In vertebrates, melatonin's functions extend tosynchronizing sleep-wake cycles, encompassing sleep-wake timing andblood pressure regulation, as well as controlling seasonal rhythmicity (circannual cycle), which includes reproduction, fattening, molting, and hibernation.[4] Its effects are mediated through the activation ofmelatonin receptors and its role as anantioxidant.[5][6][7] In plants and bacteria, melatonin primarily serves as a defense mechanism againstoxidative stress, indicating its evolutionary significance.[8] Themitochondria, keyorganelles within cells, are the main producers of antioxidant melatonin,[9] underscoring the molecule's "ancient origins" and its fundamental role in protecting the earliest cells fromreactive oxygen species.[10][11]
In addition to itsendogenous functions as a hormone and antioxidant, melatonin is also administered exogenously as adietary supplement and medication. Melatonin is used medically primarily for sleep-related problems: for example, prolonged-release melatonin (Circadin) is approved in several countries for short-term treatment of insomnia in people over 55.[12] It is used in the treatment ofsleep disorders, including insomnia and variouscircadian rhythm sleep disorders.
Visible light entering the eye and the cascading positive and negative signalling pathways to neuronal structures in the mamallian brain that may follow: When the eyes are exposed to sunlight, the pineal gland's melatonin production is suppressed, resulting in the secretion of hormones that promote wakefulness. Conversely, in the absence of light, the pineal gland synthesizes melatonin unabated, leading to feelings of drowsiness and facilitating the onset of sleep.
In mammals, melatonin is critical for the regulation of sleep–wake cycles, or circadian rhythms.[20] The establishment of regular melatonin levels in human infants occurs around the third month after birth, withpeak concentrations observed between midnight and 8:00 am.[21] It has been documented that melatonin production diminishes as a person ages.[22] Additionally, a shift in the timing of melatonin secretion is observed during adolescence, resulting in delayed sleep and wake times, increasing their risk fordelayed sleep phase disorder during this period.[23]
The antioxidant properties of melatonin were first recognized in 1993.[24]In vitro studies reveal that melatonin directly neutralizes variousreactive oxygen species, includinghydroxyl (OH•),superoxide (O2−•), andreactive nitrogen species such asnitric oxide (NO•).[25][26] In plants, melatonin workssynergistically with other antioxidants, enhancing the overall effectiveness of each antioxidant.[26] This compound has been found to be twice as efficacious asvitamin E, a known potentlipophilic antioxidant, at scavenging peroxyl radicals.[27] The promotion of antioxidant enzyme expression, such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase, is mediated through melatonin receptor-triggered signal transduction pathways.[13][15]
Melatonin's concentration in themitochondrial matrix is significantly higher than that found in theblood plasma,[16][17][18] emphasizing its role not only in direct free radical scavenging but also in modulating the expression of antioxidant enzymes and maintaining mitochondrial integrity. This multifaceted role shows the physiological significance of melatonin as a mitochondrial antioxidant, a notion supported by numerous scholars.[15][16][17][18][19]
Melatonin's interaction with theimmune system is recognized, yet the specifics of these interactions remain inadequately defined.[28][29][30][31] An anti-inflammatory effect appears to be the most significant.[30][31] The efficacy of melatonin in disease treatment has been the subject of limited trials, with most available data deriving from small-scale, preliminary studies. It is posited that any beneficial immunological impact is attributable to melatonin's action on high-affinity receptors (MT1 and MT2), which are present on immunocompetent cells. Preclinical investigations suggest that melatonin may augmentcytokine production and promote the expansion ofT cells,[32][33] thereby potentially mitigatingacquired immunodeficiencies.[34]
Melatonin's potential to regulate weight gain is posited to involve its inhibitory effect onleptin, a hormone that serves as a long-term indicator of the body's energy status.[35][36] Leptin is important for regulatingenergy balance and body weight by signaling satiety and reducing food intake. Melatonin, by modulating leptin's actions outside of waking hours, may contribute to the restoration of leptin sensitivity during daytime, thereby counteractingleptin resistance.
