New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation

Abstract

In mammals, a central circadian clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, tunes the innate circadian physiological rhythms to the ambient 24 h light–dark cycle to invigorate and optimize the internal temporal order. The SCN‐activated, light‐inhibited production of melatonin conveys the message of darkness to the clock and induces night‐state physiological functions, for example, sleep/wake blood pressure and metabolism. Clinically meaningful effects of melatonin treatment have been demonstrated in placebo‐controlled trials in humans, particularly in disorders associated with diminished or misaligned melatonin rhythms, for example, circadian rhythm‐related sleep disorders, jet lag and shift work, insomnia in children with neurodevelopmental disorders, poor (non‐restorative) sleep quality, non‐dipping nocturnal blood pressure (nocturnal hypertension) and Alzheimer's disease (AD). The diminished production of melatonin at the very early stages of AD, the role of melatonin in the restorative value of sleep (perceived sleep quality) and its sleep‐anticipating effects resulting in attenuated activation of certain brain networks are gaining a new perspective as the role of poor sleep quality in the build‐up of β amyloid, particularly in the precuneus, is unravelled. As a result of the recently discovered relationship between circadian clock, sleep and neurodegeneration, new prospects of using melatonin for early intervention, to promote healthy physical and mental ageing, are of prime interest in view of the emerging link to the aetiology of Alzheimer's disease.Linked ArticlesThis article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…Melatonin ( N ‐acetyl‐5‐methoxytryptamine) is a hormone associated with circadian rhythms especially in the dark phase. Melatonin synthesis is facilitated at night and inhibited by light at daytime detected by retinas . Melatonin is produced primarily by the pineal gland from the amino acid tryptophan .…”

Melatonin induces mechanisms of brain resilience against neurodegeneration

“…The benefits of melatonin treatment for AD patients can be substantiated by the regulation of circadian rhythm and improved quality of sleep, thus slowing down the progression of cognitive loss. Nevertheless, evidence of cognitive improvement remains to be shown …”

Recent developments in research of melatonin and its potential therapeutic applications

“…To start on familiar territory, Zisapel (2018) updates the evidence for regulation of sleep rhythms by melatonin. Whereas the suprachiasmatic nucleus (SCN) is the 'metronome' for the circadian cycle (and many other aspects of internal body state, such as thermoregulation and autonomic arousal), melatonin is a major contributor to the process of entraining its rhythmic activity.…”

“…This hormone prevents arousal, which is mediated by the SCN, and promotes (but does not induce) sleep. Zisapel (2018) discusses evidence that the epicentre for this latter action is probably the precuneus, in the cerebral cortex, but involves several other brain regions, collectively known as the 'default mode network' (DMN).…”

“…In that respect, this field can claim translational success because PRM now has regulatory approval for short-term treatment (<3 weeks) of insomnia in the elderly. However, Zisapel (2018) also comments on the interesting, bidirectional association between disrupted sleep rhythms and other disorders, such as hypertension and Alzheimer's disease (AD). An association between sleep disruption and obesity can be added to that list too.…”