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The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders
Abstract
Normal circadian rhythms are synchronized to a regular 24 h environmental light-dark cycle, and the suprachiasmatic nucleus and the hormone melatonin have important roles in this process. Desynchronization of circadian rhythms, as occurs in chronobiological disorders, can produce severe disturbances in sleep patterns. According to the International Classification of Sleep Disorders, circadian rhythm sleep disorders (CRSDs) include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 h sleep-wake disorder, jet lag and shift-work sleep disorder. Disturbances in the circadian phase position of plasma melatonin levels have been documented in all of these disorders. There is compelling evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology, although further research involving large numbers of patients will be required to clarify whether the disruption of melatonin secretion is a causal factor in CRSDs. In this Review, we focus on the use of exogenous melatonin and light therapy to treat the disturbed sleep-wake rhythms seen in CRSDs.
... Sleep is regulated by circadian rhythms, which may be associated with rest-activity rhythms. Melatonin released from pinealocytes may inhibit the suprachiasmatic nuclei (SCN) and influence circadian rhythms (Pandi-Perumal et al., 2008). Diurnal variations in melatonin levels are closely linked to sleep (Pandi-Perumal et al., 2008). ...
... Melatonin released from pinealocytes may inhibit the suprachiasmatic nuclei (SCN) and influence circadian rhythms (Pandi-Perumal et al., 2008). Diurnal variations in melatonin levels are closely linked to sleep (Pandi-Perumal et al., 2008). Melatonin plays an important role in several aspects of the circadian rhythm. ...
... is the pineal gland's primary product. Melatonin regulates circadian rhythm, sleep and sexual behaviour (Pandi-Perumal et al. 2008). Melatonin is known to have antioxidant and anti-inflammatory effects (Watson et al. 2016). ...
... Melatonin is known to have antioxidant and anti-inflammatory effects (Watson et al. 2016). The virtues of melatonin as a medicament may explain a large part of scientists' interest in this substance (Pandi-Perumal et al. 2008). Several researchers have looked into the effects of melatonin on endurance exercise (Alonso et al. 2006;Veneroso et al. 2009;Maldonado et al. 2012;Souissi et al. 2019Souissi et al. , 2020aSouissi et al. , 2020bSouissi et al. , 2022c. ...
The regulation of the balance between glucose and lipid use during exercise has gained increasing attention in the last decades. The contribution of fat and glucose to energy expenditure can be modulated by hormones and other endogenous factors. The increase in melatonin during exercise may be linked to an enhancement in lipid utilization, reflected by an increase in triglyceride concentration. The purpose of this study was to explore the effect of daytime melatonin administration on plasma glucose, triglycer-ides, and cortisol responses to submaximal exercise. Eight physical education students were asked to run for 45 minutes at 60% of their maximum aerobic speed after 50 minutes of either melatonin-(6 mg) or placebo consumption. Cortisol, triglycerides, and glucose were measured in plasma samples before and immediately after exercise. Post-exercise cortisol, triglycerides, and glucose levels were corrected for fluid shifts. In both conditions , post-exercise cortisol significantly increased (by ≥20%). Post-exercise glucose levels significantly increased only in the placebo condition. However, post-exercise triglyceride levels significantly increased only in the melatonin condition. To conclude, acute melatonin administration decreases the glucose response while increasing triglycerides' response to exercise. Therefore, it would be possible to suggest that exogenous melatonin administration before endurance exercise could promote fat burning. ARTICLE HISTORY
... As mentioned early, the circadian disruptions in humans and mice alter microbiota diversity [54]. Light exposure, melatonin, and microbiota-targeted treatments may readjust circadian rhythms [135,136]. Microbiota also relates to sleep disorders in psychiatric conditions [137,138]. Overall, the microbiota-gut-brain axis bidirectionally regulates sleep physiology through various pathways [139]. ...
Background
Gut microbiota plays a pivotal role in the gut-brain axis and can influence neurodevelopment and mental health outcomes. This review summarizes the current evidence on the associations between gut microbiota alterations and various psychiatric illnesses.
