Journal Mobile Options
Table of Contents
Vol. 9, No. 3-4, 2000
Issue release date: May–August 2000
Biol Signals Recept 2000;9:160–171
(DOI:10.1159/000014636)

Pharmacology and Physiology of Melatonin in the Reduction of Oxidative Stress in vivo

Reiter R.J. · Tan D.-X. · Qi W. · Manchester L.C. · Karbownik M. · Calvo J.R.
Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, Tex., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

This brief resume summarizes the evidence which shows that melatonin is a significant free radical scavenger and antioxidant at both physiological and pharmacological concentrations in vivo. Surgical removal of the pineal gland, a procedure which lowers endogenous melatonin levels in the blood, exaggerates molecular damage due to free radicals during an oxidative challenge. Likewise, providing supplemental melatonin during periods of massive free radical production greatly lowers the resulting tissue damage and dysfunction. In the current review, these findings are considered in terms of neurodegenerative diseases, cancer, ischemia/reperfusion injury and aging. Besides being a highly effective direct free radical scavenger and indirect antioxidant, melatonin has several features that make it of clinical interest. Thus, melatonin is readily absorbed when it is administered via any route, it crosses all morphophysiological barriers, e.g., blood-brain barrier and placenta, with ease, it seems to enter all parts of every cell where it prevents oxidative damage, it preserves mitochondrial function, and it has low toxicity. While blood melatonin levels are normally low, tissue levels of the indoleamine can be considerably higher and at some sites, e.g., in bone marrow cells and bile, melatonin concentrations exceed those in the blood by several orders of magnitude. What constitutes a physiological level of melatonin must be redefined in terms of the bodily fluid, tissue and subcellular compartment being examined.

Copyright © 2000 S. Karger AG, Basel



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ: Melatonin: A potent, endogenous hydroxyl radical scavenger. Endocr J 1993;1:57–60.
  2. Reiter RJ, Oh CS, Fujimori O: Melatonin: Its intracellular and genomic actions. Trends Endocrinol Metab 1996;7:22–26.
  3. Reiter RJ, Tan DX, Qi W: Suppression of oxygen toxicity by melatonin. Acta Pharmacol Sin 1998;19:575–581.
  4. Reiter RJ: Oxidative damage in the central nervous system: Protection by melatonin. Prog Neurobiol 1998;56:359–384.
  5. Reiter RJ, Tan DX, Cabrera J, D’Arpa D, Sainz RM, Mayo JC, Ramos S: The oxidant/antioxidant network: Role of melatonin. Biol Signals Recept 1999;8:56–63.
  6. Tan DX, Reiter RJ, Chen LD, Poeggeler B, Manchester LC, Barlow-Walden LR: Both physiological and pharmacological levels of melatonin reduce DNA adduct formation induced by the carcinogen safrole. Carcinogenesis 1994;15:215–218.

    External Resources

  7. Manev H, Uz T, Kharlamov A, Joo JY: Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats. FASEB J 1996;10:1546–1551.

    External Resources

  8. Reiter RJ, Tan DX, Kim SJ, Manchester LC, Qi W, Garcia JJ, Cabrera JC, El-Sokkary G, Rouvier-Garay V: Augmentation of indices of oxidative damage in life-long melatonin-deficient rats. Mech Aging Dev 1999;110:157–173.
  9. Stasica P, Ulanski P, Rosiak JM: Melatonin as a hydroxyl radical scavenger. J Pineal Res 1998;25:65–66.
  10. Tan DX, Manchester LC, Reiter RJ, Plummer BF, Hardies LJ, Weintraub ST, Vijayalaxmi Shepherd AMM: A novel melatonin metabolite, cyclic 3-hydroxymelatonin: A biomarker of in vivo hydroxyl radical generation. Biochem Biophys Res Commun 1998;253:614–620.
  11. Mahal HS, Sharma HS, Mukerjee T: Antioxidant properties of melatonin: A pulse radiolysis study. Free Radic Biol Med 1999;26:557–565.
  12. Pähkla R, Zilmer M, Kullisar M, Rägo L: Comparison of the antioxidant activity of melatonin and pinoline in vivo. J Pineal Res 1998;24:96–101.

