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Pharmacy World and Science

, Volume 20, Issue 1, pp 18–27 | Cite as

Melatonin and its physiological and therapeutic properties

  • J.Z. Nowak
  • J.B. Zawilska
Article

Abstract

Melatonin is a hormone produced mainly by the pineal gland in most vertebrate species, including humans. Recent metabolic, receptor and functional studies created a picture of the melatoninergic system(s) in living organisms, its organization, physiology and a role in some pathologic conditions. The melatonin‐generating system is characterized by three basic features: (1) photosensitivity, (2) diurnal (or circadian) rhythmicity (with highest levels of melatonin production occurring at night in darkness), and (3) age‐related decline in its activity. Cyclic nocturnal increases of melatonin levels are proportional to the length of nights (or dark periods of an imposed light‐dark cycle); the hormone thus conveys a photoperiodic message, and functions in an organism as an internal biochemical clock and calendar. Biological actions of melatonin are mediated via specific melatonin receptors, whose distribution in the body is uneven, yet with decisively highest density in the suprachiasmatic nuclei of the hypothalamus, pars tuberalis of the pituitary, and the retina (particularly in birds and lower vertebrates). Such a distribution of melatonin receptors suggests that the principal physiological role of the hormone is related to both chronobiology and modulation of the body hormonal milieu. This review surveys recent developments in the melatonin field, and summarizes current knowledge on the melatoninergic mechanisms, including the therapeutic aspect related to the hormone.

Melatonin Pineal gland Serotonin N‐acetyltransferase Circadian rhythm Seasonal reproduction Circadian rhythm sleep disorders Free radicals 

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References

  1. 1.
    Poeggeler B, Balzer I, Harderland R, Lerchl A. Pineal hormone melatonin oscillates also in the dinoflagellate Gonyaulax polyedra. Naturwissenschaften 1991;78:268–9.Google Scholar
  2. 2.
    Vivien-Roels B, Pévet P. Melatonin: presence and formation in invertebrates. Experientia 1993;49:642–7.Google Scholar
  3. 3.
    Binkley S (ed.). The Pineal: Endocrine and Nonendocrine Function. Englewood Cliffs: Prentice Hall, 1988.Google Scholar
  4. 4.
    Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 1991;12:151–80.PubMedGoogle Scholar
  5. 5.
    Arendt J (ed.). Melatonin and the Mammalian Pineal Gland. London: Chapman & Hall, 1995.Google Scholar
  6. 6.
    Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ. Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Molec Biol Int 1995;35:627–34.PubMedGoogle Scholar
  7. 7.
    Zawilska JB, Nowak JZ. Regulatory mechanisms in melatonin biosynthesis in retina. Neurochem Int 1992;20:23–36.CrossRefPubMedGoogle Scholar
  8. 8.
    Huether G. The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experientia 1993;49:665–70.PubMedGoogle Scholar
  9. 9.
    Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W. Isolation of melatonin, the pineal factor that lightens melanocytes. J Am Chem Soc 1958;80:2587.Google Scholar
  10. 10.
    Axelrod J. The pineal gland: a neurochemical transducer. Science 1974;184:1341–8.PubMedGoogle Scholar
  11. 11.
    Klein DC, Weller JL. Indole metabolism in the pineal gland: a circadian rhythm in N-acetyltransferase. Science 1970;169:1093–5.PubMedGoogle Scholar
  12. 12.
    Thomas KB, Iuvone PM. Circadian rhythm of tryptophan hydroxylase activity in chicken retina. Cell Molec Neurobiol 1991;11:511–7.PubMedGoogle Scholar
  13. 13.
    Sugden D, Klein DC. Adrenergic stimulation of rat pineal hydroxyindole-O-methyltransferase. Brain Res 1983;265:348–51.CrossRefPubMedGoogle Scholar
  14. 14.
