Cellular and Molecular Life Sciences

, Volume 71, Issue 16, pp 2997–3025 | Cite as

Extrapineal melatonin: sources, regulation, and potential functions

  • Darío Acuña-Castroviejo
  • Germaine Escames
  • Carmen Venegas
  • María E. Díaz-Casado
  • Elena Lima-Cabello
  • Luis C. López
  • Sergio Rosales-Corral
  • Dun-Xian Tan
  • Russel J. Reiter
Review

Abstract

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.

Keywords

Melatonin receptors Oxidative stress Free radicals Mitochondria Cytoprotection Homeostasis 

References

  1. 1.
    Lerner AB, Case JD, Takahasi Y, Lee TH, Mori W (1958) Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc 80:2587Google Scholar
  2. 2.
    Cardinali DP, Rosner JM (1971) Retinal localization of the hydroxyindole-O-methyl transferase (HIOMT) in the rat. Endocrinology 89:301–303PubMedGoogle Scholar
  3. 3.
    Bubenik GA, Brown GM, Uhlir I, Grota LJ (1974) Immunohistological localization of N-acetylindolealkylamines in pineal gland, retina and cerebellum. Brain Res 81:233–242PubMedGoogle Scholar
  4. 4.
    Stefulj J, Hortner M, Ghosh M, Schauenstein K, Rinner I, Wolfler A, Semmler J, Liebmann PM (2001) Gene expression of the key enzymes of melatonin synthesis in extrapineal tissues of the rat. J Pineal Res 30:243–247PubMedGoogle Scholar
  5. 5.
    Reiter RJ (1991) Melatonin: that ubiquitously-acting pineal hormone. News Physiol Sci 6:223–227Google Scholar
  6. 6.
    Tan DX, Manchester LC, Hardeland R, Lopez-Burillo S, Mayo JC, Sainz RM, Reiter RJ (2003) Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res 34:75–78PubMedGoogle Scholar
  7. 7.
    Reiter RJ, Fuentes-Broto L, Tan DX (2010) Melatonin: a multitasking molecule. Prog Brain Res 181:127–151PubMedGoogle Scholar
  8. 8.
    Vlahakes GJ, Wurtman RJ (1972) A Mg 2+ dependent hydroxyindole O-methyltransferase in rat Harderian gland. Biochim Biophys Acta 261:194–197PubMedGoogle Scholar
  9. 9.
    Reiter RJ, Richardson BA, Matthews SA, Lane SJ, Ferguson BN (1983) Rhythms in immunoreactive melatonin in the retina and Harderian gland of rats: persistence after pinealectomy. Life Sci 32:1229–1236PubMedGoogle Scholar
  10. 10.
    Raikhlin NT, Kvetnoy IM, Tolkachev VN (1975) Melatonin may be synthesised in enterochromaffin cells. Nature 255:344–345PubMedGoogle Scholar
  11. 11.
    Raikhlin NT, Kvetnoy IM (1976) Melatonin and enterochromaffine cells. Acta Histochem 55:19–24PubMedGoogle Scholar
  12. 12.
    Ozaki Y, Lynch HJ (1976) Presence of melatonin in plasma and urine or pinealectomized rats. Endocrinology 99:641–644PubMedGoogle Scholar
  13. 13.
    Poeggeler B, Cornelissen G, Huether G, Hardeland R, Jozsa R, Zeman M, Stebelova K, Olah A, Bubenik G, Pan W, Otsuka K, Schwartzkopff O, Bakken EE, Halberg F (2005) Chronomics affirm extending scope of lead in phase of duodenal vs. pineal circadian melatonin rhythms. Biomed Pharmacother 59(Suppl 1):S220–S224Google Scholar
  14. 14.
    Sanchez-Hidalgo M, de la Lastra CA, Carrascosa-Salmoral MP, Naranjo MC, Gomez-Corvera A, Caballero B, Guerrero JM (2009) Age-related changes in melatonin synthesis in rat extrapineal tissues. Exp Gerontol 44:328–334PubMedGoogle Scholar
  15. 15.
    Venegas C, García JA, Escames G, Ortiz F, López A, Doerrier C, García Corzo L, López LC, Reiter RJ, Acuña-Castroviejo D (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52:217–227PubMedGoogle Scholar
  16. 16.
    Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1:52–60Google Scholar
  17. 17.
    Reiter RJ, Paredes SD, Manchester LC, Tan DX (2009) Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol 44:175–200PubMedGoogle Scholar
  18. 18.
    Korkmaz A, Reiter RJ, Topal T, Manchester LC, Oter S, Tan DX (2009) Melatonin: an established antioxidant worthy of use in clinical trials. Mol Med 15:43–50PubMedCentralPubMedGoogle Scholar
  19. 19.
    Bonnefont-Rousselot D, Collin F, Jore D, Gardes-Albert M (2011) Reaction mechanism of melatonin oxidation by reactive oxygen species in vitro. J Pineal Res 50:328–335PubMedGoogle Scholar
  20. 20.
    Hardeland R, Madrid JA, Tan DX, Reiter RJ (2012) Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling. J Pineal Res 52:139–166PubMedGoogle Scholar
  21. 21.
    Reppert SM, Weaver DR, Ebisawa T (1994) Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13:1177–1185PubMedGoogle Scholar
  22. 22.
    Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF (1995) Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci USA 92:8734–8738PubMedCentralPubMedGoogle Scholar
  23. 23.
    Dubocovich ML, Markowska M (2005) Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 27:101–110PubMedGoogle Scholar
  24. 24.
    Brydon L, Roka F, Petit L, de CP, Tissot M, Barrett P, Morgan PJ, Nanoff C, Strosberg AD, Jockers R (1999) Dual signaling of human Mel1a melatonin receptors via G(i2), G(i3), and G(q/11) proteins. Mol Endocrinol 13:2025–2038Google Scholar
  25. 25.
    Petit L, Lacroix I, de CP, Strosberg AD, Jockers R (1999) Differential signaling of human Mel1a and Mel1b melatonin receptors through the cyclic guanosine 3′-5′-monophosphate pathway. Biochem Pharmacol 58:633–639Google Scholar
  26. 26.
    Garcia-Perganeda A, Pozo D, Guerrero JM, Calvo JR (1997) Signal transduction for melatonin in human lymphocytes: involvement of a pertussis toxin-sensitive G protein. J Immunol 159:3774–3781PubMedGoogle Scholar
  27. 27.
    Nosjean O, Ferro M, Coge F, Beauverger P, Henlin JM, Lefoulon F, Fauchere JL, Delagrange P, Canet E, Boutin JA (2000) Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 275:31311–31317PubMedGoogle Scholar
  28. 28.
    Acuña-Castroviejo D, Reiter RJ, Menéndez Peláez A, Pablos MI, Burgos A (1994) Characterization of high-affinity melatonin binding sites in purified cell nuclei of rat liver. J Pineal Res 16:100–112PubMedGoogle Scholar
  29. 29.
    Becker-Andre M, Wiesenberg I, Schaeren-Wiemers N, Andre E, Missbach M, Saurat JH, Carlberg C (1994) Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem 269:28531–28534PubMedGoogle Scholar
  30. 30.
    Wiesenberg I, Missbach M, Carlberg C (1998) The potential role of the transcription factor RZR/ROR as a mediator of nuclear melatonin signaling. Restor Neurol Neurosci 12:143–150PubMedGoogle Scholar
  31. 31.
    Benitez-King G, Huerto-Delgadillo L, Anton-Tay F (1993) Binding of 3H-melatonin to calmodulin. Life Sci 53:201–207PubMedGoogle Scholar
  32. 32.
    Macias M, Escames G, León J, Coto-Montes A, Sbihi Y, Osuna A, Acuña-Castroviejo D (2003) Calreticulin-melatonin. An unexpected relationship. Eur J Biochem 270:832–840PubMedGoogle Scholar
  33. 33.
    Moore RY (2007) Suprachiasmatic nucleus in sleep-wake regulation. Sleep Med 8(Suppl 3):27–33PubMedGoogle Scholar
  34. 34.
    Sugden D, Klein DC (1983) Beta-adrenergic receptor control of rat pineal hydroxyindole-O-methyltransferase. Endocrinology 113:348–353PubMedGoogle Scholar
  35. 35.
    Schomerus C, Maronde E, Laedtke E, Korf HW (1996) Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) induce phosphorylation of the transcription factor CREB in subpopulations of rat pinealocytes: immunocytochemical and immunochemical evidence. Cell Tissue Res 286:305–313PubMedGoogle Scholar
  36. 36.
    Gonzalez S, Moreno-Delgado D, Moreno E, Perez-Capote K, Franco R, Mallol J, Cortes A, Casado V, Lluis C, Ortiz J, Ferre S, Canela E, McCormick PJ (2012) Circadian-related heteromerization of adrenergic and dopamine D(4) receptors modulates melatonin synthesis and release in the pineal gland. PLoS Biol 10:e1001347PubMedCentralPubMedGoogle Scholar
  37. 37.
    Klein DC (2007) Arylalkylamine N-acetyltransferase: “the Timezyme”. J Biol Chem 282:4233–4237PubMedGoogle Scholar
  38. 38.
    Ribelayga C, Pevet P, Simonneaux V (2000) HIOMT drives the photoperiodic changes in the amplitude of the melatonin peak of the Siberian hamster. Am J Physiol Regul Integr Comp Physiol 278:R1339–R1345PubMedGoogle Scholar
  39. 39.
    Cardinali DP, Lynch HJ, Wurtman RJ (1972) Binding of melatonin to human and rat plasma proteins. Endocrinology 91:1213–1218PubMedGoogle Scholar
  40. 40.
    Stehle JH, Saade A, Rawashdeh O, Ackermann K, Jilg A, Sebesteny T, Maronde E (2011) A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases. J Pineal Res 51:17–43PubMedGoogle Scholar
  41. 41.
    Coon SL, Del OE, Young WS III, Klein DC (2002) Melatonin synthesis enzymes in Macaca mulatta: focus on arylalkylamine N-acetyltransferase (EC 2.3.1.87). J Clin Endocrinol Metab 87:4699–4706PubMedGoogle Scholar
  42. 42.