    External Resources

  13. Tan DX, Manchester LC, Reiter RJ, Plummer BF: Cyclic 3-hydroxymelatonin: A melatonin metabolite generated as a result of hydroxyl radical scavenging. Biol Signals Recept 1999;8:70–74.
  14. Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR: Significance of melatonin in antioxidative defense system: Reactions and products. Biol Signals Recept 2000;9:137–159.

    External Resources

  15. Zang LY, Cosma G, Gardner H, Vallynathan V: Scavenging of reactive oxygen species by melatonin. Biochim Biophys Acta 1998;1425:469–477.

    External Resources

  16. Noda Y, Mori A, Liburty R, Packer L: Melatonin and its precursors scavenge nitric oxide. J Pineal Res 1999;27:159–163.
  17. Zhang H, Squadrito GL, Pryor WA: Reaction of peroxynitrite with melatonin: A mechanistic study. Chem Res Toxicol 1999;12:526–534.
  18. Pablos MI, Guerrero JM, Ortiz GG, Agapito MT, Reiter RJ: Both melatonin and a putative nuclear receptor agonist CGP 52608 stimulate glutathione peroxidase and glutathione reductase activities in mouse brain in vivo. Neuroendocrinol Lett 1997;18:49–58.
  19. Reiter RJ, Tang L, Garcia JJ, Muñoz-Hoyos A: Pharmacological actions of melatonin in oxygen radical pathophysiology. Life Sci 1997;60:2255–2271.

    External Resources

  20. Hara M, Iigo M, Ohtani-Kaneko R, Nakamura N, Suzuki T, Reiter RJ, Hirata K: Administration of melatonin and related indoles prevents exercise-induced cellular oxidative changes in rats. Biol Signals 1997;6:90–100.
  21. Garcia JJ, Reiter RJ, Guerrero JM, Escames G, Yu B, Oh CS, Muñoz-Hoyos A: Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation. FEBS Lett 1997;408:297–300.
  22. Garcia JJ, Reiter RJ, Ortiz GG, Oh CS, Tang L, Yu BP, Escames G: Melatonin enhances tamoxifen’s ability to prevent the reduction in microsomal membrane fluidity induced by lipid peroxidation. J Membr Biol 1998;162:59–65.
  23. Menendez-Pelaez A, Reiter RJ: Distribution of melatonin in mammalian tissues: Relative importance of nuclear verses cytosolic localization. J Pineal Res 1993;15:59–69.
  24. Menendez-Pelaez A, Poeggeler B, Reiter RJ, Barlow-Walden LR, Pablos MI, Tan DX: Nuclear localization of melatonin in different mammalian tissues: Immunocytochemical and radioimmunoassay evidence. J Cell Biochem 1993;53:572–582.
  25. Troiani ME, Reiter RJ, Tannenbaum MG, Puig-Domingo M, Guerrero JM, Menendez-Pelaez A: Neither the pituitary gland nor the sympathetic nervous system is responsible for eliciting the large drop in elevated rat pineal melatonin levels due to swimming. J Neural Transm 1988;74:149–160.
  26. Pohjanvirta R, Laitinen JT, Vakkuri O, Linden J, Kokkola T, Unkila M, Tuomisto J: Mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reduces circulating melatonin levels in the rat. Toxicology 1996;107:85–97.

    External Resources

  27. Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni GJM: Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res, in press.
  28. Tan DX, Manchester LC, Reiter RJ, Qi W, Zhang M, Weintraub ST, Cabrera J, Sainz RM, Mayo JC: Identification of highly elevated levels of melatonin in bone marrow: Its origin and significance. Biochim Biophys Acta 1999;1472:206–214.
  29. Tan DX, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ: High physiological levels of melatonin in the bile of mammals. Life Sci 1999;65:2523–2529.
  30. Skinner DC, Malpaux B: High melatonin concentrations in third ventricular cerebrospinal fluid are not due to Galen vein blood recirculating through the choroid plexus. Endocrinology 1999;140:4399–4405.
  31. Antolin I, Obst B, Burkhardt S, Hardeland R: Antioxidative protection in a high-melatonin organism: The dinoflagellate Gonyaulax polyedra is rescued from lethal stress by strongly elevated, but physiologically possible concentrations of melatonin. J Pineal Res 1997;23:182–190.

