Extrapineal melatonin: sources, regulation, and potential functions
Tóm tắt
Từ khóa
Tài liệu tham khảo
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 80:2587
Cardinali DP, Rosner JM (1971) Retinal localization of the hydroxyindole-O-methyl transferase (HIOMT) in the rat. Endocrinology 89:301–303
Bubenik GA, Brown GM, Uhlir I, Grota LJ (1974) Immunohistological localization of N-acetylindolealkylamines in pineal gland, retina and cerebellum. Brain Res 81:233–242
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 30:243–247
Reiter RJ (1991) Melatonin: that ubiquitously-acting pineal hormone. News Physiol Sci 6:223–227
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 34:75–78
Reiter RJ, Fuentes-Broto L, Tan DX (2010) Melatonin: a multitasking molecule. Prog Brain Res 181:127–151
Vlahakes GJ, Wurtman RJ (1972) A Mg 2+ dependent hydroxyindole O-methyltransferase in rat Harderian gland. Biochim Biophys Acta 261:194–197
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 32:1229–1236
Raikhlin NT, Kvetnoy IM, Tolkachev VN (1975) Melatonin may be synthesised in enterochromaffin cells. Nature 255:344–345
Ozaki Y, Lynch HJ (1976) Presence of melatonin in plasma and urine or pinealectomized rats. Endocrinology 99:641–644
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–S224
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 44:328–334
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 52:217–227
Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1:52–60
Reiter RJ, Paredes SD, Manchester LC, Tan DX (2009) Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol 44:175–200
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 15:43–50
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 50:328–335
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 52:139–166
Reppert SM, Weaver DR, Ebisawa T (1994) Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13:1177–1185
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 92:8734–8738
Dubocovich ML, Markowska M (2005) Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 27:101–110
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 13:2025–2038
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 58:633–639
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 159:3774–3781
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 275:31311–31317
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 16:100–112
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 269:28531–28534
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 12:143–150
Benitez-King G, Huerto-Delgadillo L, Anton-Tay F (1993) Binding of 3H-melatonin to calmodulin. Life Sci 53:201–207
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 270:832–840
Sugden D, Klein DC (1983) Beta-adrenergic receptor control of rat pineal hydroxyindole-O-methyltransferase. Endocrinology 113:348–353
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 286:305–313
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:e1001347
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–R1345
Cardinali DP, Lynch HJ, Wurtman RJ (1972) Binding of melatonin to human and rat plasma proteins. Endocrinology 91:1213–1218
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 51:17–43
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 87:4699–4706
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 51:145–155
Hardeland R, Poeggeler B (2012) Melatonin and synthetic melatonergic agonists: actions and metabolism in the central nervous system. Cent Nerv Syst Agents Med Chem 12:189–216
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 36:1–9
Goldsmith CS, Bell-Pedersen D (2013) Diverse roles for MAPK signaling in circadian clocks. Adv Genet 84:1–39
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 24:3603–3624
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 46:161–171
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 46:339–351
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 1227:19–25
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:ra89
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 58:967–975
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 84:213–220
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 11:221–240
Acuña-Castroviejo D, Martín M, Macías M, Escames G, León J, Khaldy H, Reiter RJ (2001) Melatonin, mitochondria and cellular bioenergetics. J Pineal Res 30:65–74
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 2:181–197
Tomas-Zapico C, Coto-Montes A (2005) A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 39:99–104
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
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 45:1333–1341
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:e52010
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 1171:472–478
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 17:1483–1496
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 25:49–53
