Melatonin

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Melatonin chemical structure
Melatonin
Systematic (IUPAC) name
N-[2-(5-methoxy-1H-indol-3-yl)ethyl]ethanamide
Identifiers
CAS number 73-31-4
ATC code N05CM17
PubChem 896
DrugBank APRD00742
Chemical data
Formula C13H16N2O2 
Mol. weight 232.278 g/mol
Pharmacokinetic data
Bioavailability 30 - 50%
Metabolism Liver
Half life 35 to 50 minutes
Excretion Urine
Therapeutic considerations
Pregnancy cat.

?
Legal status

POM(UK)
Routes  ?

Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae[1] to humans, at levels that vary in a diurnal cycle. In higher animals melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina and GI tract. It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase.

Many biological effects of melatonin are produced through activation of melatonin receptors,[2] others are due to its role as a pervasive and extremely powerful antioxidant[3] with a particular role in the protection of nuclear and mitochondrial DNA.[4] Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.[5][6]

Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus of the hypothalamus (SCN) which receives information from the retina about the daily pattern of light and darkness. This signal forms part of the system that regulates the circadian cycle, but it is the SCN that controls the daily cycle in most components of the paracrine and endocrine systems[7][8] rather than the melatonin signal (as was once postulated). Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood, whereas melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.

Contents

[edit] Role in the biological clock

Nobel Prize laureate Julius Axelrod performed many of the seminal experiments that elucidated the role of melatonin and the pineal gland in regulating sleep-wake cycles (circadian rhythms). In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, that is located in the center of the brain.

Normally, the production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness". The secretion of melatonin peaks in the middle of the night, and gradually falls during the second half of the night. Until recent history, humans in temperate climates were exposed to up to eighteen hours of darkness in the winter. In this modern world, artificial lighting typically reduces this to eight hours or less per day all year round. Even low light levels inhibit melatonin production to some extent, but over-illumination can create significant reduction in melatonin production. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers,[9] and the effect of modern lighting practice on endogenous melatonin has been proposed as a contributory factor to the larger overall incidence of some cancers in the developed world.[10] As inadequate as blood concentrations may be in brightly-lit environments, some scientists now believe that people's overnight output of melatonin can be further jeopardized each time they interrupt their sleep and turn on a bright light (suggesting that the lower brightness level of a nightlight would be safer).[11] Others suggest that such short exposures do no harm.

See Also: Phase response curve

[edit] Role as an antioxidant

Although the primary site of melatonin's action is via the melatonin receptors, melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.[3] Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.[12] In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.[13]

The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.[14][15][16]

"According to University of Milan lead researcher Iriti Marcello, the melatonin content in wine grapes could help regulate human sleep-wake patterns, known as the circadian rhythm, just like the melatonin produced by the pineal gland in mammals." (Quoted from http://www.decanter.com/news/88311.html)

[edit] Role in immune system

The body of research is overwhelmingly supportive of the claim that melatonin interacts with the immune system[17]. Melatonin may help fight disease,[18] but its true role in disease treatment is unknown. There have been very few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on very small, incomplete, clinical trials.

Melatonin is an immunoregulator that enhances T cell production somewhat. When taken in conjunction with calcium, it is a very potent immunostimulator of the T cell response. Due to these immunoregulatory effects, it is used as an adjuvant in many clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders.

[edit] Medical applications

Melatonin appears to have some use against circadian rhythm sleep disorders, such as jet lag and delayed sleep phase syndrome. It has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), and sexual dysfunction. A study by Alfred J. Lewy and other researchers at OHSU found that it may ameliorate SAD and circadian misalignment,[19] but as of 2006 it is known to affect the timing of endogenous melatonin production, raising the risk that it can exacerbate both clinical depression and SAD.[20] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.[21]

Melatonin receptors appear to be important in mechanisms of learning and memory,[22] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). Melatonin has been shown to prevent the hyperphosphorylation of the tau protein. Hyperphosphorylation of tau protein can result in the formation of neurofibrillary tangles, a pathological feature seen in Alzheimer's disease). Thus, melatonin may be effective for treating Alzheimer's Disease.[23] These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their body's production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called "sundowning," which has been shown in many studies to be effectively treated with melatonin supplements in the evening.[24]

