Melatonin was first discovered as a product of the pineal gland, although we now know that it is produced throughout the body. Extrapineal melatonin production sites include the retina, thymus, intestine, liver, brain, skeletal and cardiac muscle, immune system cells, ovaries, testicles, and skin, among others. The role of the pineal gland is to cyclically produce melatonin so that this hormone can generate a circadian rhythm with a nocturnal peak; it also synchronises other endocrine and non-endocrine rhythms, such as the sleep-wake rhythm, antioxidant activity, and the organism’s innate immune system response. Melatonin production decreases with age, and after the age of 40 years, this decrease becomes significant. This hormone is also has non-hormonal functions, including playing antioxidant, anti-inflammatory, and free radical scavenging roles. Melatonin is the most important component in the body’s antioxidant system and maintains cellular redox homeostasis. It has a high capacity to purify hydroxyl radicals and peroxynitrites, as well as superoxide anions, hydrogen peroxide, and NO, thus protecting cells from the attack of these free radicals.
Melatonin’s antioxidant activity is threefold: (1) it is a very lipophilic molecule and so penetrates all the intracellular structures and protects them from oxidative attack; (2) it purifies free radicals and increases glutathione (GSH), thus maintaining the redox balance of cells; and (3) through a genomic effect, it increases the expression (and activity) of glutathione reductase and peroxidase. This antioxidant activity may be the basis of melatonin’s role in regulating the cell cycle, including inhibition of apoptosis. Aside from its other well-documented and experimentally-researched antioxidant and anti-inflammatory activities, melatonin’s ability to inhibit dopamine oxidation makes it a more potent antioxidant than selegiline and vitamins E and C. In addition, it can reverse the mitochondrial complex I oxidation induced by potent neurotoxins such as MPTP in parkinsonian mice, helping the recovery of mitochondrial energy and normal locomotor activity. In a similar line, melatonin prevents the multi-organ failure induced in rats or mice by administration of bacterial lipopolysaccharides, by reducing the expression and activity of iNOS and excessive NO production. Above all, melatonin reduces the expression and activity of i‑mtNOS, significantly reducing the mitochondrial levels of NO, normalising ETC activity and ATP production. These examples of melatonin’s antioxidant and anti-inflammatory efficacy are the basis of its clinical utility.
Melatonin also protects against oxidative damage induced by a wide variety of agents and situations which produce free radicals such as the carcinogen safrole, cyanide, the depletion of glutathione, and ionising radiation. Melatonin is very effective in protecting DNA, RNA, membrane lipids, and cytosolic proteins against oxidative damage, thus increasing membrane fluidity. Likewise, it scavenges the peroxyl radicals generated during lipid peroxidation by very different agents, including paraquat, bacterial lipopolysaccharides, and MPTP, among others. The generation of safrole-induced free radicals, which severely damage DNA and is carcinogenic, is almost completely blocked by melatonin at doses 100 times lower than safrole. Likewise, melatonin is 100,000 times more effective than vitamins E and C in protecting mitochondria from the damage induced by hydroperoxides. In addition, the DNA damage produced by free radicals from other sources, such as ionising radiation, is reduced if melatonin is administered beforehand.
Cytosolic proteins are also protected by melatonin against free radicals; in experimental situations of glutathione depletion (by administering buthionine sulfoximine, BSO), melatonin prevents the appearance of cataracts in newborn rats. The chronic administration of melatonin to mice with an accelerated aging profile (SAMP8) prevented the deterioration of mitochondrial function associated with aging, because it counteracted the oxidative and nitrosative stress and the inflammatory reactions that cause aging, thus ‘rescuing’ these senescent mice.