Poynton RA, Hampton MB (2014) Peroxiredoxins as biomarkers of oxidative stress. Biochim Biophys Acta 1840:906–912
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 469:554–558
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 485:459–464
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 46:300–306
Kvetnoy IM (1999) Extrapineal melatonin: location and role within diffuse neuroendocrine system. Histochem J 31:1–12
Menendez-Pelaez A, Reiter RJ (1993) Distribution of melatonin in mammalian tissues: the relative importance of nuclear versus cytosolic localization. J Pineal Res 15:59–69
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 51:136–144
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 51:945–953
Sjoblom M, Flemstrom G (2003) Melatonin in the duodenal lumen is a potent stimulant of mucosal bicarbonate secretion. J Pineal Res 34:288–293
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 1:173–181
Mackenzie SM, Connell JM, Davies E (2012) Non-adrenal synthesis of aldosterone: a reality check. Mol Cell Endocrinol 350:163–167
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 39:87–92
Reppert SM, Perlow MJ, Tamarkin L, Klein DC (1979) A diurnal melatonin rhythm in primate cerebrospinal fluid. Endocrinology 104:295–301
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 140:4399–4405
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 8:162–167
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 42:240–246
Deguchi T (1978) Ontogenesis of circadian rhythm of melatonin synthesis in pineal gland of rat. J Neural Transm Suppl 13:115–128
Uz T, Qu T, Sugaya K, Manev H (2002) Neuronal expression of arylalkylamine N-acetyltransferase (AANAT) mRNA in the rat brain. Neurosci Res 42:309–316
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 134:1309–1316
Pang SF, Brown GM (1983) Regional concentrations of melatonin in the rat brain in the light and dark period. Life Sci 33:1199–1204
Hardeland R (2010) Melatonin metabolism in the central nervous system. Curr Neuropharmacol 8:168–171
Sallanon M, Claustrat B, Touret M (1982) Presence of melatonin in various cat brainstem nuclei determined by radioimmunoassay. Acta Endocrinol (Copenh) 101:161–165
Reiter RJ (1986) Normal patterns of melatonin levels in the pineal gland and body fluids of humans and experimental animals. J Neural Transm Suppl 21:35–54
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 43:232–238
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 52:397–402
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 3:101–109
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 43:24–31
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 51:97–103
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 164:149–153
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 19:57–63
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 75:201–208
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 29:209–216
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 35:283–287
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 36:177–185
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–R706
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 15:147–152
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 13:459–466
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 24:491–500
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 23:97–105
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 35:54–60
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 38:122–125
Philo R, Reiter RJ (1978) Characterization of pinealectomy induced convulsions in the Mongolian gerbil (Meriones unguiculatus). Epilepsia 19:485–492
Anton-Tay F, Diaz JL, Fernandez-Guardiola A (1971) On the effect of melatonin upon human brain. Its possible therapeutic implications. Life Sci I 10:841–850
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 95:296–301
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 5:80–90
Cardinali DP, Srinivasan V, Brzezinski A, Brown GM (2012) Melatonin and its analogs in insomnia and depression. J Pineal Res 52:365–375
Esposito E, Cuzzocrea S (2010) Antiinflamatory activity of melaotnin in central nervous system. Curr Neuropharmacol 8:228–242
Rosales-Corral S, Reiter RJ, Tan DX, Ortiz GG, Lopez-Armas G (2010) Functional aspects of redox control during neuroinflammation. Antioxid Redox Signal 13:193–247
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 50:319–327
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 51:104–112
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 52:228–235
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 52:167–202
Dominguez-Alonso A, Ramirez-Rodriguez G, Benitez-King G (2012) Melatonin increases dendritogenesis in the hilus of hippocampal organotypic cultures. J Pineal Res 52:427–436
Jimenez-Rubio G, Ortiz-Lopez L, Benitez-King G (2012) Melatonin modulates cytoskeletal organization in the rat brain hippocampus. Neurosci Lett 511:47–51