Rozerem (ramelteon) is an agonist with high affinity for both MT1 and MT2 melatonin receptors. This is a newly available prescription medication that can be helpful for insomnia.[citation needed]

Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.[25]

Several clinical studies indicate that supplementation with melatonin is an effective preventative treatment for migraine sufferers.[26][27]

There may be other, far-reaching therapeutic uses for melatonin, such as in the treatment of various forms of cancer, HIV, and other viral diseases.[28]

[edit] Use as a dietary supplement

The primary motivation for the use of melatonin as a supplement is as a natural aid to better sleep, with other incidental benefits to health and well-being due to its role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.

Victor Herbert, M.D., J.D., of the Mt. Sinai School of Medicine, cites studies from Massachusetts Institute of Technology that say melatonin pills sold as supplements contain three to 10 times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for enhancement of nighttime rest. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses are just as effective at improving sleep quality.[29]

A number of studies indicate melatonin supplementation helps to reduce the age-related decline in hormone production from the thyroid and pituitary glands, among others, with animal models suggesting these effects are associated with an overall enhancement of health.

Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).[30]

[edit] Safety

Melatonin is practically nontoxic and exhibits almost no toxic side effects. However, melatonin taken in combination with monoamine oxidase inhibitors (MAOIs) can lead to overdose because MAOIs inhibit the breakdown of melatonin by the body. Exogenous melatonin normally does not affect the endogenous melatonin profile in the short or medium-term, merely advancing the phase of endogenous melatonin production in time.

In individuals with auto-immune disorders, there is concern that melatonin supplementation may exacerbate symptoms due to stimulation of the immune system.[31]

Melatonin causes somnolence, and therefore should not be taken within five hours before driving, operating machinery, etc. As melatonin is almost always taken at the end of the waking day, this is generally not an issue.

Individuals who experience orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate the symptoms by reducing nerve activity in those who experience the condition, the study found.[32]

As a natural substance with a virtual absence of problematic side effects, with health benefits to users without illnesses, melatonin has been classified as a dietary supplement and made freely available in the USA, but in the EU over the counter sale without prescription is not yet officially permitted.

[edit] Role in zoology

Many animals use the variation in duration and quantity of melatonin production in each day as a seasonal clock.[33] In seasonal breeders which do not have long gestation periods, and which mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[34] and hamsters.[35] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long.

Melatonin is also related to the mechanism by which some amphibians and reptiles change the color of their skin.[36][37]

