The Role of Melatonin in the Neuroendocrine System: Multiplicity of Sites and Mechanisms of Action

Abstract

Melatonin is synthesized and secreted during the dark period of the light-dark cycle, a rhythm generated by a circadian clock located within the suprachiasmatic nuclei (SCN) of the hypothalamus and entrained to a 24-h period by the light-dark cycle. Direct effects of melatonin on the SCN, perhaps affecting γ-aminobutyric acid (GABA)-containing neurons, can explain melatonin’s effects on the circadian system. In addition, the periodic secretion of melatonin is a potential circadian signal to several non-neural cells that can “read” the message. Duration of melatonin nocturnal secretion is proportional to the length of the night and has experimentally been demonstrated to be an integral part of photoperiodic mechanisms. The intracellular sites and mechanisms of action of melatonin to affect circadian and photoperiodic responses are far from being elucidated. Although action through specific membrane receptor sites has been identified as important, interactions with specific intracellular proteins like calmodulin or tubulin, or with nuclear receptor sites should also be considered in view of the lipophilic nature of the melatonin molecule. Melatonin is also a potent free radical scavenger and pharmacologic effects of melatonin could be explained through direct scavenging of free radicals, or through induction of enzymes that improve total antioxidative defense capacity. Melatonin has a significant immunomodulatory activity, playing a major role in the organism’s defense. Melatonin seems to act as an arm of the circadian clock, giving a time-related signal to a number of restorative body functions.