    Lovenberg W, Jequier E, Sjoerdsma A. Tryptophan hydroxylation: measurement in pineal gland, brainstem and carcinoid tumor. Science 1967;155:217–9.PubMedGoogle Scholar
  15. 15.
    Ehret M, Gobaille S, Cash CD, Mandel P, Maitre M (1987). Regional distribution of rat brain tryptophan hydroxylase apoenzyme determined by enzyme-linked immunoassay. Neurosci Lett 1987;73:71–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Florez JC, Takahashi JS. Quantitative 2-dimensional gel-electrophoretic analysis of clock-controlling proteins in cultured chick pineal cells ¶ circadian regulation of tryptophan hydroxylase. J Biol Rhythms 1996;11:241–57.PubMedGoogle Scholar
  17. 17.
    Green CB, Besharse JC. Tryptophan hydroxylase expression is regulated by a circadian clock in Xenopus laevis retina. J Neurochem 1994;62:2420–8.PubMedGoogle Scholar
  18. 18.
    Ehret M, Pévet P, Maitre M. Tryptophan hydroxylase synthesis is induced by 3',5'-cyclic adenosine monophosphate during circadian rhythm in the rat pineal gland. J Neurochem 1991;57:1516–21.PubMedGoogle Scholar
  19. 19.
    Shibuya H. Toru M, Watanabe S. A circadian rhythm of tryptophan hydroxylase in rat pineals. Brain Res 1978;138:364–8.CrossRefGoogle Scholar
  20. 20.
    Deguchi T. Physiology and molecular biology of arylamine N-acetyltransferases. Biomed Res 1992;13:231–42.Google Scholar
  21. 21.
    Klein DC, Roseboom PH, Coon SL. New light is shining on the melatonin rhythm enzyme. Trends Endocrinol Metab 1996;7:106–12.CrossRefGoogle Scholar
  22. 22.
    Nowak JZ, Zurawska E, Zawilska J. Melatonin and its generating system in vertebrate retina: circadian rhythm, effect of environmental lighting, and interaction with dopamine. Neurochem Int 1989;14:397–406.CrossRefGoogle Scholar
  23. 23.
    Coon SL, Mazurek K, Bernard M, Roseboom PH, Klein DC, Rodriguez IR. The human serotonin N-acetyltransferase (EC2.3.1.87) gene (AANAT): structure, chromosomal localization, and tissue expression. Genomics 1996;34:76–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Klein DC. The melatonin rhythm-generating system. In: Wetterberg L, ed. Light and Biological Rhythms in Man. Oxford: Pergamon Press, 1993:55.Google Scholar
  25. 25.
    Moore RY. Neural control of the pineal gland. Behav Brain Res 1996;73:125–30.CrossRefPubMedGoogle Scholar
  26. 26.
    Sudgen D. Melatonin biosynthesis in the mammalian pineal gland. Experientia 1989;45:922–32.PubMedGoogle Scholar
  27. 27.
    Sugden D, Klein DC. Essential role of calcium influx in the adrenergic regulation of cAMP and cGMP in rat pinealocytes. J Biol Chem 1986;261:11608–12.PubMedGoogle Scholar
  28. 28.
    Lane EA, Moss HB. Pharmacokinetics of melatonin in man: first pass hepatic metabolism. J Clin Endocrinol Metab 1985;61:1214–6.PubMedGoogle Scholar
  29. 29.
    Cahill GM, Besharse JC. Retinal melatonin is metabolized within the eye of Xenopus laevis. Proc Natl Acad Sci USA 1989;80:1098–102.Google Scholar
  30. 30.
    Grace MS, Cahill GM, Besharse JC. Melatonin deacetylation: retinal vertebrate class distribution and Xenopus laevis tissue distribution. Brain Res 1991;559:56–63.CrossRefPubMedGoogle Scholar
  31. 31.
    Reiter RJ. The melatonin message: duration versus coincidence hypotheses. Life Sci 1987;46:2119–31.CrossRefGoogle Scholar
  32. 32.