[edit] External links

[edit] Footnotes

  1. ^ Caniato R, Filippini R, Piovan A, Puricelli L, Borsarini A, Cappelletti E (2003). "Melatonin in plants.". Adv Exp Med Biol 527: 593-7. PMID 15206778.
  2. ^ Boutin J, Audinot V, Ferry G, Delagrange P (2005). "Molecular tools to study melatonin pathways and actions.". Trends Pharmacol Sci 26 (8): 412-9. PMID 15992934.
  3. ^ a b Hardeland R (2005). "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance.". Endocrine 27 (2): 119-30. PMID 16217125.
  4. ^ Reiter R, Acuña-Castroviejo D, Tan D, Burkhardt S (2001). "Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.". Ann N Y Acad Sci 939: 200-15. PMID 11462772.
  5. ^ Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter R (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 (3): 627-34. PMID 7773197.
  6. ^ Uz T, Arslan A, Kurtuncu M, Imbesi M, Akhisaroglu M, Dwivedi Y, Pandey G, Manev H (2005). "The regional and cellular expression profile of the melatonin receptor MT1 in the central dopaminergic system.". Brain Res Mol Brain Res 136 (1-2): 45-53. PMID 15893586.
  7. ^ Richardson G (2005). "The human circadian system in normal and disordered sleep.". J Clin Psychiatry 66 Suppl 9: 3-9; quiz 42-3. PMID 16336035.
  8. ^ Perreau-Lenz S, Pévet P, Buijs R, Kalsbeek A (2004). "The biological clock: the bodyguard of temporal homeostasis.". Chronobiol Int 21 (1): 1-25. PMID 15129821.
  9. ^ Schernhammer E, Rosner B, Willett W, Laden F, Colditz G, Hankinson S (2004). "Epidemiology of urinary melatonin in women and its relation to other hormones and night work.". Cancer Epidemiol Biomarkers Prev 13 (62): 936-43. PMID 15184249.
  10. ^ Pauley S (2004). "Lighting for the human circadian clock: recent research indicates that lighting has become a public health issue.". Med Hypotheses 63 (4): 588-96. PMID 15325001.
  11. ^ Harder B (Jan 2006). "Bright Lights, Big Cancer: Melatonin-depleted blood spurs tumor growth.". Science News 169 (1): 8-10. Retrieved on 2006-07-21.
  12. ^ Tan D, Manchester L, Reiter R, Qi W, Karbownik M, Calvo J (2000). "Significance of melatonin in anti oxidative defense system: reactions and products.". Biol Signals Recept 9 (3-4): 137-59. PMID 10899700.
  13. ^ Karbownik M, Reiter R, Cabrera J, Garcia J (2001). "Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage.". Mutat Res 474 (1-2): 87-92. PMID 11239965.
  14. ^ Ward Dean, John Morgenthaler, Steven William Fowkes (1993). Smart Drugs II: The Next Generation : New Drugs and Nutrients to Improve Your Memory and Increase Your Intelligence (Smart Drug Series, V. 2). Smart Publications. ISBN 0-9627418-7-6.
  15. ^ Anisimov V, Alimova I, Baturin D, Popovich I, Zabezhinski M, Rosenfeld S, Manton K, Semenchenko A, Yashin A (2003). "Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice.". Exp Gerontol 38 (4): 449-61. PMID 12670632.
  16. ^ Oaknin-Bendahan S, Anis Y, Nir I, Zisapel N (1995). "Effects of long-term administration of melatonin and a putative antagonist on the ageing rat.". Neuroreport 6 (5): 785-8. PMID 7605949.
  17. ^ Carrillo-Vico A, Guerrero J, Lardone P, Reiter R (2005). "A review of the multiple actions of melatonin on the immune system.". Endocrine 27 (2): 189-200. PMID 16217132.
  18. ^ Arushanian E, Beier E (2002). "Immunotropic properties of pineal melatonin". Eksp Klin Farmakol 65 (5): 73-80. PMID 12596522.
  19. ^ Lewy A, Sack R, Miller L, Hoban T (1987). "Antidepressant and circadian phase-shifting effects of light.". Science 235 (4786): 352-4. PMID 3798117.
  20. ^ Sankaran M, Subramanian P (2006). "Modulation of biochemical circadian rhythms during long-term melatonin treatment in rats.". Singapore Med J 47 (1): 42-7. PMID 16397720.
  21. ^ Uz T, Akhisaroglu M, Ahmed R, Manev H (2003). "The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice.". Neuropsychopharmacology 28 (12): 2117-23. PMID 12865893.
  22. ^ Larson J, Jessen R, Uz T, Arslan A, Kurtuncu M, Imbesi M, Manev H (2006). "Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice.". Neurosci Lett 393 (1): 23-6. PMID 16203090.
  23. ^ Wang X, Zhang J, Yu X, Han L, Zhou Z, Zhang Y, Wang J (2005). "Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat.". Sheng Li Xue Bao 57 (1): 7-12. PMID 15719129.
  24. ^ Volicer L, Harper D, Manning B, Goldstein R, Satlin A (2001). "Sundowning and circadian rhythms in Alzheimer's disease.". Am J Psychiatry 158 (5): 704-11. PMID 11329390.
  25. ^ Bellipanni G, DI Marzo F, Blasi F, Di Marzo A (2005). "Effects of melatonin in perimenopausal and menopausal women: our personal experience.". Ann N Y Acad Sci 1057 (Dec): 393-402. PMID 16399909.
  26. ^ Dodick D, Capobianco D (2001). "Treatment and management of cluster headache.". Curr Pain Headache Rep 5 (1): 83-91. PMID 11252143.
  27. ^ Gagnier J (2001). "The therapeutic potential of melatonin in migraines and other headache types.". Altern Med Rev 6 (4): 383-9. PMID 11578254.
  28. ^ Maestroni G (1999). "Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer.". Adv Exp Med Biol 467: 217-26. PMID 10721059.
  29. ^ Zhdanova I, Wurtman R, Regan M, Taylor J, Shi J, Leclair O (2001). "Melatonin treatment for age-related insomnia.". J Clin Endocrinol Metab 86 (10): 4727-30. PMID 11600532.
  30. ^ Barrenetxe J, Delagrange P, Martínez J (2004). "Physiological and metabolic functions of melatonin.". J Physiol Biochem 60 (1): 61-72. PMID 15352385.
  31. ^ Morera A, Henry M, de La Varga M (2001). "[Safety in melatonin use]". Actas Esp Psiquiatr 29 (5): 334-7. PMID 11602091.
  32. ^ Penn State College of Medicine, Milton S. Hershey Medical Center (September 2003). Study Shows Melatonin Supplements May Make Standing A Hazard For The Cardiovascular-Challenged. Press release. Retrieved on 2006-07-21. (MS Word Format)
  33. ^ Lincoln G, Andersson H, Loudon A (2003). "Clock genes in calendar cells as the basis of annual timekeeping in mammals--a unifying hypothesis.". J Endocrinol 179 (1): 1-13. PMID 14529560.
  34. ^ CM Chaturvedi. "Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis". Australian Journal of Zoology 32 (6): 803-809. DOI:10.1071/ZO9840803.
  35. ^ Chen H (1981). "Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition.". Neuroendocrinology 33 (1): 43-6. PMID 7254478.
  36. ^ Filadelfi A, Castrucci A (1996). "Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates.". J Pineal Res 20 (4): 175-86. PMID 8836950.
  37. ^ Sugden D, Davidson K, Hough K, Teh M (2004). "Melatonin, melatonin receptors and melanophores: a moving story.". Pigment Cell Res 17 (5): 454-60. PMID 15357831.