Reiter RJ, Benitez-King G (2009) Melatonn reduces neuronal loss and cytoskeletal deterioration: implications for psychiatry. Salud Mental 32:3–11
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 52:1634–1647
Manda K, Reiter RJ (2010) Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation. Prog Neurobiol 90:60–68
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 51:353–360
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 50:29–37
Rennie K, De BM, Pappas BA (2009) Melatonin promotes neurogenesis in dentate gyrus in the pinealectomized rat. J Pineal Res 47:313–317
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 52:21–28
López LC, Escames G, López A, García JA, Doerrier C, Acuña-Castroviejo D (2010) Melatonin, neurogenesis, and aging brain. Open Neuroendocrinol J 3:121–133
Wiechmann AF, Summers JA (2008) Circadian rhythms in the eye: the physiological significance of melatonin receptors in ocular tissues. Prog Retin Eye Res 27:137–160
Tosini G, Baba K, Hwang CK, Iuvone PM (2012) Melatonin: an underappreciated player in retinal physiology and pathophysiology. Exp Eye Res 103:82–89
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 27:323–333
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 91:477–481
Miller L, Stier M, Lovenberg W (1980) Evidence for the presence of N-acetyl transferase in rat retina. Comp Biochem Physiol C 66:213–216
Tosini G, Menaker M (1998) The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration. Brain Res 789:221–228
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 315:197–201
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 27:116–121
Zmijewski MA, Sweatman TW, Slominski AT (2009) The melatonin-producing system is fully functional in retinal pigment epithelium (ARPE-19). Mol Cell Endocrinol 307:211–216
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 250:86–92
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 18:1640–1648
Marchiafava PL, Longoni B (1999) Melatonin as an antioxidant in retinal photoreceptors. J Pineal Res 26:184–189
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 27:122–128
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 15:72–89
Rohde BH, McLaughlin MA, Chiou LY (1985) Existence and role of endogenous ocular melatonin. J Ocul Pharmacol 1:235–243
Mhatre MC, van Jaarsveld AS, Reiter RJ (1988) Melatonin in the lacrimal gland: first demonstration and experimental manipulation. Biochem Biophys Res Commun 153:1186–1192
Abe M, Itoh MT, Miyata M, Shimizu K, Sumi Y (2000) Circadian rhythm of serotonin N-acetyltransferase activity in rat lens. Exp Eye Res 70:805–808
Quay WB (1984) Increases in volume, fluid content, and lens weight of eyes following systemic administration of melatonin. J Pineal Res 1:3–13
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 68:255–262
Itoh MT, Takahashi N, Abe M, Shimizu K (2007) Expression and cellular localization of melatonin-synthesizing enzymes in the rat lens. J Pineal Res 42:92–96
Biesalski HK, Welker HA, Thalmann R, Vollrath L (1988) Melatonin and other serotonin derivatives in the guinea pig membranous cochlea. Neurosci Lett 91:41–46
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 238:81–83
Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (2005) A review of the multiple actions of melatonin on the immune system. Endocrine 27:189–200
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 18:537–539
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 90:992–1000
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 39:77–83
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 64:781–790
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 219:271–276
Tamarkin L, Reppert SM, Klein DC, Pratt B, Goldman BD (1980) Studies on the daily pattern of pineal melatonin in the Syrian hamster. Endocrinology 107:1525–1529
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 75:1116–1121
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 22:629–635
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 1472:206–214
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 28:193–202
Kuehn HS, Gilfillan AM (2007) G protein-coupled receptors and the modification of FcepsilonRI-mediated mast cell activation. Immunol Lett 113:59–69
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 62:282–287
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 101:660–665
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 271:12281–12286
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 511:102–106
Slominski A, Pruski D (1993) Melatonin inhibits proliferation and melanogenesis in rodent melanoma cells. Exp Cell Res 206:189–194
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 49:45–54
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 16:896–898
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 196:144–153
