Information about Melatonin

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.

Many biological effects of melatonin are produced through activation of melatonin receptors,[2] while 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 was released into the general health supplement market in the United States in 1993, and met with good consumer acceptance and enthusiasm.[5]

Production

In higher animals, melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina, lens and GI tract. It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase.

Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus (SCN) of the hypothalamus which receives information from the retina about the daily pattern of light and darkness. This pattern that entrains both the SCN rhythmicity and melatonin production occurs through recently defined pathways of non visual light detection. Light reaches the SCN through a subpopulation of inner retinal ganglion cells (intrinsically photosensitive retinal ganglion cells which are photoreceptor cells distinct from those involved in the visual system). These cells represent approximately 2% of retinal ganglion cells and express the non-visual photopigment melanopsin (1). The sensitivity of melanopsin fits with that of a vitamin A-based photopigment with a peak sensitivity at 484 nm (blue) (2). This photoperiod cue entrains the circadian rhythm and the resultant production of specific “dark” and “ light” induced neural and endocrine signals regulates behavioral and physiological circadian rhythms ).[6]

However, melatonin may be produced by a variety of peripheral cells such as bone marrow cells (3,4), lymphocytes and epithelial cells. Usually, the melatonin concentration in these cells is much higher than that found in the blood but it does not seem to be regulated by the photoperiod.[7]

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.[8][9]

Distribution

Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.

Roles

Biological clock

See also:
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, on the dorsal surface of diencephalon. The melatonin signal forms part of the system that regulates the circadian cycle by chemically causing drowsiness to fall upon the mind, but it is the Central nervous system that controls the daily cycle in most components of the paracrine and endocrine systems[10][11] rather than the melatonin signal (as was once postulated).

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,[12] 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.[13] 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). Others suggest that such short exposures do no harm.[14]

Antioxidant

Although the primary site of melatonin's action in humans is the melatonin receptors, it first evolved as an antioxidant. In many lower life forms, it serves only this purpose.[15]

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.[16]

Recent research indicates that the beginning of the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine or AFMK rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neuralize up to 10 ROS/RNS since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants, and so on. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.[15]

In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.[17]

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.[18][19][20]

Immune system

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This section has been nominated to be checked for its neutrality. Discussion of this nomination can be found on the .


While it is clear that melatonin interacts with the immune system,[21][22] the details of those interactions are unclear. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete, clinical trials.

By using the key words melatonin and immune in the PubMed data base one can find 493 papers including 156 reviews describing various immunological effects of melatonin . In general , melatonin acts on the immune system via high affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production and by doing this counteract secondary immunodeficiences. Some studies also suggest that melatonin might be useful to fight infectious disease including viral and bacterial infections. Endogenous melatonin in human lymphocytes has been related to interleukin-2(IL-2)production and to the expression of IL-2 receptor. This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human T lymphocytes. When taken in conjunction with calcium, it is an immunostimulator and is used as an adjuvant in some clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders. In rheumatoid arthritis patients, melatonin production has been found increased when compared to age-matched healthy controls.

Dreaming

Many supplemental melatonin users have reported an increase in the vividness or frequency of dreams. High doses of melatonin (50mg) dramatically increased REM sleep time and dream activity in both narcoleptics and those without narcolepsy.[22]

Many psychoactive drugs, such as LSD and cocaine, increase melatonin synthesis.[22] It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.[22]

In a 2005 editorial of the British Journal of Psychiatry, Ben Sessa suggested that psychotropic drugs be readmitted in the field of scientific enquiry and therapy.[24] Melatonin, being two endogenous hallucinogenic indoles like N,N-dimethyltryptamine (DMT), is likely to be research priorities in this reemerging field of psychiatry.[25]

Use as medicinal supplement

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 Oregon Health & Science University found that it may ameliorate SAD and circadian misalignment,[26] 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.[27] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.[28]

Proposed medical indications

Preventing ischemic damage

Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain[29] and the heart;[30] however, this has not been tested in humans.

