Clinical perspectives for the use of melatonin as a chronobiotic and cytoprotective agent.

The circadian time system involves periodic gene expression at the cellular level, synchronized by a hierarchically superior structure located in the hypothalamic suprachiasmatic nuclei. Treatment of circadian rhythm disorders has led to the development of a new type of agent called "chronobiotics," among which melatonin is the prototype. In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency, particularly slow-wave sleep. The effect of melatonin on sleep is the consequence of increasing sleep propensity (by augmenting the amplitude of circadian clock oscillation via MT1 receptors) and of synchronizing the circadian clock via MT2 receptors. Daily melatonin production decreases with age and in several pathologies, attaining its lowest values in Alzheimer's disease (AD) patients. About 45% of AD patients have disruptions in their sleep and "sundowning" agitation. Generally, melatonin treatment decreases sundowning in AD patients and reduced variability of sleep onset time. Both open and controlled studies have indicated a significant decrease of cognitive deterioration in AD patients treated with melatonin. The mechanisms accounting for the possible therapeutic effect of melatonin in AD patients may be manifold. On one hand, melatonin treatment promotes slow-wave sleep in the elderly and could be beneficial by augmenting the restorative phases of sleep. On the other hand, melatonin protects neurons against beta-amyloid toxicity. By its combined chronobiotic and cytoprotective properties melatonin provides an innovative neuroprotective strategy to reduce the cost of lifetime treatment of some neuropsychiatric disorders.