, Qi W. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem Biophys 2001, 34: 237–56.PubMedCrossRefGoogle Scholar
  16. 16.
    Reiter RJ, Tan DX, Burkhardt S. Reactive oxygen and nitrogen species and cellular and organismal decline: amelioration with melatonin. Mech Ageing Dev 2002, 30: 1007–19.CrossRefGoogle Scholar
  17. 17.
    Poeggeler B, Saarela S, Reiter RJ, et al. Melatonin a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Ann N Y Acad Sci 1994, 738: 419–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Noda Y, Mori A, Liburdy R, Packer L. Melatonin and its precursors scavenge nitric oxide. J Pineal Res 1999, 27: 159–63.PubMedCrossRefGoogle Scholar
  19. 19.
    Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F. Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci 1994, 55: 271–6.CrossRefGoogle Scholar
  20. 20.
    Taysi S, Koc M, Buyukokuroglu ME, Altinkaynak K, Sahin YN. Melatonin reduces lipid peroxidation and nitric oxide during irradiation-induced oxidative injury in the rat liver. J Pineal Res 2003, 34: 173–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Wink DA, Mitchell JB. Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med 1998, 25: 434–56.PubMedCrossRefGoogle Scholar
  22. 22.
    Morgan PJ, Barret P, Howell HE, Halliwell R. Melatonin receptors: localization, molecular pharmacology and physiological significance. Neurochem Int 1994, 24: 101–46.PubMedCrossRefGoogle Scholar
  23. 23.
    Blanchard B, Pompon D, Ducrocq C. Nitrosation of melatonin by nitric oxide and peroxynitrite. J Pineal Res 2000, 29: 184–92.PubMedCrossRefGoogle Scholar
  24. 24.
    Anwar MM, Meki AR, Rahma HH. Inhibitory effects of melatonin on vascular reactivity: possible role of vasoactive mediators. Comp Biochem Physiol C Toxicol Pharmacol 2001, 130: 357–67.PubMedCrossRefGoogle Scholar
  25. 25.
    Yoo YM, Yim SV, Kim SS, et al. Melatonin suppresses NO-induced apoptosis via induction of Bcl-2 expression in PGT-beta immortalized pineal cells J Pineal Res 2002, 33: 146–50.PubMedCrossRefGoogle Scholar
  26. 26.
    Sharman EH, Vaziri ND, Ni Z, Sharman KG, Bondy SC. Reversal of biochemical and behavioral parameters of brain aging by melatonin and acetyl L-carnitine. Brain Res 2002, 12: 223–30.CrossRefGoogle Scholar
  27. 27.
    Bikjdaouene L, Escames G, Leon J, et al. Changes in brain amino acids and nitric oxide after melatonin administration in rats with pentylenetetrazole-induced seizures. J Pineal Res 2003, 35: 54–60.PubMedCrossRefGoogle Scholar
  28. 28.
    Pozo D, Reiter RJ, Calvo JM, Guerrero JM. Inhibition of cerebellar nitric oxide synthase and cyclic GMP production by melatonin via complex formation with calmodulin. J Cell Biochem 1997, 65: 430–2.PubMedCrossRefGoogle Scholar
  29. 29.
    Bettahi I, Pozo O, Osuna C, Reiter RJ, Acuna-Castroviejo D, Guerrero JM. Melatonin reduces nitric oxide synthase activity in rat hypothalamus. J Pineal Res 1996, 20: 205–10.PubMedCrossRefGoogle Scholar
  30. 30.
    Pozo D, Reiter RJ, Calvo JR, Guerrero JM. Physiological concentrations of melatonin inhibit nitric oxide synthase in rat cerebellum. Life Sci 1994, 55: 455–60.CrossRefGoogle Scholar
  31. 31.
    Chang HM, Ling E, Chen CF, Lue H, Wen CY, Shieh JY. Melatonin attenuates the neuronal NADPH-d/NOS expression in the nodose ganglion of acute hypoxic rats. J Pineal Res 2002, 32: 65–73.PubMedCrossRefGoogle Scholar
  32. 32.
    Rao VS, Santos FA, Silva RM, Teixiera MG. Effects of nitric oxide synthase inhibitors and melatonin on the hyperglycemic response to streptozotocin in rats. Vascul Pharmacol 2002, 38: 127–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Storr M, Koppitz P, Sibaev A, et al. Melatonin reduces non-adrenergic, non-cholinergic relaxant neurotransmission by inhibition of nitric oxide synthase activity in the gastrointestinal tract of rodents in vitro. J Pineal Res 2002, 33: 101–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Gilad E, Wong HR, Zingarelli B, et al. Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: role of inhibition of NFκ B activation. FASEB J 1998, 12: 685–93.PubMedGoogle Scholar
  35. 35.
    Escames G, Macías M, León J, et al. Calcium-Dependent Effects of Melatonin Inhibition of Glutamatergic Response in Rat Striatum. J Neuroendocrinol 2001, 13: 459–66.PubMedCrossRefGoogle Scholar