Slominski A, Pisarchik A, Wortsman J (2004) Expression of genes coding melatonin and serotonin receptors in rodent skin. Biochim Biophys Acta 1680:67–70
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 27:137–148
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 76:1259–1265
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 23:739–745
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 20:1564–1566
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 17:713–730
Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R (2008) Melatonin in the skin: synthesis, metabolism and functions. Trends Endocrinol Metab 19:17–24
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 73:241–253
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 107:1543–1548
Bubenik GA, Brown GM, Grota LJ (1977) Immunohistological localization of melatonin in the rat digestive system. Experientia 33:662–663
Bubenik GA (1980) Localization of melatonin in the digestive tract of the rat. Effect of maturation, diurnal variation, melatonin treatment and pinealectomy. Horm Res 12:313–323
Bubenik GA (2002) Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 47:2336–2348
Hong GX, Pang SF (1995) N-acetyltransferase activity in the quail (Coturnix coturnix jap) duodenum. Comp Biochem Physiol B Biochem Mol Biol 112:251–255
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 21:251–256
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 27:164–169
Huether G (1993) The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experientia 49:665–670
Huether G (1994) Melatonin synthesis in the gastrointestinal tract and the impact of nutritional factors on circulating melatonin. Ann N Y Acad Sci 719:146–158
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 24:146–151
Bubenik GA, Pang SF (1997) Melatonin levels in the gastrointestinal tissues of fish, amphibians, and a reptile. Gen Comp Endocrinol 106:415–419
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 24:62–66
Bubenik GA (2008) Thirty-four years since the discovery of gastrointestinal melatonin. J Physiol Pharmacol 59(Suppl 2):33–51
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 25:251–259
Bubenik GA, Brown GM (1997) Pinealectomy reduces melatonin levels in the serum but not in the gastrointestinal tract of rats. Biol Signals 6:40–44
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 12:7–16
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) 115:507–513
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 18:28–31
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 35:627–634
Reiter RJ, Manchester LC, Tan DX (2005) Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood. Nutrition 21:920–924
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 16:91–99
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 26:56–63
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 65:2523–2529
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 41:391–395
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 85:607–623
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 28:9–15
Iriti M, Varoni EM, Vitalini S (2010) Melatonin in traditional Mediterranean diets. J Pineal Res 49:101–105
Peuhkuri K, Sihvola N, Korpela R (2012) Dietary factors and fluctuating levels of melatonin. Food Nutr Res 56
Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ (2009) Phytomelatonin: a review. Exp Bot 60:57–69
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 51:226–232
Ramakrishna A, Giridhar P, Sankar KU, Ravishankar GA (2012) Melatonin and serotonin profiles in beans of Coffea species. J Pineal Res 52:470–476
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 23:5–14
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 53:373–382
Acuña-Castroviejo D, Pablos M, Menéndez Peláez A, Reiter RJ (1993) Melatonin receptors in purified cell nuclei of liver. Res Commun Chem Pathol Pharmacol 82:253–256
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 121:1775–1781
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 17:4150–4165
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–R69
Bubenik GA (1986) The effect of serotonin, N-acetylserotonin, and melatonin on spontaneous contractions of isolated rat intestine. J Pineal Res 3:41–54
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 3:277–284
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 312:319–325
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 4:212–224
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 10:104–108
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–G1096
Sjoblom M, Flemstrom G (2004) Central nervous alpha1-adrenoceptor stimulation induces duodenal luminal release of melatonin 2. J Pineal Res 36:103–108
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–G380
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–G105
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 54:282–291
