It was first isolated from the Bovine Pineal gland in 1958. Nevertheless, in humans, it is the main hormone secreted by the pineal gland. Melatonin was considered a sleeping aid, and it was widely used to reduce jet-lag. Nevertheless, the chronobiological hormone has proven to have multiple health benefits, like antioxidant, anti-inflammatory, and immunomodulatory effects.
Extra pineal sources like:
-Bone marrow cells-.
-Gi tract (vertebrates)
Melatonin in the GI tract
In the gastrointestinal tract, melatonin can be synthesized by the enterochromaffin cells; the release of gastrointestinal melatonin into the circulation seems to follow food periodicity intake, particularly tryptophan intake.
The concentration of melatonin is greater than the blood levels by 10-100 times, and there is a 400 fold greater concentration in the GI tract than in the pineal gland.
Melatonin in Childhood
The amount of melatonin in the GI tract of lactating babies or mammals is determined by the mother’s melatonin concentration. In fact, melatonin can easily pass the placenta membrane, and after birth, the mother’s milk provides melatonin.
Melatonin in human milk follows a circadian rhythm (in preterm and term milk) with higher melatonin levels at night and undetectable levels during the day.
Human colostrum, secreted during the first 4 or 5 days after birth, contains immune-competent cells (colostral mononuclear cells), which can synthesize melatonin in an autocrine manner.
Infants secrete shallow levels of melatonin for the first 3 months, and then it starts to increase to become circadian along with the child development.
In children, the nocturnal concentration peaks are the highest between the 4th and 7th years of age and then decline progressively.
Melatonin is synthesized from the AA tryptophan in the pinealocytes. Indeed, the AA tryptophan is hydroxylated (by the tryptophan-5-hydroxylase) in 5-hydroxytryptophan, then decarboxylated (by the 5-hydroxytryptophan decarboxylase) in serotonin. Afterward, Serotonin goes into two more transformations to synthesize melatonin: the first one is acetylation by arylalkylamine-N-acetyltransferase, also called “Timezyme.” Following the metabolic pathways, N-acetylserotonin is methylated by acetylserotonin-O-methyltransferase (ASMT, also called hydroxyindole-O– methyltransferase HIOMT) to form melatonin.
Both AA-NAT and ASMT are mediated by noradrenergic signaling that activates adenylate cyclase, up-regulating AA- NAT function.
Melatonin is activated in the dark and inhibited by the light: Luminous information is transmitted from the retina to the pineal gland through the suprachiasmatic nucleus (SCN) of the hypothalamus.
In humans, melatonin secretion starts son after sundown and reaches its peak at 2-4 am. Afterward, it slowly decreases until its concentration is undetectable in the morning:
-After intravenous administration, melatonin is rapidly distributed (distribution half-life of 0.5 to 5.6 minutes) and eliminated.
-After oral administration, plasma concentration peak arises within 60 minutes.
-The intake of a dose of 1 to 5 mg can allow within the hour after ingestion, melatonin concentrations 10 to 100 times higher than the physiological nocturnal peak to be obtained, with a return to basal concentrations in 4 to 8 hours.
Effects of melatonin:
– Ingestion of melatonin induces fatigue, sleepiness, and a diminution of sleep latency. Disturbed circadian rhythms are associated with sleep disorders and impaired health.
– Melatonin administration in children with multiple developmental, neuropsychiatric, and health difficulties often show improvement in multiple symptoms. Indeed, when circadian rhythms are restored, behavior, mood, development, intellectual function, health, and even seizure control may improve. Several studies show circadian rhythms are important for typical (normal) neurodevelopment, and their absence suppresses neurogenesis in animal models.
Glial Cells and Melatonin
– In vitro studies have shown that neural stem/progenitor cells express melatonin receptors, and melatonin induces glial cell-line derived neurotrophic factor (GDNF) expression in neural stem cells, suggesting an early role for melatonin in central nervous system development. As indicated previously, maternal origin’s melatonin crosses the placenta and can therefore influence fetal neurodevelopment.
Studies in nonhuman primate fetuses have shown that maternal melatonin stimulates the primate fetal adrenal gland growth and entrains fetal circadian rhythms, including SCN rhythms.
– In mice, the suppression of melatonin rhythm by maternal exposure to constant light changes the rhythmic expression in fetal clock genes; these changes are reversed when melatonin is injected daily into the mother.
– Melatonin has the potential to synchronize biological rhythms and is considered a chronobiotic molecule.
Chronobiotic molecule: a substance that reinforces oscillations or adjusts the central biological clock’s timing located in the suprachiasmatic nuclei (SNC) of the hypothalamus to stabilize bodily rhythms.
– Authors Pevet and Chalet called melatonin a master clock output. Indeed, melatonin distributes temporal cues to all the tissue targets that contain melatonin receptors. These include adenohypophysis, fetal adrenal gland, and major organs like pancreas, liver, kidney, lungs, fat, and gut.
– Circadian rhythms, and more precisely the circadian clock network, allow the temporal organization of biological functions. Therefore, the melatonin secretion reflects adaptation to the environment. Meaning, the sleep–wake rhythm associated with biological circadian rhythms can be seen as an adaptation to the day-night cycle.
Melatonin chronobiologic function serves as a master clock that synchronizes the hormonal secretion of target tissues. Nevertheless, melatonin has proven to synchronize the immunologic reaction and modulate the inflammatory response and serve as a potent antioxidant agent. Besides, these aforementioned characteristics allow melatonin to be a possible therapeutic option to treat COVID-19.- Ana Paola Rodríguez Arciniega, MS
Tordjman, Sylvie et al. “Melatonin: Pharmacology, Functions and Therapeutic Benefits.” Current neuropharmacology vol. 15,3 (2017): 434-443. doi:10.2174/1570159X14666161228122115
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