Functional pleiotropy of the neurohormone melatonin: antioxidant protection and neuroendocrine regulation

The pineal hormone melatonin exhibits remarkable functional versatility. Shortly after its discovery, melatonin was functionally linked to the regulation of the neuroendocrine axis, particularly to the reproductive system. However, judging from the wide variety of cellular changes that occurred following either pinealectomy, to remove the primary source of melatonin, or the exogenous administration of the indole, it was obvious that the activity of melatonin far transcended its actions on the hypothalamo-pituitary-gonadal system. Roughly 30 months ago it was discovered that melatonin is a highly efficient free radical scavenger and general antioxidant. This implied that melatonin, which is both lipophilic and hydrophilic, has effects not only in every cell but also within every subcellular compartment. These intracellular actions of melatonin, some of which are independent of any receptor interaction and some of which are mediated by nuclear receptors, have become the focus of much of the current investigation. As an antioxidant, melatonin has been shown in vitro to be a highly efficient scavenger of the very reactive and toxic hydroxyl radical. Indeed, on an equimolar basis melatonin proved significantly more efficient in neutralizing the hydroxyl radical than did the two well-known scavengers, glutathione and mannitol. Likewise, melatonin was found to also scavenge the peroxyl radical which is generated during lipid peroxidation; in this regard it was roughly twice as effective as vitamin E (alpha-tocopherol). The antioxidant activities of melatonin have been well documented in tissue homogenates and organisms as well. When rats are treated with the chemical carcinogen safrole, this agent induces the generation of free radicals which in turn extensively damage nuclear DNA; this damage is almost totally eliminated if the animals are cotreated with melatonin. Also, damage to DNA in human lymphocytes due to ionizing radiation, another treatment which is known to induce free radical formation, is greatly reduced if the cells are treated with melatonin prior to radiation. Cytosolic protein seems also to be protected from free radical damage when melatonin is present. When newborn rats are treated with a glutathione-depleting drug at birth, by 2 weeks of age the animals have cataracts. Cataracts form because oxidants damage protein in the presence of low intracellular levels of glutathione. Cataracts induced by this means are essentially prevented if the glutathione-depleted rats are supplemented with melatonin. Finally, membrane lipid peroxidation, induced either in vivo or in vitro by any of several means, all of which involve free radicals, is drastically attenuated in the presence of melatonin. Considering melatonin's ability to cross all morphophysiological barriers and to enter every cell, and all subcellular compartments, the implication is that this indole may play a very important role in the antioxidative defense system of the organism. These findings potentially have important implications for a wide variety of age-related diseases and to aging itself. Melatonin's control of reproductive physiology in photoperiodic mammals is well documented. However, the site of interaction of melatonin with the neuroendocrine axis has been especially difficult to determine. The discovery and cloning of a membrane melatonin receptor on neurosecretory cells in the hypothalamus and on hormone secreting cells of the anterior pituitary gland stimulated a great deal of investigation which has failed to prove the involvement of these receptors in the processes by which melatonin influences reproductive physiology. The recent identification of nuclear melatonin receptors as well as the nonreceptor-mediated actions of the indole are currently being examined as to their association with reproductive function.