Konturek PC, Brzozowski T, Konturek SJ (2011) Gut clock: implication of circadian rhythms in the gastrointestinal tract. J Physiol Pharmacol 62:139–150
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 62:269–274
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 17:3888–3898
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 5:720–725
Heubner O (1898) Tumor der glandula pinealis. M Tsch Med Wschr 10:146–166
Lane EA, Moss HB (1985) Pharmacokinetics of melatonin in man: first pass hepatic metabolism. J Clin Endocrinol Metab 61:1214–1216
Messner M, Huether G, Lorf T, Ramadori G, Schworer H (2001) Presence of melatonin in the human hepatobiliary-gastrointestinal tract. Life Sci 69:543–551
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 25:789–795
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 44:2257–2262
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 13:184–191
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 129:442–445
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 77:699–703
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 91:1824–1828
Aizawa S, Tokura H, Morita T (2002) The administration of exogenous melatonin during the daytime lowers the thermoregulatory setpoint in humans. J Therm Biol 27:115–119
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 15:1195–1201
Hoffman RA, Reiter RJ (1965) Pineal gland: influence on gonads of male hasmters. Science 148:1609–1611
Reiter RJ (1980) The pineal and its hormones in the control of reproduction in mammals. Endocr Rev 1:109–131
Revel FG, Masson-Pevet M, Pevet P, Mikkelsen JD, Simonneaux V (2009) Melatonin controls seasonal breeding by a network of hypothalamic targets. Neuroendocrinology 90:1–14
Reiter RJ, Tan DX, Manchester LC, Paredes SD, Mayo JC, Sainz RM (2009) Melatonin and reproduction revisited. Biol Reprod 81:445–456
Turek FW, Desjardins C, Menaker M (1976) Melatonin-induced inhibition of testicular function in adult golden hamsters. Proc Soc Exp Biol Med 151:502–506
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):40–47
Brzezinski A, Seibel MM, Lynch HJ, Deng MH, Wurtman RJ (1987) Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab 64:865–867
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 71:492–496
Cohen M, Roselle D, Chabner B, Schmidt TJ, Lippman M (1978) Evidence for a cytoplasmic melatonin receptor. Nature 274:894–895
Niles LP, Wang J, Shen L, Lobb DK, Younglai EV (1999) Melatonin receptor mRNA expression in human granulosa cells. Mol Cell Endocrinol 156:107–110
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 80:1012–1016
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 5:402–408
Klein DC, Roseboom PH, Coon SL (1996) New light is shining on the melatonin rhythm enzyme: the first postcloning view. Trends Endocrinol Metab 7:106–112
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 136:7–13
Tijmes M, Pedraza R, Valladares L (1996) Melatonin in the rat testis: evidence for local synthesis. Steroids 61:65–68
Tinajero JC, Fabbri A, Dufau ML (1992) Regulation of corticotropin-releasing factor secretion from Leydig cells by serotonin. Endocrinology 130:1780–1788
Vera H, Tijmes M, Ronco AM, Valladares LE (1993) Melatonin binding sites in interstitial cells from immature rat testes. Biol Res 26:337–340
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 25:291–303
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 44:280–287
Tamura H, Takayama H, Nakamura Y, Reiter RJ, Sugino N (2008) Fetal/placental regulation of maternal melatonin in rats. J Pineal Res 44:335–340
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 5:5
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 50:271–279
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 25:129–134
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) 11:97–103
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) 11:89–96
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 18:713–714
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 39:261–265
Lanoix D, Beghdadi H, Lafond J, Vaillancourt C (2008) Human placental trophoblasts synthesize melatonin and express its receptors. J Pineal Res 45:50–60
Schlabritz-Loutsevitch N, Hellner N, Middendorf R, Muller D, Olcese J (2003) The human myometrium as a target for melatonin. J Clin Endocrinol Metab 88:908–913
Lanoix D, Ouellette R, Vaillancourt C (2006) Expression of melatoninergic receptors in human placental choriocarcinoma cell lines. Hum Reprod 21:1981–1989
Handwerger S (1991) Clinical counterpoint: the physiology of placental lactogen in human pregnancy. Endocr Rev 12:329–336
Bronson FH (1995) Seasonal variation in human reproduction: environmental factors. Q Rev Biol 70:141–164
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 74:476–481
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 65:823–828
Berga SL, Mortola JF, Yen SS (1988) Amplification of nocturnal melatonin secretion in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 66:242–244