    Reiter RJ. Pineal function during aging: attenuation of the melatonin rhythm and its neurobiological consequences. Acta Neurobiol Exp 1994;54(Suppl.):31–9.Google Scholar
  33. 33.
    Robertson LM, Takahashi JS. Circadian clock in cell culture: I. Oscillation of melatonin release from dissociated chick pineal cells. J Neurosci 1988;8:22–30.PubMedGoogle Scholar
  34. 34.
    Underwood H, Barrett RK, Siopes T. The quail's eye: a biological clock. J Biol Rhythms 1990;5:257–65.PubMedGoogle Scholar
  35. 35.
    Cahill GM, Besharse JC. Resetting the circadian clock in cultured Xenopus eyecups: regulation of retinal melatonin rhythm by light and D2 dopamine receptors. J Neurosci 1991;11:2959–71.PubMedGoogle Scholar
  36. 36.
    Zawilska JB, Wawrocka M. Chick retina and pineal gland differentially respond to constant light and darkness: in vivo studies on serotonin N-acetyltransferase (NAT) activity and melatonin content. Neurosci Lett 1993;153:21–4.CrossRefPubMedGoogle Scholar
  37. 37.
    Murakami N, Nakamura H, Nishi R, Marumoto N, Nasu T. Comparison of circadian oscillation of melatonin release in pineal cells of house sparrow, pigeon and Japanese quail using cell perfusion systems. Brain Res 1994;651:209–14.CrossRefPubMedGoogle Scholar
  38. 38.
    Zatz M, Mullen DA, Moskal JR. Photoendocrine transduction in cultured chick pineal cells: Effects of light, dark, and potassium on the melatonin rhythm. Brain Res 1988;438:199–215.CrossRefPubMedGoogle Scholar
  39. 39.
    Zawilska JB, Iuvone PM. Melatonin synthesis in chicken retina: effect of kainic acid-induced lesion on the diurnal rhythm and D2-dopamine receptor-mediated regulation of serotonin N-acetyltransferase activity. Neurosci Lett 1992;135:71–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Cahill GM, Besharse JC. Circadian clock functions localized in Xenopus retinal photoreceptors. Neuron 1993;10:573–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Klein DC, Moore RY, Reppert SM (eds.). Suprachiasmatic Nucleus, The Mind's Clock. Oxford: Oxford University Press, 1991.Google Scholar
  42. 42.
    Reiter RJ. The mammalian pineal gland as an end organ of the visual system. In: Wetterberg L, ed. Light and Biological Rhythms in Man. Oxford: Pergamon Press 1993;145.Google Scholar
  43. 43.
    Zawilska JB, Jarmak A, Woldan-Tambor A, Nowak JZ. Light-induced suppression of nocturnal serotonin N-acetyltransferase activity in chick pineal gland and retina: a wavelength comparison. J Pineal Res 1995;19:87–92.PubMedGoogle Scholar
  44. 44.
    Zawilska JB. Melatonin as a chemical indicator of environmental light-dark cycle. Acta Neurobiol Exp 1996;56:757–67.Google Scholar
  45. 45.
    Brainard GC, Gaddy JR, Barker FM, Hanifin JP, Rollag MD. Mechanisms in the eye that mediate the biological and therapeutic effects of light in humans. In: Wetterberg L, ed. Light and Biological Rhythms in Man. Oxford: Pergamon Press, 1993;29.Google Scholar
  46. 46.
    Laakso ML, Hatonen T, Stenberg D, Alila A, Smith S. One-hour exposure to moderate illuminance (500 lux) shifts the human melatonin rhythm. J Pineal Res 1993;15:21–6.PubMedGoogle Scholar
  47. 47.
    Boivin DB, Duffy JF, Kronauer RE, Czeisler CA. Dose-response relationships for resetting of human circadian clock by light. Nature 1996;379:540–2.CrossRefPubMedGoogle Scholar
  48. 48.