    Maronde E, Saade A, Ackermann K, Goubran-Botros H, Pagan C, Bux R, Bourgeron T, Dehghani F, Stehle JH (2011) Dynamics in enzymatic protein complexes offer a novel principle for the regulation of melatonin synthesis in the human pineal gland. J Pineal Res 51:145–155PubMedGoogle Scholar
  43. 43.
    Hardeland R, Poeggeler B (2012) Melatonin and synthetic melatonergic agonists: actions and metabolism in the central nervous system. Cent Nerv Syst Agents Med Chem 12:189–216PubMedGoogle Scholar
  44. 44.
    Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ (2004) Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36:1–9PubMedGoogle Scholar
  45. 45.
    Goldsmith CS, Bell-Pedersen D (2013) Diverse roles for MAPK signaling in circadian clocks. Adv Genet 84:1–39PubMedGoogle Scholar
  46. 46.
    Luchetti F, Canonico B, Betti M, Arcangeletti M, Pilolli F, Piroddi M, Canesi L, Papa S, Galli F (2010) Melatonin signaling and cell protection function. FASEB J 24:3603–3624PubMedGoogle Scholar
  47. 47.
    Jarzynka MJ, Passey DK, Johnson DA, Konduru NV, Fitz NF, Radio NM, Rasenick M, Benloucif S, Melan MA, Witt-Enderby PA (2009) Microtubules modulate melatonin receptors involved in phase-shifting circadian activity rhythms: in vitro and in vivo evidence. J Pineal Res 46:161–171PubMedCentralPubMedGoogle Scholar
  48. 48.
    Luchetti F, Betti M, Canonico B, Arcangeletti M, Ferri P, Galli F, Papa S (2009) ERK MAPK activation mediates the antiapoptotic signaling of melatonin in UVB-stressed U937 cells. Free Radic Biol Med 46:339–351PubMedGoogle Scholar
  49. 49.
    Imbesi M, Uz T, Dzitoyeva S, Giusti P, Manev H (2008) Melatonin signaling in mouse cerebellar granule cells with variable native MT1 and MT2 melatonin receptors. Brain Res 1227:19–25PubMedCentralPubMedGoogle Scholar
  50. 50.
    Baba K, Benleulmi-Chaachoua A, Journe AS, Kamal M, Guillaume JL, Dussaud S, Gbahou F, Yettou K, Liu C, Contreras-Alcantara S, Jockers R, Tosini G (2013) Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Sci Signal 6:ra89Google Scholar
  51. 51.
    León J, Macias M, Escames G, Camacho E, Khaldy H, Martin M, Espinosa A, Gallo MA, Acuña-Castroviejo D (2000) Structure-related inhibition of calmodulin-dependent nNOS activity by melatonin and synthetic knurenines. Mol Pharmacol 58:967–975Google Scholar
  52. 52.
    Tomás-Zapico T, Álvarez-García O, Sierra V, Vega-Naredo I, Caballero B, García JJ, Acuña-Castroviejo D, Rodríguez MI, Tolivia D, Rodríguez-Colunga MJ, Coto-Montes A (2006) Oxidative damage in liver of senescence accelerated mice: gender-related response 4574. Can J Physiol Pharmacol 84:213–220PubMedGoogle Scholar
  53. 53.
    Acuña-Castroviejo D, López LC, Escames G, López A, García JA, Reiter RJ (2011) Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 11:221–240PubMedGoogle Scholar
  54. 54.
    Acuña-Castroviejo D, Martín M, Macías M, Escames G, León J, Khaldy H, Reiter RJ (2001) Melatonin, mitochondria and cellular bioenergetics. J Pineal Res 30:65–74PubMedGoogle Scholar
  55. 55.
    Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R (2002) Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2:181–197PubMedGoogle Scholar
  56. 56.
    Tomas-Zapico C, Coto-Montes A (2005) A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 39:99–104PubMedGoogle Scholar
  57. 57.
    Venegas C, García JA, Doerrier C, Volt H, Escames G, López LC, Reiter RJ, Acuña-Castroviejo D (2012) Analysis of the daily changes of melatonin receptors in the rat liver. J Pineal Res. doi:10.1111/jpi.12019 Google Scholar
  58. 58.
    Sánchez-Sánchez AM, Martin V, Garcia-Santos G, Rodriguez-Blanco J, Casado-Zapico S, Suarez-Garnacho S, Antolin I, Rodriguez C (2011) Intracellular redox state as determinant for melatonin antiproliferative vs cytotoxic effects in cancer cells. Free Radic Res 45:1333–1341PubMedGoogle Scholar
  59. 59.
    Muxel SM, Pires-Lapa MA, Monteiro AW, Cecon E, Tamura EK, Floeter-Winter LM, Markus RP (2012) NF-kappaB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene. PLoS One 7:e52010PubMedCentralPubMedGoogle Scholar
  60. 60.
    Cristofanon S, Uguccioni F, Cerella C, Radogna F, Dicato M, Ghibelli L, Diederich M (2009) Intracellular prooxidant activity of melatonin induces a survival pathway involving NF-kappaB activation. Ann N Y Acad Sci 1171:472–478PubMedGoogle Scholar
  61. 61.
    Bizzarri M, Proietti S, Cucina A, Reiter RJ (2013) Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert Opin Ther Targets 17:1483–1496PubMedGoogle Scholar
  62. 62.
    Kadoma Y, Fujisawa S (2011) Radical-scavenging activity of melatonin, either alone or in combination with vitamin E, ascorbate or 2-mercaptoethanol as co-antioxidants, using the induction period method. In Vivo 25:49–53PubMedGoogle Scholar
  63. 63.
    Poynton RA, Hampton MB (2014) Peroxiredoxins as biomarkers of oxidative stress. Biochim Biophys Acta 1840:906–912PubMedGoogle Scholar
  64. 64.
    O’Neill JS, van OG, Dixon LE, Troein C, Corellou F, Bouget FY, Reddy AB, Millar AJ (2011) Circadian rhythms persist without transcription in a eukaryote. Nature 469:554–558Google Scholar
  65. 65.
    Edgar RS, Green EW, Zhao Y, van OG, Olmedo M, Qin X, Xu Y, Pan M, Valekunja UK, Feeney KA, Maywood ES, Hastings MH, Baliga NS, Merrow M, Millar AJ, Johnson CH, Kyriacou CP, O’Neill JS, Reddy AB (2012) Peroxiredoxins are conserved markers of circadian rhythms. Nature 485:459–464Google Scholar
  66. 66.
    Sung JH, Cho EH, Kim MO, Koh PO (2009) Identification of proteins differentially expressed by melatonin treatment in cerebral ischemic injury–a proteomics approach. J Pineal Res 46:300–306PubMedGoogle Scholar
  67. 67.
    Kvetnoy IM (1999) Extrapineal melatonin: location and role within diffuse neuroendocrine system. Histochem J 31:1–12PubMedGoogle Scholar
  68. 68.
    Menendez-Pelaez A, Reiter RJ (1993) Distribution of melatonin in mammalian tissues: the relative importance of nuclear versus cytosolic localization. J Pineal Res 15:59–69PubMedGoogle Scholar
  69. 69.
    Lapi D, Vagnani S, Cardaci E, Paterni M, Colantuoni A (2011) Rat pial microvascular responses to melatonin during bilateral common carotid artery occlusion and reperfusion. J Pineal Res 51:136–144PubMedGoogle Scholar
  70. 70.
    Huether G, Poeggeler B, Reimer A, George A (1992) Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Life Sci 51:945–953PubMedGoogle Scholar
  71. 71.
    Sjoblom M, Flemstrom G (2003) Melatonin in the duodenal lumen is a potent stimulant of mucosal bicarbonate secretion. J Pineal Res 34:288–293PubMedGoogle Scholar
  72. 72.
    LeRoith D, McGuinness M, Shemer J, Stannard B, Lanau F, Faria TN, Kato H, Werner H, Adamo M, Roberts CT Jr (1992) Insulin-like growth factors. Biol Signals 1:173–181PubMedGoogle Scholar
  73. 73.
    Mackenzie SM, Connell JM, Davies E (2012) Non-adrenal synthesis of aldosterone: a reality check. Mol Cell Endocrinol 350:163–167PubMedGoogle Scholar
  74. 74.
    Young SN, Gauthier S, Kiely ME, Lal S, Brown GM (1984) Effect of oral melatonin administration on melatonin, 5-hydroxyindoleacetic acid, indoleacetic acid, and cyclic nucleotides in human cerebrospinal fluid. Neuroendocrinology 39:87–92PubMedGoogle Scholar
  75. 75.
    Reppert SM, Perlow MJ, Tamarkin L, Klein DC (1979) A diurnal melatonin rhythm in primate cerebrospinal fluid. Endocrinology 104:295–301PubMedGoogle Scholar
  76. 76.
    Skinner DC, Malpaux B (1999) High melatonin concentrations in third ventricular cerebrospinal fluid are not due to Galen vein blood recirculating through the choroid plexus. Endocrinology 140:4399–4405PubMedGoogle Scholar
  77. 77.
    Tan DX, Manchester LC, Sanchez-Barcelo E, Mediavilla MD, Reiter RJ (2010) Significance of high levels of endogenous melatonin in Mammalian cerebrospinal fluid and in the central nervous system. Curr Neuropharmacol 8:162–167PubMedCentralPubMedGoogle Scholar
  78. 78.
    Jimenez-Jorge S, Guerrero JM, Jimenez-Caliani AJ, Naranjo MC, Lardone PJ, Carrillo-Vico A, Osuna C, Molinero P (2007) Evidence for melatonin synthesis in the rat brain during development. J Pineal Res 42:240–246PubMedGoogle Scholar
  79. 79.
    Deguchi T (1978) Ontogenesis of circadian rhythm of melatonin synthesis in pineal gland of rat. J Neural Transm Suppl 13:115–128Google Scholar
  80. 80.
    Uz T, Qu T, Sugaya K, Manev H (2002) Neuronal expression of arylalkylamine N-acetyltransferase (AANAT) mRNA in the rat brain. Neurosci Res 42:309–316PubMedGoogle Scholar
  81. 81.
    Uz T, Ahmed R, Akhisaroglu M, Kurtuncu M, Imbesi M, Dirim AA, Manev H (2005) Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum. Neuroscience 134:1309–1316PubMedGoogle Scholar
  82. 82.
