Clinical Perspectives for the Use of Melatonin as a Chronobiotic and Cytoprotective Agent

doi:10.1196/annals.1356.025

The circadian time system involves periodic gene expressionat the cellular level, synchronized by a hierarchically superiorstructure located in the hypothalamic suprachiasmatic nuclei.Treatment of circadian rhythm disorders has led to the developmentof a new type of agent called "chronobiotics," among which melatoninis the prototype. In elderly insomniacs, melatonin treatmentdecreased sleep latency and increased sleep efficiency, particularlyslow-wave sleep. The effect of melatonin on sleep is the consequenceof increasing sleep propensity (by augmenting the amplitudeof circadian clock oscillation via MT₁ receptors) and of synchronizingthe circadian clock via MT₂ receptors. Daily melatonin productiondecreases with age and in several pathologies, attaining itslowest values in Alzheimer's disease (AD) patients. About 45%of AD patients have disruptions in their sleep and "sundowning"agitation. Generally, melatonin treatment decreases sundowningin AD patients and reduced variability of sleep onset time.Both open and controlled studies have indicated a significantdecrease of cognitive deterioration in AD patients treated withmelatonin. The mechanisms accounting for the possible therapeuticeffect of melatonin in AD patients may be manifold. On one hand,melatonin treatment promotes slow-wave sleep in the elderlyand could be beneficial by augmenting the restorative phasesof sleep. On the other hand, melatonin protects neurons againstß-amyloid toxicity. By its combined chronobiotic andcytoprotective properties melatonin provides an innovative neuroprotectivestrategy to reduce the cost of lifetime treatment of some neuropsychiatricdisorders.