Inbacteria,protists,fungi, and plants, the synthesis of melatonin also involves tryptophan as an intermediate but originates indirectly from the shikimate pathway. The pathway commences withD-erythrose 4-phosphate andphosphoenolpyruvate, and inphotosynthetic cells, additionally involvescarbon dioxide. While the subsequent biosynthetic reactions share similarities with those in animals, there are slight variations in the enzymes involved in the final stages.[39][40]
The hypothesis that melatonin synthesis occurs within mitochondria andchloroplasts suggests an evolutionary and functional significance of melatonin in cellularenergy metabolism and defense mechanisms against oxidative stress, reflecting the molecule's ancient origins and its multifaceted roles across differentdomains of life.[41]
The mechanism of melatonin biosynthesis initiates with the hydroxylation ofL-tryptophan, a process that requires thecofactortetrahydrobiopterin (THB) to react with oxygen and the active site iron of tryptophan hydroxylase. Although the complete mechanism is not entirely understood, two main mechanisms have been proposed:
The first mechanism involves a slow transfer of oneelectron from THB to molecular oxygen (O2), potentially producing a superoxide (O−2). This superoxide could then recombine with the THBradical to form 4a-peroxypterin. 4a-peroxypterin may either react with the active site iron (II) to create an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron, facilitating the hydroxylation ofL-tryptophan.
Alternatively, the second mechanism proposes that oxygen interacts with the active site iron (II) first, forming iron (III) superoxide. This molecule could then react with THB to form an iron-peroxypterin intermediate.
Following the formation of iron (IV) oxide from the iron-peroxypterin intermediate, this oxide selectivelyattacks adouble bond to yield acarbocation at the C5 position of the indole ring. A subsequent1,2-shift of the hydrogen and the loss of one of the two hydrogen atoms on C5 would restorearomaticity, producing 5-hydroxy-L-tryptophan.[42]
The decarboxylation of 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine is then facilitated by a decarboxylase enzyme withpyridoxal phosphate (PLP) as a cofactor.[43] PLP forms animine with the amino acid derivative, facilitating the breaking of thecarbon–carbon bond and release of carbon dioxide. Theprotonation of the amine derived from tryptophan restores the aromaticity of thepyridine ring, leading to the production of 5-hydroxytryptamine and PLP.[44]
SerotoninN-acetyltransferase, withhistidine residue His122, is hypothesized todeprotonate the primary amine of 5-hydroxytryptamine. This deprotonation allows thelone pair on the amine to attack acetyl-CoA, forming atetrahedral intermediate. Thethiol fromcoenzyme A then acts as aleaving group when attacked by a general base, producingN-acetylserotonin.[45]
The final step in the biosynthesis of melatonin involves the methylation ofN-acetylserotonin at the hydroxyl position by SAM, resulting in the production ofS-adenosyl homocysteine (SAH) and melatonin.[44][46]
Blue light, especially within the460–480 nm range, inhibits the biosynthesis of melatonin,[49] with the degree of suppression being directly proportional to the intensity and duration of light exposure. Historically, humans in temperate climates experienced limited exposure to blue daylight during winter months, primarily receiving light from sources that emitted predominantly yellow light, such as fires.[50] Theincandescent light bulbs used extensively throughout the 20th century emitted relatively low levels of blue light.[51] It has been found that light containing only wavelengths greater than 530 nm does not suppress melatonin under bright-light conditions.[52] The use of glasses that block blue light in the hours preceding bedtime can mitigate melatonin suppression.[53] Additionally, wearing blue-blocking goggles during the last hours before bedtime is recommended for individuals needing to adjust to an earlier bedtime since melatonin facilitates the onset of sleep.[54]
The 2023 European Insomnia Guideline recommended use of prolonged-release melatonin for treatment of insomnia in people age 55 or older for up to 3months.[63] It recommended againstfast-release orover-the-counter melatonin for treatment of insomnia.[63] These recommendations were based on severalmeta-analyses published in 2022 and 2023.[63]
Melatonin is known to reducejet lag, especially in eastward travel. However, if it is not taken at the correct time, it can instead delay adaptation.[67]