    Robertson LM, Takahashi JS. Circadian clock in cell culture: II. In vitro entrainment of melatonin oscillation from dissociated chick pineal cells. J Neurosci 1988;8:22–30.PubMedGoogle Scholar
  49. 49.
    Zawilska JB. Clonidine in vivo mimics the acute suppressive but not the phase-shifting effects of light on the circadian rhythm of serotonin N-acetyltransferase activity in chick pineal gland. J Pineal Res 1994;17:63–8.PubMedGoogle Scholar
  50. 50.
    Zawilska JB. Stimulation of D4-like dopamine receptor suppresses serotonin N-acetyltransferase activity but does not phase-shift the circadian oscillator in chick retina. Neurosci Lett 1994;179:107–10.CrossRefPubMedGoogle Scholar
  51. 51.
    Mrosovsky N. Locomotor activity and non-photic influences on circadian clocks. Biol Rev 1996;71:343–72.PubMedGoogle Scholar
  52. 52.
    Vakkuri O, Lamsa E., Rahkamaa E, Ruotsalainen H, Leppaluoto J. Iodinated melatonin: preparation and characterization of molecular structure by mass or 1H NMR spectroscopy. Analyt Biochem 1984;142:284–9.PubMedGoogle Scholar
  53. 53.
    Morgan PJ, Berrett P, Howell E, Helliwell R. Melatonin receptors: localization, molecular pharmacology and physiological significance. Neurochem Int 1994;24:101–46.CrossRefPubMedGoogle Scholar
  54. 54.
    Ebisawa T, Karne S, Lerner MR, Reppert SM. Expression cloning of a high-affinity melatonin receptor from Xenopus dermal melanophores. Proc Natl Acad Sci USA 1994;91:6133–7.PubMedGoogle Scholar
  55. 55.
    Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron, 1995;13:1177–85.CrossRefGoogle Scholar
  56. 56.
    Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor.Google Scholar
  57. 57.
    Reppert SM, Weaver DR, Cassone VM, Godson C, Kolakowski LF. Melatonin receptors are for the birds: Molecular analysis of two receptor subtypes differentially expressed in chick brain. Neuron 1995; 15:1003–15.CrossRefPubMedGoogle Scholar
  58. 58.
    Roca AL, Godson C, Weaver R, Reppert SM. Structure, characterization, and expression of the gene encoding the mouse Mel1a melatonin receptor. Endocrinology 1995;137:3469–77.CrossRefGoogle Scholar
  59. 59.
    Reppert SM, Weaver DR, Godson C. Melatonin receptors step into light: cloning and classification of subtypes. Trends Pharmacol Sci 1996;17:100–2.CrossRefPubMedGoogle Scholar
  60. 60.
    Dubocovich ML. Pharmacology and function of melatonin receptors. FASEB J 1988;2:2765–73.PubMedGoogle Scholar
  61. 61.
    Copinga S, Tepper PG, Grol CJ, Horn AS, Dubocovich ML. 2-Amido-8-methoxytetralins: A series of nonidolic melatoninlike agents. J Med Chem 1993;36:2891–8.PubMedGoogle Scholar
  62. 62.
    Mathé-Allainmat, Gaudy F, Sicsic S, Dangy-Caye A-L, Shen S, Bremont B, Zohra B, Langois M, Renard P, Delegrange P. Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors. J Med Chem 1996;39:3089–95.PubMedGoogle Scholar
  63. 63.
    Martinet L, Guardiola-Lemaitre B, Mocaer E. Entrainment of circadian rhythms by S-20098, a melatonin agonist, is dose and plasma concentration dependent. Pharmacol Biochem Behav 1996;54:713–8.CrossRefPubMedGoogle Scholar
  64. 64.
