The Clock Hormone
Melatonin is a naturally occurring compound found in animals, plants, and microbes In animals, circulating levels of melatonin vary in a daily cycle, thereby regulating the circadian rhythms of several biological functions. Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and powerful antioxidant, with a particular role in the protection of nuclear and mitochondrial DNA.
Melatonin in plants has multiple roles including regulation of the photoperiod, in plant defense responses, and as a scavenger of reactive oxygen species.
As early as 1917, it was known that an extract of cow pineal glands lightened frog skin. Dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated and named the hormone melatonin in 1958.
Melatonin is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.
Melatonin may also be produced by a variety of peripheral cells such as bone marrow cells, lymphocytes and epithelial cells. Usually, the melatonin concentration in these cells is much higher than that found in the blood but it does not seem to be regulated by the photoperiod.
Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.
Melatonin is related to the mechanism by which some amphibians and reptiles change the color of their skin and, indeed, it was in this connection the substance first was discovered. McCord and Allen discovered that extract of the pineal glands of cows lightened frog skin, while Aaron B. Lerner is credited for naming the hormone and for defining its chemical structure in 1958. In the mid-70s Lynch et al. demonstrated that also in humans the production of melatonin exhibits a circadian rhythm.
Distribution in the mammalian body
Melatonin produced in the pineal gland, which is outside of the blood-brain barrier, acts as an endocrine hormone since it is released into the blood. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.
Circadian rhythm In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, located in the center of the brain but outside the blood-brain barrier. The melatonin signal forms part of the system that regulates the sleep-wake cycle by chemically causing drowsiness and lowering the body temperature, but it is the central nervous system that controls the daily cycle in most components of the paracrine and endocrine systems rather than the melatonin signal (as was once postulated).
Light dependence Production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called “the hormone of darkness” and its onset each evening is called the Dim-Light Melatonin Onset (DLMO). Secretion of melatonin as well as its level in the blood, peaks in the middle of the night, and gradually falls during the second half of the night, with normal variations in timing according to an individual’s chronotype.
Until recent history, humans in temperate climates were exposed to only about six hours of daylight in the winter. In the modern world, artificial lighting reduces darkness exposure to typically eight or fewer hours per day all year round. Even low light levels inhibit melatonin production to some extent, but over-illumination can create significant reduction in melatonin production. Since it is principally blue light that suppresses melatonin wearing glasses that block blue light in the hours before bedtime may avoid melatonin loss. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.
Antioxidant Besides its function as synchronizer of the biological clock, melatonin also exerts a powerful antioxidant activity. The discovery of melatonin as an antioxidant was made in 1993. In many lower life forms, it serves only this purpose. Melatonin is an antioxidant that can easily cross cell membranes and the blood-brain barrier. Melatonin is a direct scavenger of OH, O2−, and NO. Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to regain their antioxidant properties. Melatonin, on the other hand, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.
In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer. It also has been found to be effective in protecting against brain injury caused by ROS release in experimental hypoxic brain damage in newborn rats. Melatonin’s antioxidant activity may reduce damage caused by some types of Parkinson’s disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.
Immune system While it is known that melatonin interacts with the immune system, the details of those interactions are unclear. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. In preclinical studies, melatonin may enhance cytokine production, and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.
Dreaming Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin (50 mg) dramatically increased REM sleep time and dream activity in both people with and without narcolepsy. Many psychoactive drugs, such as cannabis and lysergic acid diethylamide (LSD), increase melatonin synthesis.] It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.
Current and potential medical indications
Melatonin has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), circadian rhythm sleep disorders and sexual dysfunction.
Taken 30 to 90 minutes before bedtime, melatonin supplementation acts as a mild hypnotic. It causes melatonin levels in the blood to rise earlier than the brain’s own production accomplishes.
Preventing ischemic damage Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain and the heart; however, this has not been tested in humans.
Learning, memory and Alzheimer’s
Melatonin receptors appear to be important in mechanisms of learning and memory in mice, and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). There is published evidence that melatonin may be useful in Alzheimer’s disease.
Studies in rats suggest that melatonin may be effective for treating Alzheimer’s disease.
Headaches Several clinical studies indicate that supplementation with melatonin is an effective preventive treatment for migraines and cluster headaches.
Cancer A systematic review of unblinded clinical trials involving a total of 643 cancer patients using melatonin found a reduced incidence of death. Another clinical trial is due to be completed in 2012. Melatonin levels at night are reduced to 50% by exposure to a low-level incandescent bulb for only 39 minutes, and it has been shown that women with the brightest bedrooms have an increased risk for breast cancer. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers.
Gallbladder stones Melatonin presence in the gallbladder has many protective properties, such as converting cholesterol to bile, preventing oxidative stress, and increasing the mobility of gallstones from the gallbladder. It also decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. In guinea pigs, melatonin administration restored normal function by reducing inflammation after induced Cholecystitis, whether administered before or after onset of inflammation. Relatively speaking, concentration of melatonin in the bile is 2–3 times higher than the otherwise very low daytime melatonin levels in the blood across many diurnal mammals, including humans.
Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).
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