    Pang SF, Brown GM (1983) Regional concentrations of melatonin in the rat brain in the light and dark period. Life Sci 33:1199–1204PubMedGoogle Scholar
  83. 83.
    Hardeland R (2010) Melatonin metabolism in the central nervous system. Curr Neuropharmacol 8:168–171PubMedCentralPubMedGoogle Scholar
  84. 84.
    Sallanon M, Claustrat B, Touret M (1982) Presence of melatonin in various cat brainstem nuclei determined by radioimmunoassay. Acta Endocrinol (Copenh) 101:161–165Google Scholar
  85. 85.
    Reiter RJ (1986) Normal patterns of melatonin levels in the pineal gland and body fluids of humans and experimental animals. J Neural Transm Suppl 21:35–54PubMedGoogle Scholar
  86. 86.
    Liu YJ, Zhuang J, Zhu HY, Shen YX, Tan ZL, Zhou JN (2007) Cultured rat cortical astrocytes synthesize melatonin: absence of a diurnal rhythm. J Pineal Res 43:232–238PubMedGoogle Scholar
  87. 87.
    Liu YJ, Meng FT, Wang LL, Zhang LF, Cheng XP, Zhou JN (2012) Apolipoprotein E influences melatonin biosynthesis by regulating NAT and MAOA expression in C6 cells. J Pineal Res 52:397–402PubMedGoogle Scholar
  88. 88.
    Acuña-Castroviejo D, Lowenstein PR, Rosenstein RE, Cardinali DP (1986) Diurnal variations of benzodiapine binding in rat cerebral cortex: disruption by pinealectomy. J Pineal Res 3:101–109PubMedGoogle Scholar
  89. 89.
    Acuña-Castroviejo D, Romero HE, Cardinali DP (1986) Changes in gamma-aminobutiryc acid hight affinity binding to cerebral cortex membranes after pinealectomy or melatonin administrations to rats. Neuroendocrinology 43:24–31PubMedGoogle Scholar
  90. 90.
    Acuña-Castroviejo D, Fernández B, Gomar MD, Del Aguila CM, Castillo JL (1990) Influence of the pituitary-adrenal axis on benzodiazepine receptor binding to rat cerebral cortex. Neuroendocrinology 51:97–103Google Scholar
  91. 91.
    Gomar MD, Fernández B, Castillo JL, Del Aguila CM, Acuña-Castroviejo D (1993) Melatonin counteracts pinealectomy-dependent decreases in rat brain [3H] flunitrazepam binding through an opioid mechanism. Neurosci Lett 164:149–153PubMedGoogle Scholar
  92. 92.
    Acuña-Castroviejo D, Escames G, Macías M, Muñoz-Hoyos A, Molina-Carballo A, Arauzo M, Montes R, Vives F (1995) Cell protective role of melatonin in the brain. J Pineal Res 19:57–63PubMedGoogle Scholar
  93. 93.
    Khaldy H, Leon J, Escames G, Bikjdaouene L, Garcia JJ, Acuña-Castroviejo D (2002) Circadian rhythms of dopamine and dihydroxyphenyl acetic acid in the mouse striatum: effects of pinealectomy and of melatonin treatment. Neuroendocrinology 75:201–208PubMedGoogle Scholar
  94. 94.
    Marquez de Prado B, Castaneda TR, Galindo A, del AA, Segovia G, Reiter RJ, Mora F (2000) Melatonin disrupts circadian rhythms of glutamate and GABA in the neostriatum of the aware rat: a microdialysis study. J Pineal Res 29:209–216Google Scholar
  95. 95.
    de Prado BM, Reiter RJ, Mora F (2003) Perfusion of melatonin into the prefrontal cortex disrupts the circadian rhythm of acetylcholine but not of locomotor activity. J Pineal Res 35:283–287PubMedGoogle Scholar
  96. 96.
    Castaneda TR, de Prado BM, Prieto D, Mora F (2004) Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: modulation by light. J Pineal Res 36:177–185PubMedGoogle Scholar
  97. 97.
    Acuña-Castroviejo D, Castillo JL, Fernández B, Gomar MD, Del Aguila CM (1992) Modulation by pineal gland of ouabain high affinity binding sites in rat cerebral cortex. Am J Physiol 262:R698–R706PubMedGoogle Scholar
  98. 98.
    Castillo JL, Vives F, Reiter RJ, Acuña-Castroviejo D (1993) Pineal modulation of the rat caudate-putamen spontaneous neuronal activity: roles of melatonin and vasotocin. J Pineal Res 15:147–152Google Scholar
  99. 99.
    Escames G, Macías M, León J, García JJ, Khaldy H, Martín M, Vives F, Acuña-Castroviejo D (2001) Calcium-dependent effects of melatonin inhibition of glutamatergic response in rat striatum. J Neuroendocrinol 13:459–466PubMedGoogle Scholar
  100. 100.
    Khaldy H, León J, Escames G, Bikjdaouene L, Acuña-Castroviejo D (2003) Synergistic effects of melatonin and deprenyl protect against MPTP-induced mitochondrial damage and DA depletion. Neurobiol Aging 24:491–500PubMedGoogle Scholar
  101. 101.
    Molina-Carballo A, Muñoz-Hoyos A, Reiter RJ, Sánchez-Forte M, Moreno-Madrid F, Rufo-Campos M, Molina-Font JA, Acuña-Castroviejo D (1997) Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a child with severe myoclonic experience: two years’ experience. J Pineal Res 23:97–105PubMedGoogle Scholar
  102. 102.
    Bikjdaouene L, Escames G, León J, Ferrer JMR, Khaldy H, Vives F, Acuña-Castroviejo D (2003) Changes in brain amino acids and nitric oxide after melatonin administration to pentylenetetrazole-induced seizures in rats. J Pineal Res 35:54–60PubMedGoogle Scholar
  103. 103.
    Molina-Carballo A, Muñoz-Hoyos A, Sánchez-Forte M, Uberos-Fernández J, Moreno-Madrid F, Acuña-Castroviejo D (2007) Melatonin increases following convulsive seizures may be related to its anticonvulsant properties at physiological concentrations. Neuropediatrics 38:122–125PubMedGoogle Scholar
  104. 104.
    Philo R, Reiter RJ (1978) Characterization of pinealectomy induced convulsions in the Mongolian gerbil (Meriones unguiculatus). Epilepsia 19:485–492PubMedGoogle Scholar
  105. 105.
    Anton-Tay F, Diaz JL, Fernandez-Guardiola A (1971) On the effect of melatonin upon human brain. Its possible therapeutic implications. Life Sci I 10:841–850PubMedGoogle Scholar
  106. 106.
    Mason R, Brooks A (1988) The electrophysiological effects of melatonin and a putative melatonin antagonist (N-acetyltryptamine) on rat suprachiasmatic neurones in vitro. Neurosci Lett 95:296–301PubMedGoogle Scholar
  107. 107.
    Cardinali DP, Furio AM, Brusco LI (2011) The use of chronobiotics in the resynchronization of the sleep/wake cycle. Therapeutical application in the early phases of Alzheimer’s disease. Recent Pat Endocr Metab Immune Drug Discov 5:80–90PubMedGoogle Scholar
  108. 108.
    Cardinali DP, Srinivasan V, Brzezinski A, Brown GM (2012) Melatonin and its analogs in insomnia and depression. J Pineal Res 52:365–375PubMedGoogle Scholar
  109. 109.
    Esposito E, Cuzzocrea S (2010) Antiinflamatory activity of melaotnin in central nervous system. Curr Neuropharmacol 8:228–242PubMedCentralPubMedGoogle Scholar
  110. 110.
    Rosales-Corral S, Reiter RJ, Tan DX, Ortiz GG, Lopez-Armas G (2010) Functional aspects of redox control during neuroinflammation. Antioxid Redox Signal 13:193–247PubMedGoogle Scholar
  111. 111.
    Xiong YF, Chen Q, Chen J, Zhou J, Wang HX (2011) Melatonin reduces the impairment of axonal transport and axonopathy induced by calyculin A. J Pineal Res 50:319–327PubMedGoogle Scholar
  112. 112.
    Fu J, Zhao SD, Liu HJ, Yuan QH, Liu SM, Zhang YM, Ling EA, Hao AJ (2011) Melatonin promotes proliferation and differentiation of neural stem cells subjected to hypoxia in vitro. J Pineal Res 51:104–112PubMedGoogle Scholar
  113. 113.
    Kilic U, Yilmaz B, Ugur M, Yuksel A, Reiter RJ, Hermann DM, Kilic E (2012) Evidence that membrane-bound G protein-coupled melatonin receptors MT1 and MT2 are not involved in the neuroprotective effects of melatonin in focal cerebral ischemia. J Pineal Res 52:228–235PubMedGoogle Scholar
  114. 114.
    Rosales-Corral SA, Acuna-Castroviejo D, Coto-Montes A, Boga JA, Manchester LC, Fuentes-Broto L, Korkmaz A, Ma S, Tan DX, Reiter RJ (2012) Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J Pineal Res 52:167–202PubMedGoogle Scholar
  115. 115.
    Dominguez-Alonso A, Ramirez-Rodriguez G, Benitez-King G (2012) Melatonin increases dendritogenesis in the hilus of hippocampal organotypic cultures. J Pineal Res 52:427–436PubMedGoogle Scholar
  116. 116.
    Jimenez-Rubio G, Ortiz-Lopez L, Benitez-King G (2012) Melatonin modulates cytoskeletal organization in the rat brain hippocampus. Neurosci Lett 511:47–51PubMedGoogle Scholar
  117. 117.
    Reiter RJ, Benitez-King G (2009) Melatonn reduces neuronal loss and cytoskeletal deterioration: implications for psychiatry. Salud Mental 32:3–11Google Scholar
  118. 118.
    Chern CM, Liao JF, Wang YH, Shen YC (2012) Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT2 melatonin receptor in ischemic-stroke mice. Free Radic Biol Med 52:1634–1647PubMedGoogle Scholar
  119. 119.
    Manda K, Reiter RJ (2010) Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation. Prog Neurobiol 90:60–68PubMedGoogle Scholar
  120. 120.