Main body
The composition of the gut microbiome evolves from birth through old age, and disruptions during critical periods may increase disease risk. Factors like diet, medications, stress, and infections can disturb the gut microenvironment and lead to dysbiosis. Dysbiosis has been linked to conditions like depression, anxiety, autism, ADHD, and schizophrenia. Proposed mechanisms involve microbial regulation of neurotransmitters, inflammation, oxidative stress, blood-brain barrier permeability, and the immune system. Therapeutic strategies like probiotics, prebiotics, and faecal transplantation may modulate the gut-brain axis and microbial ecosystem. However, more research is needed to elucidate the causal microbiota-psychiatry relationship. Understanding gut-brain interactions may uncover new possibilities for preventing and managing psychiatric disorders.
Conclusion
A growing body of research points to a close relationship between gut microbiota and mental health. While the field is still emerging, dysbiosis of gut microbial ecosystem has been associated with various neuropsychiatric conditions. The underlying mechanisms likely involve the microbiota-gut-brain axis signalling pathways. Additional research with larger samples is required to establish causal links between specific microbial changes and psychiatric outcomes.
... Recent studies have proposed a connection between the onset and the progression of glioma and the circadian clock [20,21]. A properly functioning circadian clock is crucial for cellular homeostasis, and its dysregulation has been associated with a variety of pathologies, such as sleep disorders [22][23][24], mood disorders [25,26], neurogenerative diseases [27][28][29], and cancer [30]. In mammals, the circadian clock generates endogenous 24-hour rhythms in approximately 40% of all proteincoding genes across different tissues [31], and enables organisms to anticipate and respond timely to external stimuli and adapt behaviour and molecular processes to specific times of the day, for example, to separate incompatible metabolic processes [32,33]. ...
Background
Gliomas are tumours arising mostly from astrocytic or oligodendrocytic precursor cells. These tumours are classified according to the updated WHO classification from 2021 in 4 grades depending on molecular and histopathological criteria. Despite novel multimodal therapeutic approaches, the vast majority of gliomas (WHO grade III and IV) are not curable. The circadian clock is an important regulator of numerous cellular processes and its dysregulation had been found during the progression of many cancers, including gliomas.
Results
In this study, we explore expression patterns of clock-controlled genes in low-grade glioma (LGG) and glioblastoma multiforme (GBM) and show that a set of 45 clock-controlled genes can be used to distinguish GBM from normal tissue. Subsequent analysis identified 17 clock-controlled genes with a significant association with survival. The results point to a loss of correlation strength within elements of the circadian clock network in GBM compared to LGG. We further explored the progression patterns of mutations in LGG and GBM, and showed that tumour suppressor APC is lost late both in LGG and GBM. Moreover, HIF1A, involved in cellular response to hypoxia, exhibits subclonal losses in LGG, and TERT, involved in the formation of telomerase, is lost late in the GBM progression. By examining multi-sample LGG data, we find that the clock-controlled driver genes APC, HIF1A, TERT and TP53 experience frequent subclonal gains and losses.
Conclusions
Our results show a higher level of disrgulation at the gene expression level in GBM compared to LGG, and indicate an association between the differentially expressed clock-regulated genes and patient survival in both LGG and GBM. By reconstructing the patterns of progression in LGG and GBM, our data reveals the relatively late gains and losses of clock-regulated glioma drivers. Our analysis emphasizes the role of clock-regulated genes in glioma development and progression. Yet, further research is needed to asses their value in the development of new treatments.
... Melatonin is a hormone that has an impact on the circadian system and is crucial for sustaining circadian rhythmicity. Melatonin impacts the control of other hormone cycles as an endogenous synchronizer [67]. Melatonin production is reduced, and melatonin is changed, which can raise the risk of sickness. ...
The world has come to a halt as a result of the SARS-CoV-2 pandemic, which has forced most countries to implement lockdown for the maintenance of the spread of infection. This commentary highlights the important role of sleep as a public health problem, especially in stressful life stages such as the COVID-19 pandemic, and is evidence-based and practical for managing sleep disorders during this crisis. People’s routine has changed due to lockdown, including physical activities, eating habits, electronic usage, and sleeping habits. This has caused disruption between the external and internal zeitgebers and have the greatest impact on melatonin hormone. Melatonin is a key regulator of sleep-in body and controls other hormone cycles as endogenous synchroniser. Sleep is influenced by both circadian and homeostatic factors and sleep problems have a wide range of impacts on the body, effecting different physiological system. So, we should maintain a sleep / wake cycle which will benefit the overall health.