    External Resources

  32. Urata Y, Honma S, Goto S, Todoroki S, Iida T, Cho S, Honma K, Kondo T: Melatonin induces γ-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Radic Biol Med 1999;27:838–847.
  33. Pang SF, Allen AE: Extra-pineal melatonin in the retina: Its regulation and physiological function; in Reiter RJ (ed): Pineal Research Reviews. New York, Liss, 1986, vol IV, pp 55–95.
  34. Ebihara S, Adachi A, Hasegawa M, Nogi T, Yoshimura T, Hirunagi K: In vivo microdialysis studies of pineal and ocular melatonin rhythms in birds. Biol Signals 1997;6:233–240.

    External Resources

  35. Marchiafava PL, Longoni B: Melatonin as an antioxidant in retinal photoreceptor cells. J Pineal Res 1999;26:184–189.
  36. Costa EJX, Lopes RH, Lamy-Freund MT: Permeability of pure lipid bilayers to melatonin. J Pineal Res 1995;19:123–124.
  37. Shida CS, Castrucci AML, Lamy-Freund MT: High melatonin solubility in aqueous medium. J Pineal Res 1994;161:198–201.
  38. Tang PL, Xu MF, Qian ZM: Differential behaviour of cell membranes towards iron-induced oxidative damage and the effects of melatonin. Biol Signals 1997;6:291–300.

    External Resources

  39. Carneiro RCG, Reiter RJ: δ-Aminolevulenic acid-induced lipid peroxidation in rat kidney and liver is attenuated by melatonin: An in vitro and in vivo study. J Pineal Res 1998;24:131–136.
  40. Alarcon de la Lastra A, Motilva V, Martin MJ, Nieto A, Barranco MD, Cabeza J, Herrerias JM: Protective effect of melatonin on indomethacin-induced gastric injury in rats. J Pineal Res 1999;26:101–107.
  41. Morishima I, Okumura K, Matsui H, Kaneko S, Dumaguchi Y, Kawakami K, Makuno S, Hayakawa M, Toki Y, Ito T, Hayakawa T: Zinc accumulation in Adriamycin-induced cardiomyopathy in rats: Effects of melatonin, a cardioprotective antioxidant. J Pineal Res 1999;26:204–210.

    External Resources

  42. Tang L, Reiter RJ, Li ZR, Ortiz GG, Yu BP, Garcia JJ: Melatonin reduces the increase in 8-hydroxy-deoxyguanosine levels in the brain and liver of kainic acid-treated rats. Mol Cell Biochem 1998;178:299–303.

    External Resources

  43. Wakatsuki A, Okatani Y, Izumiya C, Ikenoue N: Melatonin protects against ischemia and reperfusion-induced oxidative lipid and DNA damage in fetal rat brain. J Pineal Res 1999;26:147–152.
  44. Vijayalaxmi, Meltz ML, Reiter RJ, Herman TS: Melatonin and protection from genetic damage in blood and bone marrow: Whole-body irradiation studies in mice. J Pineal Res 1999;27:221–225.

    External Resources

  45. Cuzzocrea S, Caputi AP: Protective effect of melatonin on zymosan-induced cellular damage. Biol Signals Recept 1999;8:136–142.
  46. Sun EY, Lin X, Zhang LM, Lu SD, Pan S: Effects of melatonin on DNA damage and repair in rat brain following a transient cerebral ischemia (abstract). Biol Signals Recept 2000;9:69.
  47. Tesoriere L, D’Arpa D, Conti S, Giaccone V, Pinaudi AM, Livrea MA: Melatonin protects human red blood cells from oxidative hemolysis: New insights into the radical-scavenging activity. J Pineal Res 1999;27:95–105.
  48. Ceraulo L, Ferrugia M, Tesoriere L, Segreto S, Livrea MA, Turco Livrea V: Interactions of melatonin with membrane models: Portioning of melatonin in AOT and lecithin reversed micelles. J Pineal Res 1999;26:108–112.
  49. Kotler M, Rodriquez C, Sainz RM, Antolin I, Menendez-Pelaez A: Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res 1998;24:83–89.
  50. El-Sokkary GH, Reiter RJ, Tan DX, Kim SJ, Cabrera J: Inhibitory effect of melatonin on products of lipid peroxidation resulting from chronic ethanol administration. Alcohol Alcohol 1999;34:842–850.