    Crupi R, Mazzon E, Marino A, La SG, Bramanti P, Spina E, Cuzzocrea S (2011) Melatonin’s stimulatory effect on adult hippocampal neurogenesis in mice persists after ovariectomy. J Pineal Res 51:353–360PubMedGoogle Scholar
  121. 121.
    Ramirez-Rodriguez G, Ortiz-Lopez L, Dominguez-Alonso A, Benitez-King GA, Kempermann G (2011) Chronic treatment with melatonin stimulates dendrite maturation and complexity in adult hippocampal neurogenesis of mice. J Pineal Res 50:29–37PubMedGoogle Scholar
  122. 122.
    Rennie K, De BM, Pappas BA (2009) Melatonin promotes neurogenesis in dentate gyrus in the pinealectomized rat. J Pineal Res 47:313–317PubMedGoogle Scholar
  123. 123.
    Yoo DY, Kim W, Lee CH, Shin BN, Nam SM, Choi JH, Won MH, Yoon YS, Hwang IK (2012) Melatonin improves d-galactose-induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression. J Pineal Res 52:21–28PubMedGoogle Scholar
  124. 124.
    López LC, Escames G, López A, García JA, Doerrier C, Acuña-Castroviejo D (2010) Melatonin, neurogenesis, and aging brain. Open Neuroendocrinol J 3:121–133Google Scholar
  125. 125.
    Wiechmann AF, Summers JA (2008) Circadian rhythms in the eye: the physiological significance of melatonin receptors in ocular tissues. Prog Retin Eye Res 27:137–160PubMedGoogle Scholar
  126. 126.
    Tosini G, Baba K, Hwang CK, Iuvone PM (2012) Melatonin: an underappreciated player in retinal physiology and pathophysiology. Exp Eye Res 103:82–89PubMedCentralPubMedGoogle Scholar
  127. 127.
    Bubenik GA, Purtill RA, Brown GM, Grota LJ (1978) Melatonin in the retina and the Harderian gland. Ontogeny, diurnal variations and melatonin treatment. Exp Eye Res 27:323–333PubMedGoogle Scholar
  128. 128.
    Yu HS, Pang SF, Tang PL (1981) Increase in the level of retinal melatonin and persistence of its diurnal rhythm in rats after pinealectomy. J Endocrinol 91:477–481PubMedGoogle Scholar
  129. 129.
    Miller L, Stier M, Lovenberg W (1980) Evidence for the presence of N-acetyl transferase in rat retina. Comp Biochem Physiol C 66:213–216PubMedGoogle Scholar
  130. 130.
    Tosini G, Menaker M (1996) Circadian rhythms in cultured mammalian retina. Science 272:419–421PubMedGoogle Scholar
  131. 131.
    Tosini G, Menaker M (1998) The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration. Brain Res 789:221–228PubMedGoogle Scholar
  132. 132.
    Liu C, Fukuhara C, Wessel JH, Iuvone PM, Tosini G (2004) Localization of Aa-nat mRNA in the rat retina by fluorescence in situ hybridization and laser capture microdissection. Cell Tissue Res 315:197–201PubMedGoogle Scholar
  133. 133.
    Wiechmann AF, Burden MA (1999) Regulation of AA-NAT and HIOMT gene expression by butyrate and cyclic AMP in Y79 human retinoblastoma cells. J Pineal Res 27:116–121PubMedGoogle Scholar
  134. 134.
    Zmijewski MA, Sweatman TW, Slominski AT (2009) The melatonin-producing system is fully functional in retinal pigment epithelium (ARPE-19). Mol Cell Endocrinol 307:211–216PubMedCentralPubMedGoogle Scholar
  135. 135.
    Dubocovich ML (1988) Pharmacology and function of melatonin receptors. FASEB J 2:2765–2773PubMedGoogle Scholar
  136. 136.
    Zawilska J, Iuvone PM (1989) Catecholamine receptors regulating serotonin N-acetyltransferase activity and melatonin content of chicken retina and pineal gland: D2-dopamine receptors in retina and alpha-2 adrenergic receptors in pineal gland. J Pharmacol Exp Ther 250:86–92PubMedGoogle Scholar
  137. 137.
    Rosen RB, Hu DN, Chen M, McCormick SA, Walsh J, Roberts JE (2012) Effects of melatonin and its receptor antagonist on retinal pigment epithelial cells against hydrogen peroxide damage. Mol Vis 18:1640–1648PubMedCentralPubMedGoogle Scholar
  138. 138.
    Marchiafava PL, Longoni B (1999) Melatonin as an antioxidant in retinal photoreceptors. J Pineal Res 26:184–189PubMedGoogle Scholar
  139. 139.
    Siu AW, Reiter RJ, To CH (1999) Pineal indoleamines and vitamin E reduce nitric oxide-induced lipid peroxidation in rat retinal homogenates. J Pineal Res 27:122–128PubMedGoogle Scholar
  140. 140.
    Ogino N, Matsumura M, Shirakawa H, Tsukahara I (1983) Phagocytic activity of cultured retinal pigment epithelial cells from chick embryo: inhibition by melatonin and cyclic AMP, and its reversal by taurine and cyclic GMP. Ophthalmic Res 15:72–89PubMedGoogle Scholar
  141. 141.
    Rohde BH, McLaughlin MA, Chiou LY (1985) Existence and role of endogenous ocular melatonin. J Ocul Pharmacol 1:235–243PubMedGoogle Scholar
  142. 142.
    Mhatre MC, van Jaarsveld AS, Reiter RJ (1988) Melatonin in the lacrimal gland: first demonstration and experimental manipulation. Biochem Biophys Res Commun 153:1186–1192PubMedGoogle Scholar
  143. 143.
    Abe M, Itoh MT, Miyata M, Shimizu K, Sumi Y (2000) Circadian rhythm of serotonin N-acetyltransferase activity in rat lens. Exp Eye Res 70:805–808PubMedGoogle Scholar
  144. 144.
    Quay WB (1984) Increases in volume, fluid content, and lens weight of eyes following systemic administration of melatonin. J Pineal Res 1:3–13PubMedGoogle Scholar
  145. 145.
    Abe M, Itoh MT, Miyata M, Ishikawa S, Sumi Y (1999) Detection of melatonin, its precursors and related enzyme activities in rabbit lens. Exp Eye Res 68:255–262PubMedGoogle Scholar
  146. 146.
    Itoh MT, Takahashi N, Abe M, Shimizu K (2007) Expression and cellular localization of melatonin-synthesizing enzymes in the rat lens. J Pineal Res 42:92–96PubMedGoogle Scholar
  147. 147.
    Biesalski HK, Welker HA, Thalmann R, Vollrath L (1988) Melatonin and other serotonin derivatives in the guinea pig membranous cochlea. Neurosci Lett 91:41–46PubMedGoogle Scholar
  148. 148.
    Lopez-Gonzalez MA, Guerrero JM, Delgado F (1997) Presence of the pineal hormone melatonin in rat cochlea: its variations with lighting conditions. J Pineal Res 238:81–83Google Scholar
  149. 149.
    Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (2005) A review of the multiple actions of melatonin on the immune system. Endocrine 27:189–200PubMedGoogle Scholar
  150. 150.
    Carrillo-Vico A, Calvo JR, Abreu P, Lardone PJ, Garcia-Maurino S, Reiter RJ, Guerrero JM (2004) Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance. FASEB J 18:537–539PubMedGoogle Scholar
  151. 151.
    Carrillo-Vico A, Lardone PJ, Fernandez-Santos JM, Martin-Lacave I, Calvo JR, Karasek M, Guerrero JM (2005) Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system. J Clin Endocrinol Metab 90:992–1000PubMedGoogle Scholar
  152. 152.
    Jimenez-Jorge S, Jimenez-Caliani AJ, Guerrero JM, Naranjo MC, Lardone PJ, Carrillo-Vico A, Osuna C, Molinero P (2005) Melatonin synthesis and melatonin-membrane receptor (MT1) expression during rat thymus development: role of the pineal gland. J Pineal Res 39:77–83PubMedGoogle Scholar
  153. 153.
    Naranjo MC, Guerrero JM, Rubio A, Lardone PJ, Carrillo-Vico A, Carrascosa-Salmoral MP, Jimenez-Jorge S, Arellano MV, Leal-Noval SR, Leal M, Lissen E, Molinero P (2007) Melatonin biosynthesis in the thymus of humans and rats. Cell Mol Life Sci 64:781–790PubMedGoogle Scholar
  154. 154.
    Pang SF, Tang PL, Yu HS, Yip MK (1982) The level of N-acetylserotonin and melatonin in the brain of male rats: diurnal variations and effects of pinealectomy. J Exp Zool 219:271–276PubMedGoogle Scholar
  155. 155.
    Tamarkin L, Reppert SM, Klein DC, Pratt B, Goldman BD (1980) Studies on the daily pattern of pineal melatonin in the Syrian hamster. Endocrinology 107:1525–1529PubMedGoogle Scholar
  156. 156.
    Martins E Jr, Ferreira AC, Skorupa AL, Afeche SC, Cipolla-Neto J, Costa Rosa LF (2004) Tryptophan consumption and indoleamines production by peritoneal cavity macrophages. J Leukoc Biol 75:1116–1121PubMedGoogle Scholar
  157. 157.
    Escames G, Khaldy H, León López J, González L, Acuña-Castroviejo D (2004) Changes in iNOS activity, oxidative stress and melatonin levels in hypertensive patients treated with lacidipine 4489. J Hypertens 22:629–635PubMedGoogle Scholar
  158. 158.
    Tan DX, Manchester LC, Reiter RJ, Qi WB, Zhang M, Weintraub ST, Cabrera J, Sainz RM, Mayo JC (1999) Identification of highly elevated levels of melatonin in bone marrow: its origin and significance. Biochim Biophys Acta 1472:206–214PubMedGoogle Scholar
  159. 159.
    Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM (2000) Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res 28:193–202PubMedGoogle Scholar
  160. 160.
    Kuehn HS, Gilfillan AM (2007) G protein-coupled receptors and the modification of FcepsilonRI-mediated mast cell activation. Immunol Lett 113:59–69PubMedCentralPubMedGoogle Scholar
  161. 161.