    Grassi-Zucconi G, Semprevivo M, Mocaer E, Kristensson K, Bentivoglio M. Melatonin and its new agonist S-20098 restore synchronized sleep fragmented by experimental trypanosome infection in the rat. Brain Res Bull 1996;39:63–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Rivkess SA, Cassone VM, Weaver DR, Reppert SM. Melatonin receptors in chick brain: characterization and localization. Endocrinology 1989;125:363–8.PubMedGoogle Scholar
  66. 66.
    Dubocovich ML. Melatonin receptors: are there multiple subtypes? Trends Pharmacol Sci 1995;16:50–6.CrossRefPubMedGoogle Scholar
  67. 67.
    Reiter RJ. The melatonin rhythm: both a clock and calendar. Experientia 1993;49:654–64.PubMedGoogle Scholar
  68. 68.
    Lewy AJ, Ahmed S, Jackson JML, Sack RL. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 1992;9:380–92.PubMedGoogle Scholar
  69. 69.
    Lewy AJ, Ahmed S, Sack RL. Phase shifting the human circadian clock using melatonin. Behav Brain Res 1996;73:131–4.PubMedGoogle Scholar
  70. 70.
    Reiter RJ. The pineal gland and its hormones in the control of reproduction in mammals. Endocrinol Rev 1980;1:109–31.Google Scholar
  71. 71.
    Armstrong M, Redman JR. Melatonin: a chronobiotic with anti-aging properties? Med Hyp 1991;34:300–9.CrossRefGoogle Scholar
  72. 72.
    Attenburrow MEJ, Dowling BA, Argent PA, Sharpley AL, Cowen PJ. Melatonin phase advances circadian rhythm. Psychopharmacol 1995;121:503–5.Google Scholar
  73. 73.
    Kräuchi K, Cajochen C, Mori D, Hetsch C, Wirz-Justice A. Evidence for a phase advance in circadian temperature regulation after acute melatonin and a melatonin agonist (S-20098). Sleep Res 1995;24:526.Google Scholar
  74. 74.
    Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacol 1990;100:222–6.Google Scholar
  75. 75.
    Tzischinsky O, Lavie P. Melatonin possesses time-dependent hypnotic effect. Sleep1994;17:638–45.PubMedGoogle Scholar
  76. 76.
    Dawson D, Encel N. Melatonin and sleep in humans. J Pineal Res 1993;15:1–12.PubMedGoogle Scholar
  77. 77.
    Dawson D, Armstrong SM. Chronobiotics ¶ drugs that shift rhythms. Pharmacol Therapeut 1996;69:15–36.CrossRefGoogle Scholar
  78. 78.
    Dahlitz M, Alvarez B, Vignau J, English J, Arendt J, Parkes JD. Delayed sleep phase syndrome response to melatonin. Lancet 1991;337:1121–4.CrossRefPubMedGoogle Scholar
  79. 79.
    Tzischinsky O, Dagan Y, Lavie P. The effects of melatonin on the timing of sleep in patients with delayed sleep phase syndrome. In: Touitou Y, Arendt J and Pévet P, eds. Melatonin and the Pineal Gland ¶ From Basic Science to Clinical Application. Amsterdam: Excerpta Medica, 1993;351.Google Scholar
  80. 80.
    Armstrong SM. Treatment of sleep disorders by melatonin administration. Adv Pineal Res 1991;6:263–74.Google Scholar
  81. 81.
    Regestein QR, Pavlova M. Treatment of delayed sleep phase syndrome. Gen Hosp Psychiatry 1995;17:335–45.CrossRefPubMedGoogle Scholar
  82. 82.
    Jan JE, Espezel H, Appleton RE. The treatment of sleep disorders with melatonin. Dev Med Child Neurol 1994;36:97–107.PubMedGoogle Scholar
  83. 83.
    Brown GM. Melatonin in psychiatric and sleep disorders. CNS Drugs 1995;3:209–26.Google Scholar
  84. 84.
    Folkard A, Arendt J, Aldhous M, Kennett H. Melatonin stabilizes sleep onset time in a blind man without entrainment of cortisol or temperature rhythms. Neurosci Lett 1990;113:193–8.CrossRefPubMedGoogle Scholar
  85. 85.
