Melatonin

Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cows that could induce skin lightening in common frogs. 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 vertebrates.

In vertebrates, melatonin's functions extend to synchronizing sleep-wake cycles, encompassing sleep-wake timing and blood pressure regulation, as well as controlling seasonal rhythmicity (circannual cycle), which includes reproduction, fattening, molting, and hibernation. Its effects are mediated through the activation of melatonin receptors and its role as an antioxidant. In plants and bacteria, melatonin primarily serves as a defense mechanism against oxidative stress, indicating its evolutionary significance. The mitochondria, key organelles within cells, are the main producers of antioxidant melatonin, underscoring the molecule's "ancient origins" and its fundamental role in protecting the earliest cells from reactive oxygen species.

In addition to its endogenous functions as a hormone and antioxidant, melatonin is also administered exogenously as a dietary 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. It is used in the treatment of sleep disorders, including insomnia and various circadian rhythm sleep disorders.

In humans, melatonin primarily acts as a potent full agonist of two types of melatonin receptors: melatonin receptor 1, with picomolar binding affinity, and melatonin receptor 2, with nanomolar binding affinity. Both receptors are part of the G-protein coupled receptors (GPCRs) family, specifically the G_i/o alpha subunit GPCRs, although melatonin receptor 1 also exhibits coupling with G_q alpha subunit.

Furthermore, melatonin functions as a high-capacity antioxidant, or free radical scavenger, within mitochondria, playing a dual role in combating cellular oxidative stress. First, it directly neutralizes free radicals, and second, it promotes the gene expression of essential antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. This increase in antioxidant enzyme expression is mediated through signal transduction pathways activated by the binding of melatonin to its receptors. Through these mechanisms, melatonin protects the cell against oxidative stress in two ways, highlighting how it serves human health beyond regulating the sleep-wake cycle.

In mammals, 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.

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•). In plants, melatonin works synergistically with other antioxidants, enhancing the overall effectiveness of each antioxidant. This compound has been found to be twice as efficacious as vitamin E, a known potent lipophilic antioxidant, at scavenging peroxyl radicals. 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.

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.