    Maldonado MD, Mora-Santos M, Naji L, Carrascosa-Salmoral MP, Naranjo MC, Calvo JR (2010) Evidence of melatonin synthesis and release by mast cells. Possible modulatory role on inflammation. Pharmacol Res 62:282–287PubMedGoogle Scholar
  162. 162.
    Gaudet SJ, Slominski A, Etminan M, Pruski D, Paus R, Namboodiri MA (1993) Identification and characterization of two isozymic forms of arylamine N-acetyltransferase in Syrian hamster skin. J Invest Dermatol 101:660–665PubMedGoogle Scholar
  163. 163.
    Slominski A, Baker J, Rosano TG, Guisti LW, Ermak G, Grande M, Gaudet SJ (1996) Metabolism of serotonin to N-acetylserotonin, melatonin, and 5-methoxytryptamine in hamster skin culture. J Biol Chem 271:12281–12286PubMedGoogle Scholar
  164. 164.
    Slominski A, Semak I, Pisarchik A, Sweatman T, Szczesniewski A, Wortsman J (2002) Conversion of l-tryptophan to serotonin and melatonin in human melanoma cells. FEBS Lett 511:102–106PubMedGoogle Scholar
  165. 165.
    Slominski A, Pruski D (1993) Melatonin inhibits proliferation and melanogenesis in rodent melanoma cells. Exp Cell Res 206:189–194PubMedGoogle Scholar
  166. 166.
    Cabrera J, Negrin G, Estevez F, Loro J, Reiter RJ, Quintana J (2010) Melatonin decreases cell proliferation and induces melanogenesis in human melanoma SK-MEL-1 cells. J Pineal Res 49:45–54PubMedGoogle Scholar
  167. 167.
    Slominski A, Pisarchik A, Semak I, Sweatman T, Wortsman J, Szczesniewski A, Slugocki G, McNulty J, Kauser S, Tobin DJ, Jing C, Johansson O (2002) Serotoninergic and melatoninergic systems are fully expressed in human skin. FASEB J 16:896–898PubMedGoogle Scholar
  168. 168.
    Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J (2003) Functional activity of serotoninergic and melatoninergic systems expressed in the skin. J Cell Physiol 196:144–153PubMedGoogle Scholar
  169. 169.
    Slominski A, Pisarchik A, Wortsman J (2004) Expression of genes coding melatonin and serotonin receptors in rodent skin. Biochim Biophys Acta 1680:67–70PubMedGoogle Scholar
  170. 170.
    Slominski A, Fischer TW, Zmijewski MA, Wortsman J, Semak I, Zbytek B, Slominski RM, Tobin DJ (2005) On the role of melatonin in skin physiology and pathology. Endocrine 27:137–148PubMedCentralPubMedGoogle Scholar
  171. 171.
    Tunali T, Sener G, Yarat A, Emekli N (2005) Melatonin reduces oxidative damage to skin and normalizes blood coagulation in a rat model of thermal injury. Life Sci 76:1259–1265PubMedGoogle Scholar
  172. 172.
    Izykowska I, Cegielski M, Gebarowska E, Podhorska-Okolow M, Piotrowska A, Zabel M, Dziegiel P (2009) Effect of melatonin on human keratinocytes and fibroblasts subjected to UVA and UVB radiation in vitro. In Vivo 23:739–745PubMedGoogle Scholar
  173. 173.
    Fischer TW, Sweatman TW, Semak I, Sayre RM, Wortsman J, Slominski A (2006) Constitutive and UV-induced metabolism of melatonin in keratinocytes and cell-free systems. FASEB J 20:1564–1566PubMedGoogle Scholar
  174. 174.
    Fischer TW, Slominski A, Zmijewski MA, Reiter RJ, Paus R (2008) Melatonin as a major skin protectant: from free radical scavenging to DNA damage repair. Exp Dermatol 17:713–730PubMedGoogle Scholar
  175. 175.
    Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R (2008) Melatonin in the skin: synthesis, metabolism and functions. Trends Endocrinol Metab 19:17–24PubMedGoogle Scholar
  176. 176.
    Lincoln GA, Ebling FJ (1985) Effect of constant-release implants of melatonin on seasonal cycles in reproduction, prolactin secretion and moulting in rams. J Reprod Fertil 73:241–253PubMedGoogle Scholar
  177. 177.
    Lincoln GA, Klandorf H, Anderson N (1980) Photoperiodic control of thyroid function and wool and horn growth in rams and the effect of cranial sympathectomy. Endocrinology 107:1543–1548PubMedGoogle Scholar
  178. 178.
    Bubenik GA, Brown GM, Grota LJ (1977) Immunohistological localization of melatonin in the rat digestive system. Experientia 33:662–663PubMedGoogle Scholar
  179. 179.
    Bubenik GA (1980) Localization of melatonin in the digestive tract of the rat. Effect of maturation, diurnal variation, melatonin treatment and pinealectomy. Horm Res 12:313–323PubMedGoogle Scholar
  180. 180.
    Bubenik GA (2002) Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 47:2336–2348PubMedGoogle Scholar
  181. 181.
    Hong GX, Pang SF (1995) N-acetyltransferase activity in the quail (Coturnix coturnix jap) duodenum. Comp Biochem Physiol B Biochem Mol Biol 112:251–255PubMedGoogle Scholar
  182. 182.
    Bubenik GA, Pang SF, Hacker RR, Smith PS (1996) Melatonin concentrations in serum and tissues of porcine gastrointestinal tract and their relationship to the intake and passage of food. J Pineal Res 21:251–256PubMedGoogle Scholar
  183. 183.
    Vician M, Zeman M, Herichova I, Jurani M, Blazicek P, Matis P (1999) Melatonin content in plasma and large intestine of patients with colorectal carcinoma before and after surgery. J Pineal Res 27:164–169PubMedGoogle Scholar
  184. 184.
    Huether G (1993) The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experientia 49:665–670PubMedGoogle Scholar
  185. 185.
    Huether G (1994) Melatonin synthesis in the gastrointestinal tract and the impact of nutritional factors on circulating melatonin. Ann N Y Acad Sci 719:146–158PubMedGoogle Scholar
  186. 186.
    Huether G, Messner M, Rodenbeck A, Hardeland R (1998) Effect of continuous melatonin infusions on steady-state plasma melatonin levels in rats under near physiological conditions. J Pineal Res 24:146–151PubMedGoogle Scholar
  187. 187.
    Bubenik GA, Pang SF (1997) Melatonin levels in the gastrointestinal tissues of fish, amphibians, and a reptile. Gen Comp Endocrinol 106:415–419PubMedGoogle Scholar
  188. 188.
    Bubenik GA, Ayles HL, Friendship RM, Brown GM, Ball RO (1998) Relationship between melatonin levels in plasma and gastrointestinal tissues and the incidence and severity of gastric ulcers in pigs. J Pineal Res 24:62–66PubMedGoogle Scholar
  189. 189.
    Bubenik GA (2008) Thirty-four years since the discovery of gastrointestinal melatonin. J Physiol Pharmacol 59(Suppl 2):33–51PubMedGoogle Scholar
  190. 190.
    Messner M, Hardeland R, Rodenbeck A, Huether G (1998) Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions. J Pineal Res 25:251–259PubMedGoogle Scholar
  191. 191.
    Bubenik GA, Brown GM (1997) Pinealectomy reduces melatonin levels in the serum but not in the gastrointestinal tract of rats. Biol Signals 6:40–44PubMedGoogle Scholar
  192. 192.
    Bubenik GA, Ball RO, Pang SF (1992) The effect of food deprivation on brain and gastrointestinal tissue levels of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin. J Pineal Res 12:7–16PubMedGoogle Scholar
  193. 193.
    Chik CL, Ho AK, Brown GM (1987) Effect of food restriction on 24-h serum and pineal melatonin content in male rats. Acta Endocrinol (Copenh) 115:507–513Google Scholar
  194. 194.
    Dubbels R, Reiter RJ, Klenke E, Goebel A, Schnakenberg E, Ehlers C, Schiwara HW, Schloot W (1995) Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J Pineal Res 18:28–31PubMedGoogle Scholar
  195. 195.
    Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ (1995) Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Int 35:627–634PubMedGoogle Scholar
  196. 196.
    Reiter RJ, Manchester LC, Tan DX (2005) Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood. Nutrition 21:920–924PubMedGoogle Scholar
  197. 197.
    Bubenik GA, Pang SF (1994) The role of serotonin and melatonin in gastrointestinal physiology: ontogeny, regulation of food intake, and mutual serotonin-melatonin feedback. J Pineal Res 16:91–99PubMedGoogle Scholar
  198. 198.
    Bubenik GA, Hacker RR, Brown GM, Bartos L (1999) Melatonin concentrations in the luminal fluid, mucosa, and muscularis of the bovine and porcine gastrointestinal tract. J Pineal Res 26:56–63PubMedGoogle Scholar
  199. 199.
    Tan DX, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ (1999) High physiological levels of melatonin in the bile of mammals. Life Sci 65:2523–2529PubMedGoogle Scholar
  200. 200.
    Manchester LC, Poeggeler B, Alvares FL, Ogden GB, Reiter RJ (1995) Melatonin immunoreactivity in the photosynthetic prokaryote Rhodospirillum rubrum: implications for an ancient antioxidant system. Cell Mol Biol Res 41:391–395PubMedGoogle Scholar
  201. 201.
    Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM, Mayo JC, Fuentes-Broto L, Reiter RJ (2010) The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness. Biol Rev Camb Philos Soc 85:607–623PubMedGoogle Scholar
  202. 202.
    Bubenik GA, Pang SF, Cockshut JR, Smith PS, Grovum LW, Friendship RM, Hacker RR (2000) Circadian variation of portal, arterial and venous blood levels of melatonin in pigs and its relationship to food intake and sleep. J Pineal Res 28:9–15PubMedGoogle Scholar
  203. 203.
    Iriti M, Varoni EM, Vitalini S (2010) Melatonin in traditional Mediterranean diets. J Pineal Res 49:101–105PubMedGoogle Scholar
  204. 204.
    Peuhkuri K, Sihvola N, Korpela R (2012) Dietary factors and fluctuating levels of melatonin. Food Nutr Res 56Google Scholar
  205. 205.
    Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ (2009) Phytomelatonin: a review. Exp Bot 60:57–69Google Scholar
  206. 206.
    Boccalandro HE, Gonzalez CV, Wunderlin DA, Silva MF (2011) Melatonin levels, determined by LC-ESI-MS/MS, fluctuate during the day/night cycle in Vitis vinifera cv. Malbec: evidence of its antioxidant role in fruits. J Pineal Res 51:226–232PubMedGoogle Scholar
  207. 207.
    Ramakrishna A, Giridhar P, Sankar KU, Ravishankar GA (2012) Melatonin and serotonin profiles in beans of Coffea species. J Pineal Res 52:470–476PubMedGoogle Scholar
  208. 208.
    Poon AM, Chow PH, Mak AS, Pang SF (1997) Autoradiographic localization of 2[125I]iodomelatonin binding sites in the gastrointestinal tract of mammals including humans and birds. J Pineal Res 23:5–14PubMedGoogle Scholar
  209. 209.
    Menendez-Pelaez A, Poeggeler B, Reiter RJ, Barlow-Walden L, Pablos MI, Tan DX (1993) Nuclear localization of melatonin in different mammalian tissues: immunocytochemical and radioimmunoassay evidence. J Cell Biochem 53:373–382PubMedGoogle Scholar
  210. 210.
    Acuña-Castroviejo D, Pablos M, Menéndez Peláez A, Reiter RJ (1993) Melatonin receptors in purified cell nuclei of liver. Res Commun Chem Pathol Pharmacol 82:253–256PubMedGoogle Scholar
  211. 211.
    Lucchelli A, Santagostino-Barbone MG, Tonini M (1997) Investigation into the contractile response of melatonin in the guinea-pig isolated proximal colon: the role of 5-HT4 and melatonin receptors. Br J Pharmacol 121:1775–1781PubMedCentralPubMedGoogle Scholar
  212. 212.
    Pozo MJ, Gómez-Pinilla PJ, Camello-Almaraz C, Martin-Cano E, Pascua P, Rol MA, Acuña-Castroviejo D, Camello PJ (2010) Melatonin, a potential therapeutic agent for smooth muscle-related pathological conditions. Curr Med Chem 17:4150–4165PubMedGoogle Scholar
  213. 213.
    Tsukamoto K, Ariga H, Mantyh C, Pappas TN, Yanagi H, Yamamura T, Takahashi T (2007) Luminally released serotonin stimulates colonic motility and accelerates colonic transit in rats. Am J Physiol Regul Integr Comp Physiol 293:R64–R69PubMedGoogle Scholar
  214. 214.
    Bubenik GA (1986) The effect of serotonin, N-acetylserotonin, and melatonin on spontaneous contractions of isolated rat intestine. J Pineal Res 3:41–54PubMedGoogle Scholar
  215. 215.
    Harlow HJ, Weekley BL (1986) Effect of melatonin on the force of spontaneous contractions of in vitro rat small and large intestine. J Pineal Res 3:277–284PubMedGoogle Scholar
  216. 216.
    Barajas-Lopez C, Peres AL, Espinosa-Luna R, Reyes-Vazquez C, Prieto-Gomez B (1996) Melatonin modulates cholinergic transmission by blocking nicotinic channels in the Guinea-pig submucous plexus. Eur J Pharmacol 312:319–325PubMedGoogle Scholar
  217. 217.
    Lee PP, Shiu SY, Chow PH, Pang SF (1995) Regional and diurnal studies of melatonin and melatonin binding sites in the duck gastro-intestinal tract. Biol Signals 4:212–224PubMedGoogle Scholar
  218. 218.
    Lewinski A, Rybicka I, Wajs E, Szkudlinski M, Pawlikowski M (1991) Influence of pineal indoleamines on the mitotic activity of gastric and colonic mucosa epithelial cells in the rat: interaction with omeprazole. J Pineal Res 10:104–108PubMedGoogle Scholar
  219. 219.
    Flemstrom G, Sjoblom M, Jedstedt G, Akerman KE (2003) Short fasting dramatically decreases rat duodenal secretory responsiveness to orexin A but not to VIP or melatonin. Am J Physiol Gastrointest Liver Physiol 285:G1091–G1096PubMedGoogle Scholar
  220. 220.
    Sjoblom M, Flemstrom G (2004) Central nervous alpha1-adrenoceptor stimulation induces duodenal luminal release of melatonin 2. J Pineal Res 36:103–108PubMedGoogle Scholar
  221. 221.
    Flemstrom G, Sjoblom M (2005) Epithelial cells and their neighbors. II. New perspectives on efferent signaling between brain, neuroendocrine cells, and gut epithelial cells. Am J Physiol Gastrointest Liver Physiol 289:G377–G380PubMedGoogle Scholar
  222. 222.
    Sommansson A, Saudi WS, Nylander O, Sjoblom M (2013) Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo. Am J Physiol Gastrointest Liver Physiol 305:G95–G105PubMedGoogle Scholar
  223. 223.
    Sommansson A, Nylander O, Sjoblom M (2013) Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivo. J Pineal Res 54:282–291PubMedGoogle Scholar
  224. 224.
    Konturek PC, Brzozowski T, Konturek SJ (2011) Gut clock: implication of circadian rhythms in the gastrointestinal tract. J Physiol Pharmacol 62:139–150PubMedGoogle Scholar
  225. 225.
    Reiter RJ, Rosales-Corral S, Coto-Montes A, Boga JA, Tan DX, Davis JM, Konturek PC, Konturek SJ, Brzozowski T (2011) The photoperiod, circadian regulation and chronodisruption: the requisite interplay between the suprachiasmatic nuclei and the pineal and gut melatonin. J Physiol Pharmacol 62:269–274PubMedGoogle Scholar
  226. 226.
    Chen CQ, Fichna J, Bashashati M, Li YY, Storr M (2011) Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol 17:3888–3898PubMedCentralPubMedGoogle Scholar
  227. 227.
    El MS, Guerin P, Menezo Y (1999) Expression of genes encoding antioxidant enzymes in human and mouse oocytes during the final stages of maturation. Mol Hum Reprod 5:720–725Google Scholar
  228. 228.
    Heubner O (1898) Tumor der glandula pinealis. M Tsch Med Wschr 10:146–166Google Scholar
  229. 229.
    Lane EA, Moss HB (1985) Pharmacokinetics of melatonin in man: first pass hepatic metabolism. J Clin Endocrinol Metab 61:1214–1216PubMedGoogle Scholar
  230. 230.
    Messner M, Huether G, Lorf T, Ramadori G, Schworer H (2001) Presence of melatonin in the human hepatobiliary-gastrointestinal tract. Life Sci 69:543–551PubMedGoogle Scholar
  231. 231.
    Lissoni P, Barni S, Crispino S, Tancini G, Fraschini F (1989) Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Cancer Clin Oncol 25:789–795PubMedGoogle Scholar
  232. 232.
    Qi W, Tan DX, Reiter RJ, Kim SJ, Manchester LC, Cabrera J, Sainz RM, Mayo JC (1999) Melatonin reduces lipid peroxidation and tissue edema in cerulein-induced acute pancreatitis in rats. Dig Dis Sci 44:2257–2262PubMedGoogle Scholar
  233. 233.
    Muñoz A, Rodríguez T, Molina A, Martínez JJ, Ruiz C, Acuña-Castroviejo D (1992) Melatonin concentration in the umbilical artery and vein in human preterm and term neonates and neonates with acute fetal distress. J Pineal Res 13:184–191Google Scholar
  234. 234.
    Jaldo Alba F, Muñoz-Hoyos A, Molina-Carballo A, Molina Font JA, Acuña-Castroviejo D (1993) Light deprivation increases plasma levels of melatonin during the first 72 h of life in human infants. Acta Endocrinol 129:442–445PubMedGoogle Scholar
  235. 235.
    Muñoz-Hoyos A, Jaldo Alba F, Molina-Carballo A, Rodríguez Cabezas T, Molina Font JA, Acuña-Castroviejo D (1993) Absence of plasma melatonin circadian rhythm during the first 72 hours of life human infants. J Clin Endocrinol Metab 77:699–703PubMedGoogle Scholar
  236. 236.
    Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH (1994) Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci USA 91:1824–1828PubMedCentralPubMedGoogle Scholar
  237. 237.
    Aizawa S, Tokura H, Morita T (2002) The administration of exogenous melatonin during the daytime lowers the thermoregulatory setpoint in humans. J Therm Biol 27:115–119Google Scholar
  238. 238.
    Nogueira K, Liberman B, Pimentel-Filho FR, Goldman J, Silva ME, Vieira JO, Buratini JA, Cukiert A (2002) hCG-secreting pineal teratoma causing precocious puberty: report of two patients and review of the literature. J Pediatr Endocrinol Metab 15:1195–1201PubMedGoogle Scholar
  239. 239.
    Hoffman RA, Reiter RJ (1965) Pineal gland: influence on gonads of male hasmters. Science 148:1609–1611PubMedGoogle Scholar
  240. 240.
    Reiter RJ (1980) The pineal and its hormones in the control of reproduction in mammals. Endocr Rev 1:109–131PubMedGoogle Scholar
  241. 241.
    Revel FG, Masson-Pevet M, Pevet P, Mikkelsen JD, Simonneaux V (2009) Melatonin controls seasonal breeding by a network of hypothalamic targets. Neuroendocrinology 90:1–14PubMedGoogle Scholar
  242. 242.
    Reiter RJ, Tan DX, Manchester LC, Paredes SD, Mayo JC, Sainz RM (2009) Melatonin and reproduction revisited. Biol Reprod 81:445–456PubMedGoogle Scholar
  243. 243.
    Turek FW, Desjardins C, Menaker M (1976) Melatonin-induced inhibition of testicular function in adult golden hamsters. Proc Soc Exp Biol Med 151:502–506PubMedGoogle Scholar
  244. 244.
    Chemineau P, Guillaume D, Migaud M, Thiery JC, Pellicer-Rubio MT, Malpaux B (2008) Seasonality of reproduction in mammals: intimate regulatory mechanisms and practical implications. Reprod Domest Anim 43(Suppl 2):40–47PubMedGoogle Scholar
  245. 245.