    Palm L, Blennow G, Wetterberg L. Correction of non-24-hour sleep/wake cycle by melatonin in a blind retarded boy. Ann Neurol 1991;29:336–9.PubMedGoogle Scholar
  86. 86.
    Sack RL, Lewy AJ, Blood ML, Stevenson J, Keith LD. Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms 1991;6:249–61.PubMedGoogle Scholar
  87. 87.
    Tzischinsky O, Pal I, Epstein R, Dagan Y, Lavie P. The importance of timing in melatonin administration in a blind man. J Pineal Res 1992;12:105–8.PubMedGoogle Scholar
  88. 88.
    Lapierre O, Dumont M. Melatonin treatment of a non-24-hour sleep-wake cycle in a blind retarded child. Biol Psychiatry 1995;38:119–22.CrossRefPubMedGoogle Scholar
  89. 89.
    Arendt J, Aldhous M, Wright J. Synchronisation of a disturbed sleep-wake cycle in a blind man by melatonin treatment (letter). Lancet 1988;1:772–3.CrossRefGoogle Scholar
  90. 90.
    Cavallo A. The pineal gland in human beings: relevance to pediatrics. J Pediatr 1993;123:843–51.PubMedGoogle Scholar
  91. 91.
    Arendt J, Aldhous M, English J, Marks V, Arendt JH. Some effects of jet-lag and their alleviation by melatonin. Ergonomics 1987;30:1379–93.Google Scholar
  92. 92.
    Skene DJ, Aldhous M, Arendt J. Melatonin, jet-lag and the sleep-wake cycle. In Sleep'88. Proceedings of the Ninth European Congress on Sleep Research, Jerusalem 1988. Horne J, ed. Stuttgart: Gustav Fischer Verlag, 1989;39.Google Scholar
  93. 93.
    Claustrat B, Brun J, David M, Sassolas G, Chazot G. Melatonin and jet lag: confirmatory result using a simplified protocol. Biol Psychiatry 1992;32:705–11.CrossRefPubMedGoogle Scholar
  94. 94.
    Arendt J, Deacon S, English J, Hampton S, Morgan L. Melatonin and adjustment to phase shift. J Sleep Res 1995;4,Suppl.2:74–9.PubMedGoogle Scholar
  95. 95.
    Nickelsen T, Lang A, Bergau L. The effect of 6-, 9-and 11-hour time shifts on circadian rhythms: adaptation of sleep parameters and hormonal patterns following the intake of melatonin or placebo. Adv Pineal Res 1991;5:303–6.Google Scholar
  96. 96.
    Folkard S, Arendt J, Clark M. Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Chronobiol Int 1993;10:315–20.PubMedGoogle Scholar
  97. 97.
    Skene DJ, Deacon S, Arendt J. Use of melatonin in circadian rhythm disorders and following phase shifts. Acta Neurobiol Exp 1996;56:359–62.Google Scholar
  98. 98.
    Haimov I, Lavie P. Potential of melatonin replacement therapy in older patients with sleep disorders. Drugs Aging 1995;2:75–8.Google Scholar
  99. 99.
    Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy of elderly insomniacs. Sleep 1995;18:598–603.PubMedGoogle Scholar
  100. 100.
    Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995;346:541–4.CrossRefPubMedGoogle Scholar
  101. 101.
    Etzioni A, Luboshitsky R, Tiosano D, Ben-Harush M, Goldsher D, Lavie P. Melatonin replacement corrects sleep disturbances in a child with pineal tumor. Neurol 1996;46:261–3.Google Scholar
  102. 102.
    Singer C, McArthur A, Hughes R, Jackon J, Moffit M, Sack R, Lewy AJ. Melatonin administration and sleep in the elderly. In: Hypothalamic Integration of Circadian Rhythm, 19th International Summer School of Brain Research, Amsterdam, 1995;103.Google Scholar
  103. 103.