Sleep Aid

Melatonin is used as an adjunct to sleep in children, for certain diagnostic tests.[31]

Learning, memory and Alzheimers

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,[32] 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 in rats. 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.[33] 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.[34]

ADHD

ADHD is most commonly treated with methylphenidate which may cause insomnia in approximately 94% of its users. Research shows that after melatonin is administered to the patients, the time needed to fall asleep is significantly reduced. Before the melatonin was administered, the time needed to fall asleep ranged from 15 minutes to 240 minutes. After the melatonin was administered, the time needed to fall asleep ranged from 15 minutes to 64 minutes. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.[35]

Fertility

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.[36]

Some resources warn women trying to conceive not to take a melatonin supplement.[37]

Headaches

Several clinical studies indicate that supplementation with melatonin is an effective preventative treatment for migraines and cluster headaches.[38][39]

Depression

Melatonin has been shown to be effective in treating one form of depression, Seasonal Affective Disorder. [1]

Other

Some studies have shown that melatonin has potential for use in the treatment of various forms of cancer, HIV, and other viral diseases; however, further testing is necessary to confirm this.[40]

Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms. (*Quoted from Ross Histology and Wheather's Functional Histology.)

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.

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.[41] High dose melatonin can even be counterproductive: Lewy & al[42] provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve." In their study, 0.5 mg of melatonin was effective while 20 mg wasn't. A practical implication of these results is that effective melatonin supplementation (for sleep problems) thus becomes very accessible: it costs a fraction of what most researchers thought it might cost. Melatonin supplementation for sleep problems is available without prescription in most cases in the United States. Melatonin supplements are available as oral supplements and transdermal melatonin or "melatonin sleep patch".

Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).[43]

Safety of supplementation

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This section has been nominated to be checked for its neutrality. Discussion of this nomination can be found on the .


Melatonin is practically nontoxic and exhibits almost no short-term side effects. However, melatonin derived from animal sources may be contaminated with viral material; synthetic melatonin may be taken to avoid this risk.[44] No studies have been conducted yet to determine whether there are any long-term side effects.

Even though it is seen as a relatively safe, benign drug, especially to herbal enthusiasts, it can cause some unwanted side effects, especially at high doses. Ingesting melatonin supplements can cause hormone fluctuations,[2] irritability,[3] reduced blood flow (see below), and increased sleep disturbances, including vivid nightmares.[4]

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.[45]

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.[46]

Role in zoology

Many animals use the variation in duration and quantity of melatonin production in each day as a seasonal clock.[47] 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[48] and hamsters.[49] 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. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.

Melatonin is also related to the mechanism by which some amphibians and reptiles change the color of their skin.[50][51]

In popular culture

See also

References

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acetyl (ethanoyl), is a functional group, the acyl of acetic acid, with chemical formula -COCH3. It is sometimes abbreviated as Ac (not to be confused with the element actinium). The acetyl radical contains a methyl group single-bonded to a carbonyl.
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Tryptamine is a monoamine alkaloid found in plants and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived.
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hormone (from Greek όρμή - "to set in motion") is a chemical messenger that carries a signal from one cell (or group of cells) to another. All multicellular organisms produce hormones (including plants - see phytohormone).
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phytoplankton — provide the food base for most marine food chains. In very high densities (so-called algal blooms) these algae may discolor the water and outcompete or poison other life forms.
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Diurnal ("daily") may refer to:
  • Diurnal animal, a plant or animal that is active in the daytime
  • Actions which are completed in 24 hours and are repeated every 24 hours, e.g. the sun reaching its zenith.