    Brzezinski A, Seibel MM, Lynch HJ, Deng MH, Wurtman RJ (1987) Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab 64:865–867PubMedGoogle Scholar
  246. 246.
    Ronnberg L, Kauppila A, Leppaluoto J, Martikainen H, Vakkuri O (1990) Circadian and seasonal variation in human preovulatory follicular fluid melatonin concentration. J Clin Endocrinol Metab 71:492–496PubMedGoogle Scholar
  247. 247.
    Cohen M, Roselle D, Chabner B, Schmidt TJ, Lippman M (1978) Evidence for a cytoplasmic melatonin receptor. Nature 274:894–895PubMedGoogle Scholar
  248. 248.
    Niles LP, Wang J, Shen L, Lobb DK, Younglai EV (1999) Melatonin receptor mRNA expression in human granulosa cells. Mol Cell Endocrinol 156:107–110PubMedGoogle Scholar
  249. 249.
    Nakamura Y, Tamura H, Takayama H, Kato H (2003) Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production. Fertil Steril 80:1012–1016PubMedGoogle Scholar
  250. 250.
    Itoh MT, Ishizuka B, Kuribayashi Y, Amemiya A, Sumi Y (1999) Melatonin, its precursors, and synthesizing enzyme activities in the human ovary. Mol Hum Reprod 5:402–408PubMedGoogle Scholar
  251. 251.
    Klein DC, Roseboom PH, Coon SL (1996) New light is shining on the melatonin rhythm enzyme: the first postcloning view. Trends Endocrinol Metab 7:106–112PubMedGoogle Scholar
  252. 252.
    Itoh MT, Ishizuka B, Kudo Y, Fusama S, Amemiya A, Sumi Y (1997) Detection of melatonin and serotonin N-acetyltransferase and hydroxyindole-O-methyltransferase activities in rat ovary. Mol Cell Endocrinol 136:7–13PubMedGoogle Scholar
  253. 253.
    Tijmes M, Pedraza R, Valladares L (1996) Melatonin in the rat testis: evidence for local synthesis. Steroids 61:65–68PubMedGoogle Scholar
  254. 254.
    Tinajero JC, Fabbri A, Dufau ML (1992) Regulation of corticotropin-releasing factor secretion from Leydig cells by serotonin. Endocrinology 130:1780–1788PubMedGoogle Scholar
  255. 255.
    Vera H, Tijmes M, Ronco AM, Valladares LE (1993) Melatonin binding sites in interstitial cells from immature rat testes. Biol Res 26:337–340PubMedGoogle Scholar
  256. 256.
    Tamura H, Nakamura Y, Terron MP, Flores LJ, Manchester LC, Tan DX, Sugino N, Reiter RJ (2008) Melatonin and pregnancy in the human. Reprod Toxicol 25:291–303PubMedGoogle Scholar
  257. 257.
    Tamura H, Takasaki A, Miwa I, Taniguchi K, Maekawa R, Asada H, Taketani T, Matsuoka A, Yamagata Y, Shimamura K, Morioka H, Ishikawa H, Reiter RJ, Sugino N (2008) Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res 44:280–287PubMedGoogle Scholar
  258. 258.
    Tamura H, Takayama H, Nakamura Y, Reiter RJ, Sugino N (2008) Fetal/placental regulation of maternal melatonin in rats. J Pineal Res 44:335–340PubMedGoogle Scholar
  259. 259.
    Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, Tamura I, Maekawa R, Aasada H, Yamagata Y, Sugino N (2012) The role of melatonin as an antioxidant in the follicle. J Ovarian Res 5:5PubMedCentralPubMedGoogle Scholar
  260. 260.
    Jahnke G, Marr M, Myers C, Wilson R, Travlos G, Price C (1999) Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague Dawley rats. Toxicol Sci 50:271–279PubMedGoogle Scholar
  261. 261.
    Okatani Y, Okamoto K, Hayashi K, Wakatsuki A, Tamura S, Sagara Y (1998) Maternal-fetal transfer of melatonin in pregnant women near term. J Pineal Res 25:129–134PubMedGoogle Scholar
  262. 262.
    Fernández B, Montero A, Del Aguila CM, Malde JL, Castillo JL, Acuña-Castroviejo D (1992) Relationship between pineal activity and the hypotalamus-hypophysis-gonadal axis in human pregnancy and in the cord blood of term Infants. II. Melatonin and protein hormones. Steroid Biochem (Life Sci Adv) 11:97–103Google Scholar
  263. 263.
    Fernández B, Malde JL, Castillo JL, Montero A, Del Aguila CM, Acuña-Castroviejo D (1992) Relationship between pineal activity and the hypotalamus-hypophysis-gonadal axis in human pregnancy and in the cord blood of term infants. I. Melatonin and steroid hormones. Steroid Biochem (Life Sci Adv) 11:89–96Google Scholar
  264. 264.
    Fernández B, Montero A, Malde JL, Acuña-Castroviejo D (1990) Relationship between renal clearance rates and plasma levels of FSH, bhCG, DHAs and melatonin during normal pregnancy. Med Sci Res 18:713–714Google Scholar
  265. 265.
    Iwasaki S, Nakazawa K, Sakai J, Kometani K, Iwashita M, Yoshimura Y, Maruyama T (2005) Melatonin as a local regulator of human placental function. J Pineal Res 39:261–265PubMedGoogle Scholar
  266. 266.
    Lanoix D, Beghdadi H, Lafond J, Vaillancourt C (2008) Human placental trophoblasts synthesize melatonin and express its receptors. J Pineal Res 45:50–60PubMedGoogle Scholar
  267. 267.
    Schlabritz-Loutsevitch N, Hellner N, Middendorf R, Muller D, Olcese J (2003) The human myometrium as a target for melatonin. J Clin Endocrinol Metab 88:908–913PubMedGoogle Scholar
  268. 268.
    Lanoix D, Ouellette R, Vaillancourt C (2006) Expression of melatoninergic receptors in human placental choriocarcinoma cell lines. Hum Reprod 21:1981–1989PubMedGoogle Scholar
  269. 269.
    Handwerger S (1991) Clinical counterpoint: the physiology of placental lactogen in human pregnancy. Endocr Rev 12:329–336PubMedGoogle Scholar
  270. 270.
    Bronson FH (1995) Seasonal variation in human reproduction: environmental factors. Q Rev Biol 70:141–164PubMedGoogle Scholar
  271. 271.
    Rojansky N, Benshushan A, Meirsdorf S, Lewin A, Laufer N, Safran A (2000) Seasonal variability in fertilization and embryo quality rates in women undergoing IVF. Fertil Steril 74:476–481PubMedGoogle Scholar
  272. 272.
    Kauppila A, Kivela A, Pakarinen A, Vakkuri O (1987) Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity. J Clin Endocrinol Metab 65:823–828PubMedGoogle Scholar
  273. 273.
    Berga SL, Mortola JF, Yen SS (1988) Amplification of nocturnal melatonin secretion in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 66:242–244PubMedGoogle Scholar
  274. 274.
    Bellastella A, Sinisi AA, Criscuolo T, De BA, Carella C, Iorio S, Sinisi AM, Parlato F, Venditto T, Pisano G (1995) Melatonin and the pituitary-thyroid axis status in blind adults: a possible resetting after puberty. Clin Endocrinol (Oxf) 43:707–711Google Scholar
  275. 275.
    Vaughan GM, Meyer GG, Reiter RJ (1978) Evidence for a pineal-gonadal relationship in humans. In: Reiter RJ (ed) The pineal and reproduction. Karger, Basel, pp 191–223Google Scholar
  276. 276.
    Debus OM, Lerchl A, Bothe HW, Bremer J, Fiedler B, Franssen M, Koehring J, Steils M, Kurlemann G (2002) Spontaneous central melatonin secretion and resorption kinetics of exogenous melatonin: a ventricular CSF study. J Pineal Res 33:213–217PubMedGoogle Scholar
  277. 277.
    Longatti P, Perin A, Rizzo V, Comai S, Giusti P, Costa CV (2007) Ventricular cerebrospinal fluid melatonin concentrations investigated with an endoscopic technique. J Pineal Res 42:113–118PubMedGoogle Scholar
  278. 278.
    Leston J, Harthe C, Brun J, Mottolese C, Mertens P, Sindou M, Claustrat B (2010) Melatonin is released in the third ventricle in humans. A study in movement disorders. Neurosci Lett 469:294–297PubMedGoogle Scholar
  279. 279.
    Tricoire H, Locatelli A, Chemineau P, Malpaux B (2002) Melatonin enters the cerebrospinal fluid through the pineal recess. Endocrinology 143:84–90PubMedGoogle Scholar
  280. 280.
    Rizzo V, Porta C, Moroni M, Scoglio E, Moratti R (2002) Determination of free and total (free plus protein-bound) melatonin in plasma and cerebrospinal fluid by high-performance liquid chromatography with fluorescence detection. J Chromatogr B Anal Technol Biomed Life Sci 774:17–24Google Scholar
  281. 281.
    Silva SO, Ximenes VF, Livramento JA, Catalani LH, Campa A (2005) High concentrations of the melatonin metabolite, N1-acetyl-N2-formyl-5-methoxykynuramine, in cerebrospinal fluid of patients with meningitis: a possible immunomodulatory mechanism. J Pineal Res 39:302–306PubMedGoogle Scholar
  282. 282.
    Seifman MA, Adamides AA, Nguyen PN, Vallance SA, Cooper DJ, Kossmann T, Rosenfeld JV, Morganti-Kossmann MC (2008) Endogenous melatonin increases in cerebrospinal fluid of patients after severe traumatic brain injury and correlates with oxidative stress and metabolic disarray. J Cereb Blood Flow Metab 28:684–696PubMedGoogle Scholar
  283. 283.
    Mayo JC, Sainz RM, Tan DX, Hardeland R, Leon J, Rodriguez C, Reiter RJ (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 165:139–149PubMedGoogle Scholar
  284. 284.
    Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF (2003) Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 35:125–130PubMedGoogle Scholar
  285. 285.
    Yaga K, Reiter RJ, Richardson BA (1993) Tryptophan loading increases daytime serum melatonin levels in intact and pinealectomized rats. Life Sci 52:1231–1238PubMedGoogle Scholar
  286. 286.
