Melatonin for Sleep

What Is Melatonin?

Melatonin is an amphiphilic tryptophan-derived indoleamine that scavenges free radicals and has remarkable antioxidant properties, stimulating antioxidant enzymes in different tissues. Some tissues and organs (e.g., retina, gastrointestinal tract, bone marrow, lymphocytes, and skin) produce localized melatonin with specific endocrine, autocrine, and paracrine effects, in addition to the presence of a specific gland, the pineal gland, in vertebrates, which synthesizes melatonin with an endocrine effect. Mammalian pineal melatonin synthesis is controlled by a master clock in the hypothalamus suprachiasmatic nucleus (SCN) and is synchronized with the light/dark cycle via retinal intrinsic photosensitive ganglion cells. Because retinal intrinsic photosensitive ganglion cells transmit ambient photoperiodic information to the SCN, melatonin secretion is restricted to the dark phase of the night. Melatonin synthesis is blocked by nocturnal light, an effect mediated by the retinal melanopsinergic system and a complex neural system that ultimately inhibits sympathetic projections to the pineal gland. In humans, this photoinhibition phenomenon is determined by light, especially blue light. Based on light/dark cycle synchronization and nocturnal photoinhibition, melatonin can function as a time-domain molecule to synchronize an organism's internal time sequence with the external daily and seasonal light/dark environment. Melatonin plays a role in promoting a sleep state, so a decrease in its expression level would keep a person awake, especially since exposure to high wavelength light suppresses melatonin circulating in the blood.

Figure 1. Neuroanatomical pathway of light stimulus to the pineal gland
(Source: Vasey C, et al. 2021)

The pineal gland of newborn mammals does not produce melatonin until after birth, so maternal melatonin is the only source of obtaining this hormone (in the fetal period through the placental circulation and in the newborn period through breastfeeding). In humans, pineal melatonin appears in full-term infants between 3 and 4 months of age, peaks in prepubertal children, decreases after puberty, and reaches young adult levels. In adults, however, pineal melatonin production continues to decline with age, with people over the age of 90 producing only 20% of their young adult levels.

How Does Melatonin Work?

Melatonin is amphiphilic and can directly interact with intracellular molecules through cell membrane, cell organ membrane and nuclear membrane. In addition, melatonin also has a receptor-mediated effect, which is the result of interaction with membrane receptors and nuclear receptors.

Non-receptor-mediated action

Melatonin and its metabolites directly scavenge free radicals, and stimulate the transcription and activity of antioxidant enzymes and inhibit the formation of hydroxyl radicals. Melatonin is highly concentrated in mitochondria and protects lipids, proteins and DNA from oxidative damage. The antioxidant properties of melatonin are critical for mitochondrial function. In addition to its protective antioxidant effects, melatonin plays key roles in mitochondrial function, such as regulating the activity of respiratory chain complexes I and IV, and protecting mitochondrial DNA from mutations and deletions. These effects are the result of direct interactions between melatonin and proteins. Melatonin also plays a role in the regulation of the ubiquitin-proteasome system, and has been found to act as an antagonist by inhibiting Ca²⁺/calmodulin-dependent protein kinase II activity and autophosphorylation through direct interaction with Ca²⁺-activated calmodulin.

Receptor-mediated action

The melatonin receptor (MT) is a high-affinity specific G protein-coupled receptor containing MT1 and MT2. Human MT1, which contains 350 amino acids, and human MT2, which contains 362 amino acids, are found in several regions of the CNS, such as the SCN, thalamus, temporal lobe, hippocampus, retina, cerebellum, and pars tuberalis (PT). MT1 and MT2 are also present in a number of peripheral tissues and organs, including adipose tissue, kidney, pancreatic islets, skin, reproductive tract, immune cells, and cardiovascular system (CVS). Melatonin receptors interact with downstream messengers such as adenylate cyclase, phospholipase A2, and phospholipase C, as well as calcium and potassium channels, and typically reduce cAMP and cGMP production and activate phospholipase C.

MT1 and MT2 usually dimerize to form homodimers or heterodimers, allowing both melatonin binding sites to function with their own selectivity. The MT1 signaling pathway involves activation of potassium channels that inhibit SCN neuronal firing, regulation of protein kinase C (PKC) and phospholipase A2, stimulation of the mitogen-activated protein kinase 1/2-ERK1/2 pathway in non-neuronal cells, and vasoconstriction. The MT2 signaling pathway includes inhibition of cGMP formation in the SCN, stimulation of PKC activity, and regulation of uterine contractility and vasodilation. Some investigators have suggested that MT2 in the SCN may correspond to G protein-coupled inwardly rectifying potassium channels.

Melatonin ELISA Kits

Melatonin Antigens

Melatonin Antibodies