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) 43:707–711
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 191–223
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 33:213–217
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 42:113–118
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 469:294–297
Tricoire H, Locatelli A, Chemineau P, Malpaux B (2002) Melatonin enters the cerebrospinal fluid through the pineal recess. Endocrinology 143:84–90
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 774:17–24
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 39:302–306
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 28:684–696
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 165:139–149
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 35:125–130
Yaga K, Reiter RJ, Richardson BA (1993) Tryptophan loading increases daytime serum melatonin levels in intact and pinealectomized rats. Life Sci 52:1231–1238
Zee PC, Mehta R, Turek FW, Blei AT (1991) Portacaval anastomosis disrupts circadian locomotor activity and pineal melatonin rhythms in rats. Brain Res 560:17–22
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 105:1773–1781
Vining RF, McGinley RA, Symons RG (1983) Hormones in saliva: mode of entry and consequent implications for clinical interpretation. Clin Chem 29:1752–1756
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 43:1397–1407
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 38:1819–1823
Bubenik GA (1980) Immunohistological localization of melatonin in the salivary gland of the rat. Adv Biosci 29:95–112
Withyachumnarnkul B, Wongprapairot P, Trakulrungsi W (1987) Dynamic uptake of radioactive substance in rat salivary gland following 3H-melatonin administration. J Pineal Res 4:169–175
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 135:389–396
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 45:413–421
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 9:39–50
McIntyre IM, Norman TR, Burrows GD, Armstrong SM (1987) Melatonin rhythm in human plasma and saliva. J Pineal Res 4:177–183
Cevik-Aras H, Godoy T, Ekstrom J (2011) Melatonin-induced protein synthesis in the rat parotid gland. J Physiol Pharmacol 62:95–99
Maestroni GJM, Sulli A, Pizzorni C, Villaggio B, Cutolo M (2002) Melatonin in rheumatoid arthritis. Ann N Y Acad Sci 966:271–275
Straub RH, Cutolo M (2007) Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management. Arthritis Rheum 56:399–408
Mitchell MD, Sayers L, Keirse MJ, Anderson AB, Turnbull AC (1978) Melatonin in amniotic fluid during human parturition. Br J Obstet Gynaecol 85:684–686
Kivela A, Kauppila A, Leppaluoto J, Vakkuri O (1989) Serum and amniotic fluid melatonin during human labor. J Clin Endocrinol Metab 69:1065–1068
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 18:980–983
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 43:74–79
Illnerova H, Buresova M, Presl J (1993) Melatonin rhythm in human milk. J Clin Endocrinol Metab 77:838–841
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 26:657–661
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 171:729–732
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 41:136–141
Jan JE, Wasdell MB, Freeman RD, Bax M (2007) Evidence supporting the use of melatonin in short gestation infants. J Pineal Res 42:22–27
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 40:1–8
Sanchez-Barcelo EJ, Mediavilla MD, Reiter RJ (2011) Clinical uses of melatonin in pediatrics. Int J Pediatr 2011:892624
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 103:833–842
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 110:157–173
Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661
Seabra ML, Bignotto M, Pinto LR Jr, Tufik S (2000) Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 29:193–200
Reiter RJ, Korkmaz A (2008) Clinical aspects of melatonin. Saudi Med J 29:1537–1547
Sanchez-Barcelo EJ, Mediavilla MD, Tan DX, Reiter RJ (2010) Clinical uses of melatonin: evaluation of human trials. Curr Med Chem 17:2070–2095
Nordlund JJ, Lerner AB (1977) The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab 45:768–774
Lerner AB, Nordlund JJ (1979) Melatonin: clinical biochemistry. J Neural Transm 13:339–347
De Bleecker JL, Lamont BH, Verstraete AG, Schelfhout VJ (1999) Melatonin and painful gynecomastia. Neurology 53:435–436
Calvo JR, Guerrero JM, Osuna C, Molinero P, Carrillo-Vico A (2002) Melatonin triggers Crohn’s disease symptoms. J Pineal Res 32:277–278
Terry PD, Villinger F, Bubenik GA, Sitaraman SV (2009) Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research. Inflamm Bowel Dis 15:134–140
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 17:1–10
Macias M, Rodriguez-Cabezas MN, Reiter RJ, Osuna A, Acuna-Castroviejo D (1999) Presence and effects of melatonin in Trypanosoma cruzi. J Pineal Res 27:86–94