The Circadian Clock and Human Health

The hormone melatonin (5-methoxy- N -acetyltryptamine) is synthesized primarily in the pineal gland and retina, and in several peripheral tissues and organs. In the circulation, the concentration of melatonin follows a circadian rhythm, with high levels at night providing timing cues to target tissues endowed with melatonin receptors. Melatonin receptors receive and translate melatonin's message to influence daily and seasonal rhythms of physiology and behavior. The melatonin message is translated through activation of two G protein-coupled receptors, MT1 and MT2, that are potential therapeutic targets in disorders ranging from insomnia and circadian sleep disorders to depression, cardiovascular diseases, and cancer. This review summarizes the steps taken since melatonin's discovery by Aaron Lerner in 1958 to functionally characterize, clone, and localize receptors in mammalian tissues. The pharmacological and molecular properties of the receptors are described as well as current efforts to discover and develop ligands for treatment of a number of illnesses, including sleep disorders, depression, and cancer.

https://pharmrev.aspetjournals.org/content/pharmrev/62/3/343.full.pdf

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

The human pineal gland is a neuroendocrine transducer that forms an integral part of the brain. Through the nocturnally elevated synthesis and release of the neurohormone melatonin, the pineal gland encodes and disseminates information on circadian time, thus coupling the outside world to the biochemical and physiological internal demands of the body. Approaches to better understand molecular details behind the rhythmic signalling in the human pineal gland are limited but implicitly warranted, as human chronobiological dysfunctions are often associated with alterations in melatonin synthesis. Current knowledge on melatonin synthesis in the human pineal gland is based on minimally invasive analyses, and by the comparison of signalling events between different vertebrate species, with emphasis put on data acquired in sheep and other primates. Together with investigations using autoptic pineal tissue, a remnant silhouette of premortem dynamics within the hormone's biosynthesis pathway can be constructed. The detected biochemical scenario behind the generation of dynamics in melatonin synthesis positions the human pineal gland surprisingly isolated. In this neuroendocrine brain structure, protein-protein interactions and nucleo-cytoplasmic protein shuttling indicate furthermore a novel twist in the molecular dynamics in the cells of this neuroendocrine brain structure. These findings have to be seen in the light that an impaired melatonin synthesis is observed in elderly and/or demented patients, in individuals affected by Alzheimer's disease, Smith-Magenis syndrome, autism spectrum disorder and sleep phase disorders. Already, recent advances in understanding signalling dynamics in the human pineal gland have significantly helped to counteract chronobiological dysfunctions through a proper restoration of the nocturnal melatonin surge.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-079X.2011.00856.x

A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases.

The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulphatoxymelatonin (aMT6S) in urine, is a defining feature of suprachiasmatic nucleus (SCN) function, the endogenous oscillatory pacemaker. A substantial number of studies have shown that, within this rhythmic profile, the onset of melatonin secretion under dim light conditions (the dim light melatonin onset or DLMO) is the single most accurate marker for assessing the circadian pacemaker. Additionally, melatonin onset has been used clinically to evaluate problems related to the onset or offset of sleep. DLMO is useful for determining whether an individual is entrained (synchronized) to a 24-h light/dark (LD) cycle or is in a free-running state. DLMO is also useful for assessing phase delays or advances of rhythms in entrained individuals. Additionally, it has become an important tool for psychiatric diagnosis, its use being recommended for phase typing in patients suffering from sleep and mood disorders. More recently, DLMO has also been used to assess the chronobiological features of seasonal affective disorder (SAD). DLMO marker is also useful for identifying optimal application times for therapies such as bright light or exogenous melatonin treatment.

Dim light melatonin onset (DLMO): A tool for the analysis of circadian phase in human sleep and chronobiological disorders

Many processes in the human body — including brain function — are regulated over the 24-hour cycle, and there are strong associations between disrupted circadian rhythms (for example, sleep–wake cycles) and disorders of the CNS. Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders. Here, we describe circadian disruptions observed in various brain disorders throughout the human lifespan and highlight emerging evidence suggesting these disruptions affect the brain. Currently, much of the evidence linking brain disorders and circadian dysfunction is correlational, and so whether and what kind of causal relationships might exist are unclear. We therefore identify remaining questions that may direct future research towards a better understanding of the links between circadian disruption and CNS disorders.

/pdf/rhythms-of-life-circadian-disruption-and-brain-disorders-1m0o2384sk.pdf

Rhythms of life: circadian disruption and brain disorders across the lifespan.

First described by Smith et al 1 in 1982, Smith-Magenis syndrome (SMS) is a contiguous gene syndrome ascribed to interstitial deletions of chromosome 17p11.2. Clinical features include infantile hypotonia, characteristic craniofacial appearance, brachydactyly, short stature, ocular anomalies, deep, hoarse voice, early speech delay, mental retardation, and behavioural disturbances.2,3 Behavioural problems include hyperactivity, attention deficit, self-injury, temper tantrums, and major sleep disturbance.4 These symptoms have a major impact on the children and their families. The diagnosis is based on high resolution karyotype analysis and fluorescence in situ hybridisation (FISH).5

Sleep disturbances occur in all cases and are predictive of maladaptive behaviour, increased by mental retardation and cognitive delay. The specific pattern of sleep disturbance in SMS includes early sleep onset, frequent awakenings, and early waking.6,7 Moreover, “sleep attacks” at the end of the day are consistent features of the disease and may represent the endogenous sleep onset of the patients. The children could therefore be regarded as having a sleep phase advance.

Normally, melatonin secretion increases soon after onset of darkness, peaks at midnight, and gradually falls during the second half of the night. Interestingly, all SMS patients display a phase shift of their circadian rhythm of melatonin, with a diurnal secretion of the hormone8–10 (fig 1). Tantrums and tiredness occur when melatonin rises in the morning and children have naps and sleep attacks when melatonin peaks at midday and in the evening. Sleep is fragmented with prolonged nocturnal awakenings and early waking when melatonin is low during the night (fig 1). This clinical and biological sleep phase advance supports the existence of an aberrant biological clock in SMS.



 Figure 1 
(A) Inversion of serum melatonin rhythm in SMS (solid lines) as compared to age matched controls (dotted lines). (B) Sleep-wake patterns correlated with melatonin …

https://jmg.bmj.com/content/jmedgenet/40/1/74.full.pdf

B Delhotal-Landes

Papers

β1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome