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 ARTICLES: This 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.

Figure 1

The fMRI‐assessed visual search task related activation of brain networks (adapted from Gorfine et al., 2006; Gorfine and Zisapel, 2009). (A) The effect of exogenous melatonin administration at 16:00 h on task‐related activity. In a double‐blind, crossover design with 10 days between treatments, subjects had a baseline and a randomized treatment fMRI session, commencing 1 h later. The drugs (melatonin 2 mg in 100 mL of 1% ethanol in water or placebo 100 mL of 1% ethanol in water) were given p.o. after the baseline session and subjects were instructed to remain awake in ambient room light for 1 h to allow the ingested melatonin to reach maximal levels in the blood. Drug effect was defined by a conjunction analysis of two contrasts: activation after melatonin intake > activation before melatonin intake and activation after melatonin intake > activation after placebo intake. This analysis identifies regions that are affected by melatonin while excluding changes resulting from placebo or second examination effects. The image depicts the statistical parametric map of melatonin versus placebo effect analysis (conjunction analysis, P < 0.05 uncorrected). Blue indicates decreased activation following melatonin but not placebo intake. (B) The experiment was repeated as described in (A) with exogenous melatonin administration at 22:00 h. To evaluate time of day effects on brain activity, group activation maps were generated for the baseline fMRI scans of the 14 subjects from the night trial and the 12 subjects of the reference (afternoon) trial. Brain areas demonstrating significant task‐related activity at 16:00 h but not 22:00 h were identified. The image depicts statistical parametric maps (P < 0.01 corrected) demonstrating task‐related activation at 16:00 h (red) and 22:00 h (blue). Purple denotes overlapped activation. The crossing white lines denote the precuneus area. (C) The effect of exogenous melatonin administration at 22:00 h on task‐related activity. The experiment was repeated as described in (A) with exogenous melatonin administration at 22:00 h. Drug effect was defined by a conjunction analysis of two contrasts: activation after melatonin intake > activation before melatonin intake and activation after melatonin intake > activation after placebo intake. This analysis identifies regions that are affected by melatonin while excluding changes resulting from placebo or second examination effects. The image depicts the statistical parametric map of melatonin versus placebo effect analysis (conjunction analysis, P < 0.05 uncorrected) showing no difference in activation of the precuneus following melatonin and placebo intake.

Figure 2

Mean plasma levels of ingested (A) and endogenous (B) melatonin. (A) Pharmacokinetics of prolonged‐release (PRM) versus immediate‐release (IR) melatonin 2 mg formulations. Results are mean plasma melatonin levels following drug intake and expressed as % of the AUC (adapted from Zisapel, 2010). (B) Mean endogenous plasma melatonin levels (adapted from Zhdanova et al., 1998).

Figure 3

Proposed effects of melatonin on mechanisms linking circadian clocks, sleep and neurodegeneration in AD (adapted from Landry and Liu‐Ambrose, 2014; Musiek and Holtzman, 2016). Sleep–wake and circadian disruption may precede neurodegeneration and the development of cognitive symptoms. The sleep–wake cycle appears to regulate levels of the pathogenic amyloid‐β peptide in the brain, blood pressure rhythms and inflammation. Improving sleep and the circadian clock functioning can influence these processes, reduce cardiovascular risk, inflammation and amyloid‐β accumulation and thereby slow down the neurodegenerative process. Melatonin, through its beneficial effects on the circadian clock functions and sleep–wake cycle, may delay AD‐related pathology.