... Pharmacological methods center on melatonin, a rhythmically circulating hormone known to be important in the regulation of sleep and circadian rhythms. Melatonin directly affects the clock phase through the activation of melatonin type 2 receptors and is prescribed for numerous sleep disorders [26][27][28]. It is this author's hypothesis that supplemental Melatonin may assist patients with chronic pain by affecting these patient's clock phase and the further research is needed. ...
The lower extremity specialist may have come to appreciate and respect that medical treatments that can be enhanced by an understanding of pharmacodynamics, pharmacogenomics, and pharmacokinetics of selected medications to include analgesics specifically opioids. Furthermore, these same foot and ankle specialist may fine- tune their prescribing abilities with analgesics by familiarizing himself or herself with the science of chronotherapy. The primary goal of chronotherapy is to determine times for drug delivery that allows for low toxicity and an increase in a medication’s efficacy. Chrono pharmaceutics has been described as a branch of pharmaceutics devoted to the design of drug delivery system to ensure that a bioactive agent’s release at a rhythm ideally matches the biological requirement of a given disease. The primary purpose of this narrative review is to describe, explore and present Chrono therapeutic concepts as they intersect with analgesics within the context of pain management and circadian rhythms. First, data and theories on the interaction of pain pathology and circadian rhythm will be introduced. Secondly, the science of pharmacogenomics and circadian rhythms as mediators of analgesic properties, specifically opioid drug-drug interactions grounded in the effects of pharmacokinetic metabolism will be presented. Lastly, relevant technology will be described to allow a lower extremity specialist to appreciate Chrono therapeutic drug delivery systems of a specific opioid analgesic.
... The circadian rhythm has been demonstrated to function in almost all cells and tissues, although the most widely studied aspects of these functions have focused on the mechanisms and effects in the hypothalamus and associated areas of the brain that regulate sleep, physiology, metabolism and behavior [15,16]. Many studies have demonstrated that dysregulation of melatonin is a critical aspect of sleep and circadian rhythm disorders, which have dramatic and debilitating effects on these patients [17][18][19]. ...
Objective: Twenty to 30 percent of children in cross-sectional studies have significant bedtime problems or night waking. Melatonin, a synthetic form of the hormone produced by the pineal gland as a biomarker of the circadian system, is a commonly used nonprescription pharmacologic treatment for sleep disorders in children. Many studies have demonstrated the effect of melatonin supplementation on sleep duration and sleep quality, which can improve overall systemic health and disease prevention. However, despite the growing number of studies demonstrating the effects of melatonin to improve disordered sleep, no available studies have evaluated the effects of melatonin on normal oral tissues. Based upon this lack of knowledge, the primary objective of this study is to evaluate any potential effects of melatonin on normal oral cells and tissues within the physiologically relevant (supplementation) range. Methods: Normal oral keratinocytes (OKF4) and human gingival fibroblasts (HGF-1) were obtained and cultured for this study. Melatonin was administered in 96-well growth assays at supplement-equivalent physiologic concentrations at the low, mid and high range (1, 5 and 10 ug/uL) to determine any effects on cellular growth and proliferation. Changes in cellular viability and expression of cell cycle and apoptosis-related pathways were also evaluated. Results: Curvilinear U-shaped dose responses were observed in OKF cells under melatonin administration, ranging from -11.4% (low), to a maximum of -13.6% (mid) and -5.0% (high) compared with non-treated controls, p=0.029. Dose-responses among HGF-1 cells ranged from +12.1% (low), +17.4% (mid), and +5.0% (high), p=0.021. No changes in cellular viability were observed between control and experimental cells. However, qPCR screening of total RNA revealed significant changes in cell cycle related pathways, including c-myc, GAPDH and P53 but no changes in any apoptosis-related pathways, including Bcl-2, Bax, caspase-3, caspase-8 and caspase-9. Conclusions: This study demonstrated that melatonin does affect growth but not viability among these cell lines, which was found to be dose-dependent. These results suggest that melatonin may have some limited effects on oral tissues that may influence wound healing and repair but may not affect normal physiologic function or other cellular pathways. In agreement with other pediatric literature supporting the safety of melatonin use, this pilot study does not reveal any deleterious effects that would caution against its use in children or adults.
Sleep is a complex physiological process and is a critical determinant of physical and mental health. In the past decades, significant progress has been made in understanding the neural mechanisms of sleep and awakening. However, the initiation and maintenance of the sleep-wake cycle is regulated not only by the central system but is also affected by signals from peripheral tissues. Growing evidence shows that the microbiota-gut-brain axis contributes to the regulation of sleep behavior both directly and indirectly and may play a critical role in the etiology and pathogenesis of sleep disorders. Sleep deprivation leads to dysfunction of gut microbiota and sleep disorders are accompanied by altered gut microbiota composition. In this review, we describe the bidirectional relationships between sleep and gut microbiota and summarize the abnormal characteristics of gut bacteria in distinct conditions including sleep disturbances, sleep disorders and sleep disorders comorbid with neuropsychiatric disorders. We also examine the potential routes of microbiota-gut-brain axis in sleep and gut microbiome interactions, including metabolic, immune, and neural pathways, and propose microbiota-targeted interventions for improving sleep. Manipulating gut microbiota may be a promising avenue for the development of novel interventions for sleep disorders.
Melatonin rhythms were assessed in 49 registered blind individuals by measurement of the urinary metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s). Subjects had different causes of visual loss and were classified as having light perception or better (LP; n = 19) or having no perception of light (NPL; n = 30). Subjects collected four-hourly urine samples (eight-hourly overnight) for 48 h at weekly intervals for 3-5 weeks. The majority of LP subjects (14 of 19) had normally entrained aMT6s rhythms (mean acrophase range, 2.4-6.2 h), 4 were abnormally entrained to 24 h (mean acrophase range, 8.9-1.0 h), and 1 was unclassified. Conversely, most NPL subjects had abnormal rhythms (23 of 30), the incidence of which was greater in uni- and bilaterally enucleated subjects. The majority of NPL subjects (17 of 30) had free-running aMT6s rhythms period range, 24.13-24.79 h), 5 were abnormally entrained to 24 h (acrophase range, 7.2-20.6 h), and 1 was unclassified. Output (micrograms of aMT6s per 24 h) and amplitude (micrograms per h) of aMT6s production did not vary between LP and NPL subjects (mean 24-h output +/- SD, 12.7 +/- 7.5 and 9.4 +/- 6.4 micrograms aMT6s/24 h, respectively; mean amplitude +/- SD, 0.6 +/- 0.4 and 0.5 +/- 0.3 microgram/h, respectively). These results indicate that a higher proportion of NPL subjects have abnormal melatonin rhythms compared to those with LP.
Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity
rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to
average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed
to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian
rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled
lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both
age groups, with a tight distribution consistent with other species. These findings have important implications for understanding
the pathophysiology of disrupted sleep in older people.
1. Non-image forming, irradiance-dependent responses mediated by the human eye include synchronisation of the circadian axis and suppression of pineal melatonin production. The retinal photopigment(s) transducing these light responses in humans have not been characterised. 2. Using the ability of light to suppress nocturnal melatonin production, we aimed to investigate its spectral sensitivity and produce an action spectrum. Melatonin suppression was quantified in 22 volunteers in 215 light exposure trials using monochromatic light (30 min pulse administered at circadian time (CT) 16-18) of different wavelengths (lambda(max) 424, 456, 472, 496, 520 and 548 nm) and irradiances (0.7-65.0 microW cm(-2)). 3. At each wavelength, suppression of plasma melatonin increased with increasing irradiance. Irradiance-response curves (IRCs) were fitted and the generated half-maximal responses (IR(50)) were corrected for lens filtering and used to construct an action spectrum. 4. The resulting action spectrum showed unique short-wavelength sensitivity very different from the classical scotopic and photopic visual systems. The lack of fit (r(2) < 0.1) of our action spectrum with the published rod and cone absorption spectra precluded these photoreceptors from having a major role. Cryptochromes 1 and 2 also had a poor fit to the data. Fitting a series of Dartnall nomograms generated for rhodopsin-based photopigments over the lambda(max) range 420-480 nm showed that rhodopsin templates between lambda(max) 457 and 462 nm fitted the data well (r(2) > or =0.73). Of these, the best fit was to the rhodopsin template with lambda(max) 459 nm (r(2) = 0.74). 5. Our data strongly support a primary role for a novel short-wavelength photopigment in light-induced melatonin suppression and provide the first direct evidence of a non-rod, non-cone photoreceptive system in humans.
