Melatonin and Its Agonist Ramelteon in Alzheimer′s Disease: Possible Therapeutic Value

Abstract

Alzheimer's disease (AD) is an age-associated neurodegenerative disease characterized by the progressive loss of cognitive function, loss of memory and insomnia, and abnormal behavioral signs and symptoms. Among the various theories that have been put forth to explain the pathophysiology of AD, the oxidative stress induced by amyloid β-protein (Aβ) deposition has received great attention. Studies undertaken on postmortem brain samples of AD patients have consistently shown extensive lipid, protein, and DNA oxidation. Presence of abnormal tau protein, mitochondrial dysfunction, and protein hyperphosphorylation all have been demonstrated in neural tissues of AD patients. Moreover, AD patients exhibit severe sleep/wake disturbances and insomnia and these are associated with more rapid cognitive decline and memory impairment. On this basis, the successful management of AD patients requires an ideal drug that besides antagonizing Aβ-induced neurotoxicity could also correct the disturbed sleep-wake rhythm and improve sleep quality. Melatonin is an effective chronobiotic agent and has significant neuroprotective properties preventing Aβ-induced neurotoxic effects in a number of animal experimental models. Since melatonin levels in AD patients are greatly reduced, melatonin replacement has the potential value to be used as a therapeutic agent for treating AD, particularly at the early phases of the disease and especially in those in whom the relevant melatonin receptors are intact. As sleep deprivation has been shown to produce oxidative damage, impaired mitochondrial function, neurodegenerative inflammation, and altered proteosomal processing with abnormal activation of enzymes, treatment of sleep disturbances may be a priority for arresting the progression of AD. In this context the newly introduced melatonin agonist ramelteon can be of much therapeutic value because of its highly selective action on melatonin MT1/MT2 receptors in promoting sleep.

Concentration-dependent effect of melatonin on DSPC membrane

“…It is wellknown that melatonin is a powerful endogenous antioxidative molecule protecting cells from oxidative damage and it has strong anti lipid peroxidation properties [52][53][54][55]. It is also known that there is a strong relevance between lipid peroxidation and fluidity of cell membranes [56,57].…”

Effects of Ramelteon on Refractory Behavioral and Psychological Symptoms of Dementia in Alzheimer Disease

“…6 Ramelteon's higher affinity for MT1 receptors is suggested to target sleep onset more specifically than melatonin does. 6 Moreover, ramelteon, unlike other hypnotic agents, does not cause rebound insomnia, oversedation, withdrawal symptoms, or drug dependence.…”

“…6 Ramelteon's higher affinity for MT1 receptors is suggested to target sleep onset more specifically than melatonin does. 6 Moreover, ramelteon, unlike other hypnotic agents, does not cause rebound insomnia, oversedation, withdrawal symptoms, or drug dependence. 6 Although the role of melatonin receptors for BPSD in AD has not been clarified pharmacologically, severe sleep disturbance might be improved by ramelteon through highly selective action on MT1 receptors.…”

“…6 Although both MT1 and MT2 receptors are involved in the regulation of sleep, the selectivity of ramelteon for MT1 receptors has been shown as greater than 1000-fold higher than that of MT2 receptors. 6 Because the MT1 receptors are deeply implicated in regulation of the sleep cycle, ramelteon is also inferred on a theoretical basis to be beneficial in treating sleep-wake and circadian rhythm disturbances in AD. 6 Some reports have described the utility of ramelteon for insomnia in an aging population.…”

“…6 Because the MT1 receptors are deeply implicated in regulation of the sleep cycle, ramelteon is also inferred on a theoretical basis to be beneficial in treating sleep-wake and circadian rhythm disturbances in AD. 6 Some reports have described the utility of ramelteon for insomnia in an aging population. 7 No report has described ramelteon treatment for BPSD in AD.…”