Melatonin appears to have limited use against the sleep problems of people who workshift work.[68] Tentative evidence suggests that it increases the length of time people are able to sleep.[68]
Meta-analyses, published between 2005 and 2017, appear to show different results as to whether melatonin is effective for circadian rhythm sleep disorders or not.[69][70][71][72] Some found that it was effective,[69][70][72] while others found no evidence of effectiveness.[71] Meta-analyses of melatonin for delayed sleep phase syndrome that found it effective have reported that it improves time to sleep onset by about 40minutes (0.67hours) and advances onset of endogenous melatonin secretion by about 1.2hours (72minutes).[70][72] One meta-analysis found that melatonin was notably more effective in improving sleep onset latency in people with delayed sleep phase syndrome than in people with insomnia (improvement of 39minutes vs. 7minutes, respectively).[72] One meta-analysis found that melatonin was probably effective forjet lag syndrome.[73]
Low doses of melatonin may be advantageous to high doses in the treatment of sleep-cycle disorders.[74]
A 2020Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severedementia due toAlzheimer's disease.[79] A 2019 review found that while melatonin may improve sleep inminimal cognitive impairment, after the onset of Alzheimer's disease it has little to no effect.[80] Melatonin may, however, help withsundowning (increased confusion and restlessness at night) in people with dementia.[81]
Melatonin is also available as anover-the-counterdietary supplement in many countries. It is available in both immediate-release and less commonly prolonged-release forms. The compound is available in supplements at doses ranging from 0.3mg to 10mg or more. It is also possible to buy raw melatonin powder by weight.[83] Immediate-release formulations of melatonin cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, oral films, or as a liquid.[84] It is also available for usesublingually, or astransdermal patches.[85] Several inhalation-based melatonin products with a wide range of doses are available but their safety remains to be evaluated.[84]
The American Academy of Sleep Medicine (AASM) says that the melatonin content in unregulated (without aUSP verified mark) supplements can diverge widely from the claimed amount; a study found that the melatonin content ranged from one half to four times the stated dose.[86]
Melatonin's discovery is linked to the study of skin color changes in some amphibians and reptiles, a phenomenon initially observed through the administration of pineal gland extracts.[87][88] In 1917, Carey Pratt McCord and Floyd P. Allen found that feeding extracts from the pineal glands of cows caused the skin of tadpoles to lighten by contracting the darkepidermalmelanophores.[89][90]
The hormone melatonin was isolated in 1958 byAaron B. Lerner, adermatology professor, and his team atYale University. Motivated by the possibility that a substance from the pineal gland could be beneficial in treatingskin diseases, they extracted and identified melatonin from bovine pineal gland extracts.[91] Subsequent research in the mid-1970s by Lynch and others demonstrated that melatonin production follows a circadian rhythm in human pineal glands.[92]
The etymology ofmelatonin stems from its skin-lightening properties. As detailed in their publication in theJournal of the American Chemical Society,[94] Lerner and his colleagues proposed the name melatonin, derived from the Greek wordsmelas, meaning 'black' or 'dark', andtonos, meaning 'labour',[95] 'colour'[96] or 'suppress'.[97] This naming convention follows that ofserotonin, another agent affecting skin color, discovered in 1948 as a modulator ofvascular tone, which influenced its name based on its serumvasoconstrictor effect.[98] Melatonin was thus aptly named to reflect its role in preventing the darkening of the skin, highlighting the intersection of biochemistry and linguistics in scientific discovery.[94]
In vertebrates, melatonin is produced in darkness, thus usually at night, by thepineal gland, a smallendocrine gland[99]located in the center of the brain but outside theblood–brain barrier. Light/dark information reaches thesuprachiasmatic nuclei from retinalphotosensitive ganglion cells of the eyes[100][101] rather than the melatonin signal (as was once postulated). Known as "the hormone of darkness", the onset of melatonin at dusk promotes activity innocturnal (night-active) animals and sleep indiurnal ones including humans.[102]
