Melatonin,
an indoleamine, is a natural compound produced by various organisms, including
bacteria and eukaryotes. 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 dark epidermal melanophores.
The hormone
melatonin was isolated from
bovine pineal gland extracts in 1958 by Aaron B. Lerner, a dermatology
professor, and his team at Yale University. Lerner and his colleagues proposed the name melatonin,
derived from the Greek words melas, meaning 'black' or 'dark', and tonos,
meaning 'labour', 'colour' or 'suppress' as it was found to lighten skin
colour. Subsequent research in the
mid-1970s by Lynch and others demonstrated that melatonin production follows a
circadian rhythm in human pineal glands. This compound was later identified as
a hormone secreted in the brain during the night, playing a crucial role in
regulating the sleep-wake cycle, also known as the circadian rhythm, in human.
Biosynthesis
The
biosynthesis of melatonin in animals involves a sequence of enzymatic reactions
starting with L-tryptophan, which can be synthesized through the shikimate
pathway from chorismate, found in plants, or obtained from protein catabolism.
The initial step in the melatonin biosynthesis pathway is the hydroxylation of
L-tryptophan's indole ring by the enzyme tryptophan hydroxylase, resulting in
the formation of 5-hydroxytryptophan (5-HTP). Subsequently, 5-HTP undergoes
decarboxylation, facilitated by pyridoxal phosphate and the enzyme
5-hydroxytryptophan decarboxylase, yielding serotonin.
Serotonin, itself
an essential neurotransmitter, is further converted into N-acetylserotonin by
the action of serotonin N-acetyltransferase, using acetyl-CoA. The final step
in the pathway involves the methylation of N-acetylserotonin's hydroxyl group
by hydroxyindole O-methyltransferase, with S-adenosyl methionine as the methyl
donor, to produce melatonin.
Regulation
of secretion
In human,
the secretion of melatonin is regulated through the activation of the beta-1
adrenergic receptor by the hormone norepinephrine. Norepinephrine increases the
concentration of intracellular cAMP via beta-adrenergic receptors, which in
turn activates the cAMP-dependent protein kinase A (PKA). PKA then
phosphorylates arylalkylamine N-acetyltransferase (AANAT), the penultimate
enzyme in the melatonin synthesis pathway. When exposed to daylight,
noradrenergic stimulation ceases, leading to the immediate degradation of the
protein by proteasomal proteolysis.
Blue light,
especially within the 460–480 nm range, inhibits the biosynthesis of melatonin,
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. The incandescent light bulbs used extensively throughout the 20th
century emitted relatively low levels of blue light. It has been found that
light containing only wavelengths greater than 530 nm does not suppress
melatonin under bright-light conditions. The use of glasses that block blue
light in the hours preceding bedtime can mitigate melatonin suppression.
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.
Metabolism
Melatonin is
metabolized in liver by liver enzymes, with an elimination half-life ranging
from 20 to 50 minutes. The primary metabolic pathway transforms melatonin into
6-hydroxymelatonin, which is then conjugated with sulfate and excreted in urine
as a waste product.
Measurement
For both
research and clinical purposes, melatonin levels in humans can be determined
through saliva or blood plasma analysis.
Physiological
functions
Circadian
rhythm
In human,
melatonin is critical for the regulation of sleep–wake cycles, or circadian
rhythms. The establishment of regular melatonin levels in human infants occurs
around the third month after birth, with peak concentrations observed between
midnight and 8:00 am. It has been documented that melatonin production
diminishes as a person ages. Additionally, a shift in the timing of melatonin
secretion is observed during adolescence, resulting in delayed sleep and wake
times, increasing their risk for delayed sleep phase disorder during this
period.
Antioxidant
Properties
The
antioxidant properties of melatonin were first recognized in 1993. In vitro
studies reveal that melatonin directly neutralizes various reactive oxygen
species, including hydroxyl (OH•), superoxide (O2−•), and reactive nitrogen
species such as nitric oxide (NO•).
Melatonin's
concentration in the mitochondrial matrix is significantly higher than that
found in the blood plasma, 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.
Furthermore,
the interaction of melatonin with reactive oxygen and nitrogen species results
in the formation of metabolites capable of reducing free radicals. These
metabolites, including cyclic 3-hydroxymelatonin,
N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and
N1-acetyl-5-methoxykynuramine (AMK), contribute to the broader antioxidative
effects of melatonin through further redox reactions with free radicals.
Immune
system
Melatonin's
interaction with the immune system is recognized, yet the specifics of these
interactions remain inadequately defined. An anti-inflammatory effect appears
to be the most significant. 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 augment cytokine
production and promote the expansion of T cells, thereby potentially mitigating
acquired immunodeficiencies.
Weight
regulation
Melatonin's
potential to regulate weight gain is posited to involve its inhibitory effect
on leptin, a hormone that serves as a long-term indicator of the body's energy
status.
Use as a
medication and supplement
As a
medicine it is used in following conditions under medical supervision-
1.
Insomnia- in persons above 55 years
2.
Circadian rhythm sleep disorders like- delayed sleep phase syndrome and to reduce jet lag syndrome
3.
REM sleep behavior disorders- like Parkinson's disease and dementia
with Lewy bodies.
4.
Dementia- melatonin may improve sleep in minimal cognitive impairment
only in cases of dementia.