To determine the prevalence and severity of sleep disturbance in blind subjects and its relation to the form and duration of visual loss.
Of 403 blind subjects (visual acuity of less than 20/200 or a visual field of less than 5 degrees) recruited for the study, 15 were excluded because of affective disorder as identified by Montgomery Asberg Depression Scale. The remaining 388 subjects and a comparison group of 44 normally sighted individuals underwent an interview, and the Pittsburgh Sleep Quality Index questionnaire was administered. Sleep disturbance was classified as mild, moderate, or severe.
Disturbance of sleep was recorded in 189 (48.7%) of the blind subjects. The prevalence was higher and the sleep disturbance was more severe in those with no perception of light than in those with light perception or better visual acuity. In the comparison group, four (9.1%) had mild sleep disturbance only. The differences between blind subjects and normally sighted individuals were highly significant (P < .001). The most common sleep-related problem among the blind subjects was interrupted sleep, followed by increased sleep latency, short sleep duration, and daytime naps. Among the blind subjects, no correlation was found between the extent of sleep disturbance and the duration and pattern of visual loss.
Blind subjects who retain light perception, as well as those with total loss of vision, have a high frequency of sleep disturbance, although disorder is more common and more severe in subjects with no light perception. Management of the sleep disturbance may improve the quality of life in the visually handicapped.
• We describe a new syndrome called "delayed sleep phase insomnia." Thirty of 450 patients seen for a primary insomniac complaint had the following characteristics: (1) chronic inability to fall asleep at a desired clock time; (2) when not on a strict schedule, the patients have a normal sleep pattern and after a sleep of normal length awaken spontaneously and feel refreshed; and (3) a long history of unsuccessful attempts to treat the problem. These patients were younger than the general insomniac population and as a group did not have a specific psychiatric disorder. Six patients' histories are described in detail, including the successful nonpharmacological chronotherapy regimen (resetting the patients' biological clock by progressive phase delay). Delayed sleep phase insomnia is proposed to be a disorder of the circadian sleep-wake rhythm in which the "advance" portion of the phase response curve is small.
The present article presents a survey of the characteristics of our case series of 322 patients suffering from circadian rhythm sleep disorders (CRSDs), a case-control study comparing a group of 50 CRSD patients and 56 age- and gender-matched normal subjects, and a proposal for new guidelines for improving the diagnosis of CRSD. The major findings were that 83.5% of our CRSD patients who seek medical help are of the delayed sleep phase syndrome (DSPS) type; 89.6% report that the onset of CRSD occurred in early childhood or adolescence; CRSD exhibits no gender differences; a familial trait exists in 44% of patients; and learning disorders (19.3%) and personality disorders (22.4%) in the DSPS-type patients are of high prevalence. The findings of this study point to the importance of clinician awareness of the clinical picture of patients presenting with CRSD so that early diagnosis and effective treatment can be achieved to prevent harmful consequences.
A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.
It is well known that as we age, we need fewer hours of sleep and wake up much earlier in the morning. This change has been attributed to a shortening of the period of the human circadian pacemaker. However, [Robert Moore][1] explains in a Perspective that new findings ([ Czeisler et al .][2]) demonstrate that it is not the pacemaker itself that is altered but rather the way it is entrained to the day-night cycle. The period of the circadian pacemaker is very similar (24.2 hours) in both young and old people, suggesting that this is one physiological function that does not alter with aging.
[1]: http://www.sciencemag.org/cgi/content/full/284/5423/2102
[2]: http://www.sciencemag.org/cgi/content/short/284/5423/2177