In humans, ~30 μg of melatonin is produced daily and 80% of the total amount is produced in the night (W). The plasma maximum concentration of melatonin at night are 80–120 pg/mL and the concentrations during the day are between 10–20 pg/mL.[103][104]
Many animals and humans use the variation in duration of melatonin production each day as a seasonal clock.[105] In animals including humans,[106] the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behavior, coat growth, and camouflagecoloring in seasonal animals.[106] In seasonal breeders that do not have long gestation periods and that 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 includingmynah birds[107] and hamsters.[108] Melatonin can suppresslibido by inhibiting secretion ofluteinizing hormone andfollicle-stimulating hormone from theanterior pituitary gland, especially in mammals that have abreeding season when daylight hours are long. The reproduction oflong-day breeders isrepressed by melatonin and the reproduction ofshort-day breeders is stimulated by melatonin. In sheep, melatonin administration has also shown antioxidant and immune-modulatory regime in prenatally stressed offspring helping them survive the crucial first days of their lives.[109]
During the night, melatonin regulatesleptin, lowering its levels.
Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone. When melatonin was identified in coffee extracts in the 1970s, it was believed to be a byproduct of the extraction process. Subsequently, however, melatonin has been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds, in varying proportions.[8][111] Melatonin concentrations differ not only among plant species, but also between varieties of the same species depending on the agronomic growing conditions, varying from picograms to several micrograms per gram.[40][112] Notably high melatonin concentrations have been measured in popular beverages such as coffee,tea,wine, andbeer, and crops includingcorn,rice,wheat,barley, andoats.[8] In some common foods and beverages, including coffee[8] andwalnuts,[113] the concentration of melatonin has been estimated or measured to be sufficiently high to raise the blood level of melatonin above daytime baseline values.
Although a role for melatonin as a plant hormone has not been clearly established, its involvement in processes such as growth and photosynthesis is well established. Only limited evidence of endogenous circadian rhythms in melatonin levels has been demonstrated in some plant species and no membrane-bound receptors analogous to those known in animals have been described. Rather, melatonin performs important roles in plants as a growth regulator, as well as environmental stress protector. It is synthesized in plants when they are exposed to both biological stresses, for example, fungal infection, and nonbiological stresses such as extremes of temperature, toxins, increasedsoil salinity, drought, etc.[40][114][115]
Herbicide-inducedoxidative stress has been experimentally mitigatedin vivo in a high-melatonintransgenic rice.[116][117][118] Studies conducted on lettuce grown in saline soil conditions have shown that the application of melatonin significantly mitigates the harmful effects of salinity. Foliar application increases the number of leaves, their surface area, increases fresh weight and the content of chlorophyll a and chlorophyll b, and the content of carotenoids compared to plants not treated with melatonin.[118]
Melatonin is produced by α-proteobacteria and photosynthetic cyanobacteria. There is no report of its occurrence in archaea which indicates that melatonin originated in bacteria[11] most likely to prevent the first cells from the damaging effects of oxygen in the primitive Earth's atmosphere.[10]
In 2022, the discovery of serotonin N-acetyltransferase (SNAT)—the penultimate, rate-limiting enzyme in the melatonin biosynthetic pathway—in the archaeonThermoplasma volcanium[124] firmly places melatonin biosynthesis in all three major domains of life, dating back to ~4 Gya.[125]
Naturally occurring melatonin has been reported in foods includingtart cherries to about 0.17–13.46 ng/g,[126]bananas,plums,grapes, rice,cereals,herbs,[127]olive oil, wine,[128] and beer.[129] The consumption ofmilk and sour cherries may improve sleep quality.[130] When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.[131] When humans consume foods rich in melatonin, such as banana,pineapple, andorange, the blood levels of melatonin increase significantly.[132]
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