    Dollins AB, Zhdanova IV, Wurtman JR, Lynch HJ, Deng MH. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci USA 1994;91:1824–8.PubMedGoogle Scholar
  104. 104.
    Zhdanova IV, Wurtman RJ, Lynch HJ, Ives JR, Dollins AB, Morabito C, Matheson JK, Schomer DL. Sleep-inducing effect of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 1995;57;552–8.PubMedGoogle Scholar
  105. 105.
    Attenburrow MEJ, Cowen PJ, Sharpley AL. Low dose of melatonin improves sleep in healthy middle-aged subjects. Psychopharmacol 1996;126:179–81.Google Scholar
  106. 106.
    Wirz-Justice A, Armstrong SM. Melatonin: nature's soporific? J Sleep Res 1996;5:137–41.PubMedGoogle Scholar
  107. 107.
    Brzezinski A. Melatonin in humans. New England J Med 1997;336:186–95.CrossRefGoogle Scholar
  108. 108.
    Webb SM, Puig-Domingo M. Role of melatonin in health and disease. Clin Endocrinol 1995;42:221–34.Google Scholar
  109. 109.
    Reiter RJ, Melchiori D, Sewerynek E, Poeggeler B, Barlow-Walden L, Chuang J, Ortiz GG, Acuna-Castroviejo D. A review of the evidence supporting melatonin's role as an antioxidant. J Pineal Res 1995;18:1–11.PubMedGoogle Scholar
  110. 110.
    Pierrefiche G, Laborit H. Oxygen free radicals, melatonin, and aging. Exp Gerontology 1995;30:213–27.CrossRefGoogle Scholar
  111. 111.
    Blask DE. Melatonin in oncology. In: Yu HS and Reiter RJ, eds. Melatonin: Biosynthesis, Physiological Effects, and Clinical Applications. Boca Raton: CRC Press, 1993;447.Google Scholar
  112. 112.
    Maestroni GJM, Conti A. Melatonin and the immune system. In: Touitou Y, Arendt J and Pévet P, eds. Melatonin and the Pineal Gland ¶ From Basic Science to Clinical Application. Amsterdam: Excerpta Medica, 1993:295.Google Scholar
  113. 113.
    Pieri C, Marra M, Moronin F, Recchioni R, Marcheselli F. Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci 1994;55:271–6.CrossRefGoogle Scholar
  114. 114.
    Giusti P, Guselle M, Lipartiti M, Milani D, Zhu W, Vicini S, Manev H. Melatonin protects primary cultures of cerebellar granule neurons from kainate but not from N-methyl-Daspartate excitotoxicity. Exp Neurol 1995;131:39–46.CrossRefPubMedGoogle Scholar
  115. 115.
    Lissoni P, Barni S, Cattaneo G, Tancini G, Esposti G, Fraschini F. Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 1991;48:448–50.PubMedGoogle Scholar
  116. 116.
    Lissoni P, Barni S, Brivio F, Rossini F, Fumagalli L, Ardizzoia A, Tancini G. A biological study on the efficacy of low dose subcutaneous interleukin-2 plus melatonin in the treatment of cancer-related thrombocytopenia. Oncology 1995;52:360–2.PubMedGoogle Scholar
  117. 117.
    Lissoni P, Meregalli S, Nosetto L, Barni S, Tancini G, Fossati V, Maestroni G. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 1996;53:43–6.PubMedGoogle Scholar
  118. 118.
    Nagtegaal S, Smits M, Swart W, van der Meer G, Kerkhof G. Melatonin secretion and coronary heart disease (letter). Lancet 1995;346:1299.CrossRefPubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • J.Z. Nowak
    • 1
  • J.B. Zawilska
    • 2
    • 1
  1. 1.Institute of Biogenic AminesPolish Academy of SciencesLódźPoland
  2. 2.Department of PharmacodynamicsMedical University of LódźPoland

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