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Identifiers
Symbol MTNR1B

Entrez 4544
HUGO 7464
OMIM 600804

RefSeq NM_005959
UniProt P49286
Other data

Locus Chr. 11 q21-q22 A melatonin receptor is a G protein-coupled receptor (GPCR) which binds melatonin.
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Antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent.
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Nuclear DNA , nuclear deoxyribonucleic acid (nDNA), is DNA contained within a nucleus of eukaryotic organisms. In most cases it encodes more of the genome than the mitochondrial DNA and is passed sexually rather than matrilineally.
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Mitochondrial DNA (mtDNA) is the DNA located in organelles called mitochondria. Most other DNA present in eukaryotic organisms is found in the cell nucleus. Nuclear and mitochondrial DNA are thought to be of separate evolutionary origin, with the mtDNA being derived from the
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dietary supplement (also known as food supplement) is intended to supply nutrients, (vitamins, minerals, fatty acids or amino acids) that are missing or not consumed in sufficient quantity in a person's diet.
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Pinealocytes are the main cells of the pineal gland. They produce and secrete melatonin. Pinealocytes have an organelle called the synaptic ribbon; this is considered to be a specific marker for pinealocytes.
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The pineal gland (also called the pineal body, epiphysis cerebri, or epiphysis) is a small endocrine gland in the brain. It is shaped like a tiny pine cone, and is located near the center of the brain, between the two hemispheres, tucked in a groove where the
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In animals, the brain or encephalon (Greek for "in the skull"), is the control center of the central nervous system, responsible for behavior. The brain is located in the head, protected by the skull and close to the primary sensory apparatus of vision, hearing,
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For the moth genus, see Retina (moth).


The retina is a thin layer of neural cells that lines the back of the eyeball of vertebrates and some cephalopods. It is comparable to the film in a camera.
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The lens is a transparent, biconvex (lentil-shaped) structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. Its function is thus similar to a human-made optical lens.
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gastrointestinal tract (GI tract), also called the digestive tract, or the alimentary canal, is the system of organs within multicellular animals that takes in food, digests it to extract energy and nutrients, and expels the remaining waste.
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amino acid is a molecule that contains both amine and carboxyl functional groups. In biochemistry, this term refers to alpha-amino acids with the general formula H2NCHRCOOH, where R is an organic substituent.
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Tryptophan (abbreviated as Trp or W)[1] is an essential amino acid involved in human nutrition. It is one of the 20 amino acids encoded by the genetic code (as codon UGG).
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Serotonin (pronounced IPA: /ˌsɛrəˈtoʊnən/) (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and
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Enzymes are proteins that catalyze (i.e. accelerate) chemical reactions.[1] In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, the products.
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5-hydroxyindole-O-methyltransferase is an enzyme involved in the conversion of serotonin to melatonin in pinealocytes.

See also

  • methyltransferase

External links

  • MeSH ASMTL+protein,+human

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The suprachiasmatic nucleus (SCN) is a region of the brain, located in the hypothalamus, that is responsible for controlling endogenous circadian rhythms. The neuronal and hormonal activities it generates regulate many different body functions over a 24-hour period.
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The hypothalamus links the nervous system to the endocrine system via the pituitary gland (hypophysis). The hypothalamus, (from Greek ὑποθαλαμος = under the thalamus) is located below the thalamus, just above the brain stem.
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Location Varies by type
Function Varies but often excitatory projection

Morphology Varies

A ganglion cell (more correctly, a retinal ganglion cell) is a type of neuron typically located near the inner surface of the retina of the eye that
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Photoreceptor can refer to:

In anatomy/cell biology:
  • Photoreceptor cell: a photosensitive cell, most commonly referring to a specialized type of neuron found in the retina of vertebrate eyes that is capable of phototransduction;

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Bone marrow (or medulla ossea) is the soft tissue found in the hollow interior of bones. In adults, marrow in large bones produces new blood cells.

Marrow types

There are two types of bone marrow: red marrow (also known as myeloid tissue) and
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epithelium is a tissue composed of a layer of cells. Epithelium lines both the outside (skin) and the inside cavities and lumen of bodies. The outermost layer of our skin is composed of dead stratified squamous, keratinized epithelial cells.
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Plantae
Haeckel, 1866[1]

Divisions

Green algae
  • Chlorophyta
  • Charophyta
Land plants (embryophytes)
  • Non-vascular land plants (bryophytes)

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RICE is a treatment method for soft tissue injury which is an abbreviation for Rest, Ice, Compression and Elevation.[1][2][3] When used appropriately, recovery time is usually shortened and discomfort minimized.
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In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions — in this context collectively called ligands, or more specifically, protein ligands — form a chemical bond.
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