    External Resources

  51. Okatani Y, Okamoto K, Hayashi K, Wakatsuki A, Tamura S, Sagara Y: Maternal-fetal transfer of melatonin in pregnant women near term. J Pineal Res 1998;25:129–134.
  52. Benot S, Goberna R, Reiter RJ, Garcia-Maurino S, Osuna C, Guerrero JM: Physiological levels of melatonin contribute to the antioxidant capacity of human serum. J Pineal Res 1999;27:59–64.
  53. Benot S, Molinero P, Soutto M, Goberna R, Guerrero JM: Circadian variations in the rat serum total antioxidant status: Correlation with melatonin levels. J Pineal Res 1998;25:1–4.

    External Resources

  54. Richardson JS, Zhou Y: Oxidative stress in the production and expression of neurotoxic β-amyloid. Rest Neurol Neurosci 1996;9:207–211.
  55. Reiter RJ, Garcia JJ, Pie J: Oxidative toxicity in models of neurodegeneration: Responses to melatonin. Rest Neurol Neurosci 1998;12:135–142.
  56. Pappolla MA, Chyan YJ, Poeggeler B, Frangione B, Wilson G, Ghiso J, Reiter RJ: An assessment of the antioxidant and antiamyloidogenic properties of melatonin: Implications for Alzheimer’s disease. J Neural Transm, in press.
  57. Ames BN, Shigenaga MK: Oxidants are a major contributor to cancer and aging; in Halliwell B, Aruoma-OI (eds): DNA and Free Radicals. London, Harwood, 1993, pp 1–18.
  58. Reiter RJ: Oxidative damage to nuclear DNA: Amelioration by melatonin: Neuroendocrinol Lett 1999;20:145–150.
  59. Janeiro DR: Ischemic heart disease and antioxidants: Mechanistic aspects of oxidative injury and its prevention. Crit Rev Food Sci Nutr 1995;35:65–81.

    External Resources

  60. Globus MY, Busto R, Lin B, Schnippering H, Ginsberg MD: Detection of free radical activity during transient global ischemia and recirculation: Effects of intraischemic brain temperature modulation. J Neurochem 1995;65:1250–1256.

    External Resources

  61. Harman D: The aging process: Major risk factor for disease and death. Proc Natl Acad Sci USA 1991;88:5360–5363.
  62. Reiter RJ: Aging and oxygen toxicity: Relation to changes in melatonin. Age 1997;20:201–213.
  63. Markesbury WR: Oxidative stress hypothesis of Alzheimer’s disease. Free Radic Biol Med 1997;23:134–137.
  64. Yoshikawa T: Free radicals and their scavengers in Parkinson’s disease. Eur Neurol 1993;33(suppl 1):60–68.
  65. Heyes MP: The kynurenine pathway and neurological disease. Therapeutic strategies. Adv Exp Med Biol 1996;398:125–129.
  66. Pappolla MA, Sos M, Beck RJ, Hickson Bick DML, Reiter RJ, Ethimiopoules S, Robakis NK: Melatonin prevents death of neuroblastoma cells exposed to Alzheimer amyloid peptide. J Neurosci 1997;17:1683–1690.
  67. Pappolla MA, Bozner P, Sos C, Chao H, Robakis NK, Zagorski M, Frangione B, Ghiso J: Inhibition of Alzheimer’s β-fibrillogenesis by melatonin. J Biol Chem 1998;273:185–188.
  68. Brusco LI, Marquez M, Cardinali DP: Monozygotic twins with Alzheimer’s disease treated with melatonin. Case report. J Pineal Res 1998;25:260–263.