    Zee PC, Mehta R, Turek FW, Blei AT (1991) Portacaval anastomosis disrupts circadian locomotor activity and pineal melatonin rhythms in rats. Brain Res 560:17–22PubMedGoogle Scholar
  287. 287.
    Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2010) On the origin and the consequences of circadian abnormalities in patients with cirrhosis. Am J Gastroenterol 105:1773–1781PubMedGoogle Scholar
  288. 288.
    Vining RF, McGinley RA, Symons RG (1983) Hormones in saliva: mode of entry and consequent implications for clinical interpretation. Clin Chem 29:1752–1756PubMedGoogle Scholar
  289. 289.
    Morineau G, Boudi A, Barka A, Gourmelen M, Degeilh F, Hardy N, al-Halnak A, Soliman H, Gosling JP, Julien R, Brerault JL, Boudou P, Aubert P, Villette JM, Pruna A, Galons H, Fiet J (1997) Radioimmunoassay of cortisone in serum, urine, and saliva to assess the status of the cortisol-cortisone shuttle. Clin Chem 43:1397–1407Google Scholar
  290. 290.
    Swinkels LM, van Hoof HJ, Ross HA, Smals AG, Benraad TJ (1992) Low ratio of androstenedione to testosterone in plasma and saliva of hirsute women. Clin Chem 38:1819–1823PubMedGoogle Scholar
  291. 291.
    Groschl M (2009) The physiological role of hormones in saliva. BioEssays 31:843–852PubMedGoogle Scholar
  292. 292.
    Bubenik GA (1980) Immunohistological localization of melatonin in the salivary gland of the rat. Adv Biosci 29:95–112Google Scholar
  293. 293.
    Withyachumnarnkul B, Wongprapairot P, Trakulrungsi W (1987) Dynamic uptake of radioactive substance in rat salivary gland following 3H-melatonin administration. J Pineal Res 4:169–175PubMedGoogle Scholar
  294. 294.
    Shimozuma M, Tokuyama R, Tatehara S, Umeki H, Ide S, Mishima K, Saito I, Satomura K (2011) Expression and cellular localization of melatonin-synthesizing enzymes in rat and human salivary glands. Histochem Cell Biol 135:389–396PubMedGoogle Scholar
  295. 295.
    Cevik-Aras H, Ekstsrom J (2008) Melatonin-evoked in vivo secretion of protein and amylase from the parotid gland of the anaesthetised rat. J Pineal Res 45:413–421Google Scholar
  296. 296.
    Laakso ML, Porkka-Heiskanen T, Alila A, Stenberg D, Johansson G (1990) Correlation between salivary and serum melatonin: dependence on serum melatonin levels. J Pineal Res 9:39–50PubMedGoogle Scholar
  297. 297.
    McIntyre IM, Norman TR, Burrows GD, Armstrong SM (1987) Melatonin rhythm in human plasma and saliva. J Pineal Res 4:177–183PubMedGoogle Scholar
  298. 298.
    Cevik-Aras H, Godoy T, Ekstrom J (2011) Melatonin-induced protein synthesis in the rat parotid gland. J Physiol Pharmacol 62:95–99PubMedGoogle Scholar
  299. 299.
    Maestroni GJM, Sulli A, Pizzorni C, Villaggio B, Cutolo M (2002) Melatonin in rheumatoid arthritis. Ann N Y Acad Sci 966:271–275PubMedGoogle Scholar
  300. 300.
    Straub RH, Cutolo M (2007) Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. Arthritis Rheum 56:399–408PubMedGoogle Scholar
  301. 301.
    Mitchell MD, Sayers L, Keirse MJ, Anderson AB, Turnbull AC (1978) Melatonin in amniotic fluid during human parturition. Br J Obstet Gynaecol 85:684–686PubMedGoogle Scholar
  302. 302.
    Kivela A, Kauppila A, Leppaluoto J, Vakkuri O (1989) Serum and amniotic fluid melatonin during human labor. J Clin Endocrinol Metab 69:1065–1068PubMedGoogle Scholar
  303. 303.
    Ciesla W (1998) Low ACTH and high melatonin concentrations in amniotic fluid as hormonal markers of high risk of fetal abnormalities. Preliminary studies. Prenat Diagn 18:980–983PubMedGoogle Scholar
  304. 304.
    Xu DX, Wang H, Ning H, Zhao L, Chen YH (2007) Maternally administered melatonin differentially regulates lipopolysaccharide-induced proinflammatory and anti-inflammatory cytokines in maternal serum, amniotic fluid, fetal liver, and fetal brain. J Pineal Res 43:74–79PubMedGoogle Scholar
  305. 305.
    Illnerova H, Buresova M, Presl J (1993) Melatonin rhythm in human milk. J Clin Endocrinol Metab 77:838–841PubMedGoogle Scholar
  306. 306.
    Cubero J, Valero V, Sanchez J, Rivero M, Parvez H, Rodriguez AB, Barriga C (2005) The circadian rhythm of tryptophan in breast milk affects the rhythms of 6-sulfatoxymelatonin and sleep in newborn. Neuroendocrinol Lett 26:657–661PubMedGoogle Scholar
  307. 307.
    Cohen EA, Hadash A, Shehadeh N, Pillar G (2012) Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. Eur J Pediatr 171:729–732Google Scholar
  308. 308.
    Pontes GN, Cardoso EC, Carneiro-Sampaio MM, Markus RP (2006) Injury switches melatonin production source from endocrine (pineal) to paracrine (phagocytes)—melatonin in human colostrum and colostrum phagocytes. J Pineal Res 41:136–141PubMedGoogle Scholar
  309. 309.
    Jan JE, Wasdell MB, Freeman RD, Bax M (2007) Evidence supporting the use of melatonin in short gestation infants. J Pineal Res 42:22–27PubMedGoogle Scholar
  310. 310.
    Arslanoglu S, Bertino E, Nicocia M, Moro GE (2012) WAPM Working Group on Nutrition: potential chronobiotic role of human milk in sleep regulation. J Perinat Med 40:1–8Google Scholar
  311. 311.
    Sanchez-Barcelo EJ, Mediavilla MD, Reiter RJ (2011) Clinical uses of melatonin in pediatrics. Int J Pediatr 2011:892624PubMedCentralPubMedGoogle Scholar
  312. 312.
    Muñoz-Hoyos A, Amorós-Rodriguez I, Molina-Carballo A, Uberos-Fernández J, Acuña-Castroviejo D (1996) Pineal response after pyridoxine test in children. J Neural Transm 103:833–842PubMedGoogle Scholar
  313. 313.
    Reiter RJ, Tan D, Kim SJ, Manchester LC, Qi W, Garcia JJ, Cabrera JC, El-Sokkary G, Rouvier-Garay V (1999) Augmentation of indices of oxidative damage in life-long melatonin-deficient rats. Mech Ageing Dev 110:157–173PubMedGoogle Scholar
  314. 314.
    Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661PubMedGoogle Scholar
  315. 315.
    Barchas J, DaCosta F, Spector S (1967) Acute pharmacology of melatonin. Nature 214:919–920PubMedGoogle Scholar
  316. 316.
    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 29:193–200PubMedGoogle Scholar
  317. 317.
    Reiter RJ, Korkmaz A (2008) Clinical aspects of melatonin. Saudi Med J 29:1537–1547PubMedGoogle Scholar
  318. 318.
    Sanchez-Barcelo EJ, Mediavilla MD, Tan DX, Reiter RJ (2010) Clinical uses of melatonin: evaluation of human trials. Curr Med Chem 17:2070–2095PubMedGoogle Scholar
  319. 319.
    Nordlund JJ, Lerner AB (1977) The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab 45:768–774PubMedGoogle Scholar
  320. 320.
    Lerner AB, Nordlund JJ (1979) Melatonin: clinical biochemistry. J Neural Transm 13:339–347Google Scholar
  321. 321.
    De Bleecker JL, Lamont BH, Verstraete AG, Schelfhout VJ (1999) Melatonin and painful gynecomastia. Neurology 53:435–436PubMedGoogle Scholar
  322. 322.
    Calvo JR, Guerrero JM, Osuna C, Molinero P, Carrillo-Vico A (2002) Melatonin triggers Crohn’s disease symptoms. J Pineal Res 32:277–278PubMedGoogle Scholar
  323. 323.
    Terry PD, Villinger F, Bubenik GA, Sitaraman SV (2009) Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research. Inflamm Bowel Dis 15:134–140PubMedGoogle Scholar
  324. 324.
    Poeggeler B, Hardeland R (1994) Detection and quantification of melatonin in a dinoflagellate, Gonyaulax polyedra: solutions to the problem of methoxyindole destruction in non-vertebrate material. J Pineal Res 17:1–10PubMedGoogle Scholar
  325. 325.
    Macias M, Rodriguez-Cabezas MN, Reiter RJ, Osuna A, Acuna-Castroviejo D (1999) Presence and effects of melatonin in Trypanosoma cruzi. J Pineal Res 27:86–94PubMedGoogle Scholar
  326. 326.
    Hardeland R, Balzer I, Poeggeler B, Fuhrberg B, Uria H, Behrmann G, Wolf R, Meyer TJ, Reiter RJ (1995) On the primary functions of melatonin in evolution: mediation of photoperiodic signals in a unicell, photooxidation, and scavenging of free radicals. J Pineal Res 18:104–111PubMedGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Darío Acuña-Castroviejo
    • 1
    • 2
    • 3
  • Germaine Escames
    • 1
    • 2
  • Carmen Venegas
    • 1
    • 2
  • María E. Díaz-Casado
    • 1
    • 2
  • Elena Lima-Cabello
    • 1
    • 2
  • Luis C. López
    • 1
    • 2
  • Sergio Rosales-Corral
    • 4
  • Dun-Xian Tan
    • 4
  • Russel J. Reiter
    • 4
  1. 1.Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la SaludUniversidad de GranadaGranadaSpain
  2. 2.Departamento de Fisiología, Facultad de MedicinaUniversidad de GranadaGranadaSpain
  3. 3.Unidad de Gestión Clínica de LaboratoriosHospital Universitario San CecilioGranadaSpain
  4. 4.Department of Cellular and Structural BiologyUniversity of Texas Health Science CenterSan AntonioUSA

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