[edit] See also

Tryptamines - edit

4-Acetoxy-DET | 4-Acetoxy-DIPT | 4-Acetoxy-DMT | 4-HO-DIPT | 5-MeO-α-ET | 5-MeO-α-MT | 5-MeO-DALT | 5-MeO-DET | 5-MeO-DIPT | 5-MeO-DMT | 5-MeO-DPT | 5-MeO-MIPT | α-ET | α-MT | Baeocystin | Bufotenin | DET | DIPT | DMT | DPT | Ethocybin | EIPT | Ethocin | Ibogaine | Iprocin | MET | MIPT | Miprocin | Melatonin | NMT | Norbaeocystin | Psilocin | Psilocybin | Rizatriptan | Serotonin | Sumatriptan | Tryptamine | Tryptophan
Hormones and endocrine glands - edit

Hypothalamus: - TRH - CRH - GnRH - GHRH - somatostatin - dopamine | Posterior pituitary: vasopressin - oxytocin - lipotropin | Anterior pituitary: GH - ACTH - TSH - LH - FSH - prolactin - MSH - endorphins - lipotropin

Thyroid: T3 and T4 - calcitonin | Parathyroid: PTH | Adrenal medulla: epinephrine - norepinephrine | Adrenal cortex: aldosterone - cortisol - DHEA | Pancreas: glucagon- insulin - somatostatin | Ovary: estradiol - progesterone - inhibin - activin | Testis: testosterone - AMH - inhibin | Pineal gland: melatonin | Kidney: renin - EPO - calcitriol - prostaglandin | Heart atrium: ANP

Stomach: gastrin | Duodenum: CCK - GIP - secretin - motilin - VIP | Ileum: enteroglucagon | Liver: IGF-1

Placenta: hCG - HPL - estrogen - progesterone

Adipose tissue: leptin, adiponectin

Target-derived NGF, BDNF, NT-3
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