  36. 36.
    Acuna-Castroviejo D, Escames G, Leon J, Carazo A, Khaldy H. Mitochondrial regulation by melatonin and its metabolites. Adv Exp Med Biol 2003, 527: 549–57.PubMedCrossRefGoogle Scholar
  37. 37.
    d’Emmanuele di Villa Bianca R, Marzocco S, Di Paola R, et al. Melatonin prevents lipopolysaccharide-induced hyporeactivity in rat. J Pineal Res 2004, 36: 146–54.PubMedCrossRefGoogle Scholar
  38. 38.
    Escames G, Leon J, Macias M, Khaldy H, Acuna-Castroviejo D. Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. FASEB J 2003, 17: 932–4.PubMedGoogle Scholar
  39. 39.
    Lahiri DK, Ghosh C. Interactions between melatonin, reactive oxygen species, and nitric oxide. Ann N Y Acad Sci 1999, 93: 325–30.CrossRefGoogle Scholar
  40. 40.
    Yerer MB, Aydogan S, Yapislar H, Yalcin O, Kuru O, Baskurt OK. The effect of melatonin on glutathione peroxidase activity and deformability of erythrocytes in septic rats. J Pineal Res 2003, 35: 138–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Maestroni GJM. Melatonin as a therapeutic agent in experimental endotoxic shock. J Pineal Res 1996, 20: 84–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Pei Z, Fung PC, Cheung RT. Melatonin reduces nitric oxide level during ischemia but not blood-brain barrier breakdown during reperfusion in a rat middle cerebral artery occlusion stroke model. J Pineal Res 2003, 34: 110–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Yerer MB, Aydogan S. The protective effect of melatonin on SNP-induced oxidative stress in erythrocytes. Free Radic Res 2003, 37: 50.Google Scholar
  44. 44.
    Mascio PD, Dewez B, Garcia CSR. Ghost protein damage by peroxynitrite and its protection by melatonin. Braz J Med Biol Res 2000, 33: 11–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Gilad E, Cuzzocrea S, Zingarelli B, Salzman AL, Szabò C. Melatonin is a scavenger of peroxinitrite. Life Sci 1997, 60: 169–74.CrossRefGoogle Scholar
  46. 46.
    Cuzzocrea S, Zingarelli B, Gilad E, Hake P, Salzman AL, Szabo C. Protective effect of melatonin in carrageenan-induced models of local inflammation: relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity. J Pineal Res 1997, 23: 106–16.PubMedCrossRefGoogle Scholar
  47. 47.
    Pigoelet E, Remacle J. Susceptibility of gluthatione peroxidase to proteolysis after oxidative alteration by peroxidases and hydroxyl radicals. Free Radic Biol Med 1991, 11: 191–5.CrossRefGoogle Scholar
  48. 48.
    Garcia JJ, Reiter RJ, Guerrero JM, et al. Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation. FEBS Lett 1997, 408: 297–300.PubMedCrossRefGoogle Scholar
  49. 49.
    Edward DP, Lam TT, Shahinfar S, Li J, Tso MO. Amelioration of light-induced retinal degeneration by a calcium overload blocker. Flunarizine. Arch Ophthalmol 1991, 109: 554–62.PubMedCrossRefGoogle Scholar
  50. 50.
    Ananth C, Gopalakrishnakone P, Kaur C. Protective role of melatonin in domoic acid-induced neuronal damage in the hippocampus of adult rats. Hippocampus 2003, 13: 375–87.PubMedCrossRefGoogle Scholar
  51. 51.
    Siu AW, Ortiz GG, Benitez-King G, To CH, Reiter RJ. Effects of melatonin on the nitric oxide treated retina. Br J Ophthalmol 2004, 88: 1078–81.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Siu AW, Reiter RJ, To CH. The efficacy of vitamin E and melatonin as antioxidants against lipid peroxidation in rat retinal homogenates. J Pineal Res 1998, 24: 239–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Soung do Y, Choi HR, Kim JY, et al. Peroxynitrite scavenging activity of indole derivatives: interaction of indoles with peroxynitrite. J Med Food 2004, 7: 84–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Siu AW, Reiter RJ, To CH. Pineal indoleamines and vitamin E reduce nitric oxide-induced lipid peroxidation in rat retinal homogenates. J Pineal Res 1999, 27: 122–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Aydogan S, Yerer MB, Yapislar H. In vitro effects of melatonin on the filterability of erythrocytes in SNP-induced oxidative stress. Clinical Hemorheol. Microcirc 2004, 30: 317–22.Google Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2006

Authors and Affiliations

  1. 1.Department of PhysiologyUniversity of Erciyes, Faculty of MedicineKocasinanTurkey

Personalised recommendations