    External Resources

  69. Acuña-Castroviejo D, Coto-Montes A, Monti MG, Ortiz GG, Reiter RJ: Melatonin is protective against MPTP-induced striatal and hippocampal lesions. Life Sci 1997;60:PL23–PL29.
  70. Iacovitti L, Stull ND, Johnston K: Melatonin rescues dopamine neurons from cell death in tissue culture models of oxidative stress. Brain Res 1997;768:317–326.

    External Resources

  71. Mayo JC, Sainz R, Uria H, Antolin I, Esteban MM, Rodriquez C: Melatonin prevents apoptosis induced by 6-hydroxydopamine in neuronal cells. Implications for Parkinson’s disease. J Pineal Res 1998;24:179–192.

    External Resources

  72. Southgate GS, Daya S, Potgieter B: Melatonin plays a protective role in quinolinic acid-induced neurotoxicity in the rat hippocampus. J Chem Neuroanat 1998;14:151–156.

    External Resources

  73. Cabrera J, Reiter RJ, Tan DX, Qi W, Sainz RM, Mayo JC, Carcia JJ, Kim SJ, El-Sokkary GH: Melatonin reduces oxidative neurotoxicity due to quinolinic acid: In vitro and in vivo findings. Neuropharmacology 2000;39:507–514.

    External Resources

  74. Blask DE, Sauer LA, Dauchy RT, Holowachuk EW, Ruhoff MS, Kopff HS: Melatonin inhibition of cancer growth in vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transduction events. Cancer Res 1999;59:4693–4701.
  75. Qi W, Reiter RJ, Tan DX, Manchester LC, Siu AW, Garcia JJ: Increased levels of oxidatively damaged DNA induced by chromium(III) and H2O2: Protection by melatonin and related molecules. J Pineal Res, in press.
  76. Vijayalaxmi, Reiter RJ, Herman TS, Meltz ML: Melatonin and radioprotection from genetic damage: In vivo/in vitro studies with cells from human volunteers. Mutat Res 1996;371:221–228.
  77. Tan DX, Manchester LC, Reiter RJ, Qi W, Kim SJ, El-Sokkary GH: Ischemia/reperfusion-induced arrhythmias in isolated rat heart: Prevention by melatonin. J Pineal Res 1998;25:184–191.
  78. Guerrero JM, Reiter RJ, Ortiz GG, Pablos MI, Sewerynek E, Chuang JI: Melatonin prevents increases in neural nitric oxide and cyclic GMP production after transient brain ischemia and reperfusion in the Mongolian gerbil (Meriones unguiculatus). J Pineal Res 1997;23:24–31.
  79. Kilic E, Özdemir YG, Bolay H, Kelestimur H, Dalkara T: Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia. J Cerebr Blood Flow Metab 1999;19:511–518.
  80. Pei Z, Pang SF, Cheung RTF: Melatonin protects against focal cerebral ischaemia in the rat (abstract). Biol Signals Recept 2000;9:65.
  81. Sewerynek E, Reiter RJ, Melchiorri D, Ortiz GG, Lewinski A: Oxidative damage in the liver induced by ischemia-reperfusion. Protection by melatonin. Hepatogastroenterology 1996;43:898–905.

    External Resources

  82. Cuzzocrea S, Costantino G, Mazzon E, Micali A, De Sarro A, Caputi AP: Beneficial effects of melatonin in a rat model of splanchnic artery occlusion and reperfusion. J Pineal Res 2000;28:52–63.
  83. Martin M, Macias M, Escames G, Reiter RJ, Agapito MT, Ortiz GG, Acuña-Castroviejo D: Melatonin-induced increased activity of the respiratory chain complex I and IV can prevent mitochondrial damage induced by ruthenium red in vivo. J Pineal Res, in press.
  84. Reiter RJ: The aging pineal and its physiological consequences. Bioessays 1992;14:169–175.
  85. Hardeland R: New actions of melatonin and their relevance to biometeorology. Int J Biometeorol 1997;41:47–57.

    External Resources

  86. Jahnke G, Marr M, Myers C, Wilson R, Travlos G, Price C: Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicol Res 1999;50:271–279.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50