Melatonin signaling as a link between sleep and circadian biology : practical implications

Abstract

Abstract: Normal circadian rhythms are synchronized to a regular 24 h environmental light-dark cycle. Both the suprachiasmatic nucleus (SCN) and melatonin are essential for this adaptation. Melatonin exerts its chronophysiological action in part by acting through specific membrane receptors (MT1, MT2), which have been identified in SCN cells as well as in several neural and non-neural tissues. Both receptors have been cloned and share general features with other G protein linked receptors. Melatonin also exerts direct effects on intracellular proteins, such as calmodulin or tubulin, has strong free radical scavenger properties, which are non-receptor mediated, is an effective mitochondrial protector and may interact with proteasome to affect intracellular physiology. Within the SCN, melatonin reduces neuronal activity in a time-dependent manner. The disruption of these circadian mechanisms causes a number of sleep disorders known as circadian rhythm sleep disorders (CRSDs). CRSDs include delayed or advanced sleep phase syndromes; non-24 h sleep-wake rhythm disorder, time zone change syndrome (“jet lag”) and shift work sleep disorder. Disturbances in the circadian phase position of plasma melatonin levels have been found in all these disorders. In addition, comorbidity of severe circadian alterations with neurodegenerative diseases like Alzheimer’s disease (AD) has been documented. Currently there is sufficient evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology. The documented efficacy of melatonin to reduce chronic benzodiazepine/Z drug use in insomnia patients is also discussed.