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

Abstract

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.

An autoradiographic study of cellular proliferaton, DNA synthesis and cell cycle variability in the rat liver caused by phenobarbital-induced oxidative stress: The protective role of melatonin

“…Beyond its antioxidant activities, melatonin has been tested for and successfully used in other clinical situations. It was initially taken by transmeridian travelers to quell the severity of jet lag [52], and thereafter became popular as a sleeppromoting agent [53]. Interest in its use in the suppression of growth of certain cancer types is supported by the experimental and clinical observations of a number of scientists [26,27,54].…”

Melatonin and mitochondrial function

“…In fact, results from initial therapeutic trials of melatonin in AD patients have demonstrated improved function, decreased ''sundowning'', improved sleep, and a significant slowing of the progression of the disease (Maurizi, 2001;Cardinali, 2003). In cultured cells, melatonin prevents nuclear and mtDNA cleavage and apoptosis induced by amyloid protein (Pappolla et al, 1997(Pappolla et al, , 1999(Pappolla et al, , 2000.…”

“…A decrease in the cerebrospinal fluid (CSF) melatonin was found in patients with AD and subsequently it was suggested that the loss of melatonin allowed neuronal mitochondria to be damaged by endogenously-generated S OH, with injury noted first in the most active tissues (Maurizi, 1997(Maurizi, , 2001Cardinali, 2003). In fact, results from initial therapeutic trials of melatonin in AD patients have demonstrated improved function, decreased ''sundowning'', improved sleep, and a significant slowing of the progression of the disease (Maurizi, 2001;Cardinali, 2003).…”

Sleep in Older Adults With Alzheimer's Disease

“…In the normal aging process and in the progression of AD, cell loss and decreased SCN volume cause disturbances in circadian rhythms and thus contribute to disrupted sleepYwake patterns, which is even more pronounced in those with AD (Swaab, Fisser, Kamphorst, & Troost, 1988;Wu & Swaab, 2007). The SCN is also known to regulate the secretion of melatonin, the ''sleep hormone,'' by the pineal gland and plays a major role in the circadian component that regulates the timing of sleep (Cardinali, Furio, & Reyes, 2005). A decreased melatonin level in older adults with AD is related to disrupted sleepYwake rhythms (Mishima et al, 1999;Wu & Swaab, 2005).…”