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Melatonin as chronobiotic
Abstract
Melatonin, hormone of the pineal gland, is concerned with biological timing. It is secreted at night in all species and in ourselves is thereby associated with sleep, lowered core body temperature, and other night time events. The period of melatonin secretion has been described as 'biological night'. Its main function in mammals is to 'transduce' information about the length of the night, for the organisation of daylength dependent changes, such as reproductive competence. Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during 'biological daytime', and when suitably timed (it is most effective around dusk and dawn) it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times. The shifts induced are sufficient to synchronise to 24 h most blind subjects suffering from non-24 h sleep-wake disorder, with consequent benefits for sleep. Successful use of melatonin's chronobiotic properties has been reported in other sleep disorders associated with abnormal timing of the circadian system: jetlag, shiftwork, delayed sleep phase syndrome, some sleep problems of the elderly. No long-term safety data exist, and the optimum dose and formulation for any application remains to be clarified.
... SSRIs, such as fluoxetine, have been shown to elevate blood melatonin levels in depressed patients, likely due to increased serotonin availability in the brain [66]. Since serotonin is a precursor to melatonin synthesis [67], this effect could provide an additional pathway through which SSRIs improve mood in women with PMDD, considering the potential mood-regulating effects of melatonin and melatonin receptor agonists [26]. However, despite promoting endogenous melatonin production, SSRIs may also influence pathways that regulate its synthesis and release. ...
... A study in rats found that daily subcutaneous injections of venlafaxine over four consecutive days reduced pineal concentrations of 5-hydroxyindoleacetic acid, a breakdown product of serotonin [77]. Since serotonin is a precursor for melatonin synthesis [67], this suggests that venlafaxine may help preserve serotonin for melatonin production in the pineal gland. Supporting this idea, a separate study in rats reported that acute treatment with higher doses of venlafaxine significantly increased pineal melatonin levels; however, this effect was attenuated by subchronic treatment [78]. ...
... Women with PMDD may also experience disrupted melatonin dynamics, including blunted, advanced, or delayed endogenous melatonin secretion, as well as increased sensitivity to light's melatoninsuppressing effects [27][28][29][30][31][32][33]. Given melatonin's essential role in regulating sleep timing and mood [26,67], supplementing it about 60 min before a fixed bedtime may help synchronize the body's natural rhythm while also promoting mood stability. Supporting this view, a proof-of-concept study with five women who had blunted melatonin secretion found that taking 2 mg of slow-release melatonin 1 h before bedtime during the luteal phase led to reduced sleep onset latency and clinically significant improvements in PMDD symptoms over three menstrual cycles [122]. ...
... Several studies have reported its efficacy in improving sleep [17] and its safety profile [18], even at very high doses [19]. Exo-MEL is largely recognized as a chronobiotic drug acting as a circadian rhythm synchronizer; [20] conversely, its use as a sleep-promoting drug has been under debate due to the inconsistency of its described effects [21,22]. Many possible sources of heterogeneity in experimental designs (e.g., dose, timing of administration, treatment duration, fast or slowrelease formulations, patients with sleep disorders vs. healthy volunteers, people with different chronotypes) might be accountable for these conflicting results. ...
... Individual's circadian phase could be a relevant effect modifier, as described in studies evaluating the chronobiotic effect of exo-MEL, which showed how the effect of exo-MEL depends on the interaction between clock time of administration and biological time [20,62] Unfortunately, we could not include a circadian phase measure in our analyses (i.e., chronotype, Dim Light Melatonin Onset [DLMO]) because this was not investigated in most of the studies included in the present quantitative synthesis. Only three studies reported the individual circadian phase as measured through the endogenous melatonin profiles before exo-MEL administration [30,51,60]. ...
... Specifically, we found that its ability to increase sleep duration decreases when administered close to bedtime while gradually increasing when administered earlier during the day. This is consistent with several studies demonstrating that melatonin possesses an acute sleep-promoting effect when administered during the day [20,72], that is, when endogenous circulating melatonin levels are low. Indeed, exo-MEL's sleep-promoting action is highly influenced by the phase of the endogenous melatonin rhythm [26], such that in the absence of circulating endogenous melatonin, MEL receptors may be more sensitive to exo-MEL. ...
Previous studies have reported inconsistent results about exogenous melatonin's sleep‐promoting effects. A possible explanation relies on the heterogeneity in administration schedule and dose, which might be accountable for differences in treatment efficacy. In this paper, we undertook a systematic review and meta‐analysis of double‐blind, randomized controlled trials performed on patients with insomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep‐related parameters. The standardized mean difference between treatment and placebo groups in terms of sleep onset latency and total sleep time were used as outcomes. Dose−response and meta‐regression models were estimated to explore how time of administration, dose, and other treatment‐related parameters might affect exogenous melatonin's efficacy. We included 26 randomized controlled trials published between 1987 and 2020, for a total of 1689 observations. Dose−response meta‐analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day. Meta‐regression models showed that insomnia status ( β = 0.50, p < 0.001) and time between treatment administration and the sleep episode ( β = −0.16, p = 0.023) were significant predictors of sleep onset latency, while the time of day ( β = −0.086, p < 0.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timing of administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day), as compared to the exogenous melatonin schedule most used in clinical practice (2 mg 30 min before the desired bedtime), might optimize the efficacy of exogenous melatonin in promoting sleep.
... In particular, there is a close association between the stability of the daily rhythm of eating and the psychoemotional state of young people [26]. The use of food products containing chronobiotics, a class of substances that affect the function of the CS [27], to stabilize circadian rhythms has also shown its effectiveness. ...
... The average score on the life satisfaction scale was 24.7 (5.9) points, and positive and negative affect scores were 17.6 (4.4) and 12.0 (5.1), respectively. The average value of social jetlag in the study participants was 0. 27 A total of 79% of the study participants were women (Table 1). A proportion of 52.6% had secondary and specialized secondary education, and 34.5% had higher and postgraduate education. ...
... The positive association between FMT consumption and psychoemotional state noted in this study, as well as in our previous study with the participation of young adults [29], is most likely due to the fact that melatonin belongs to chronobiotics [27]. It is known that exogenous melatonin is able to change the phase of the endogenous circadian rhythm and, thus, have a therapeutic effect on patients with various forms of depression [53]. ...
The purpose of this study was to test the hypothesis that melatonin-containing food (FMT) consumption is associated with a better sleep schedule and cognitive and psychoemotional state in older adults. A cross-sectional study of 557 (79% females) older adults living in the community with a mean age of 68.9 ± 7.7, ranging from 50 to 90 years, was conducted. The study, conducted in May and September 2023 using a face-to-face interview, collected personal data and assessed FMT intake during the day (FMTday) and for dinner (FMTdinner), life satisfaction, positive and negative affect, depression severity, cognitive functions, and sleep characteristics. Multiple regression and logistic regression analysis, adjusted for co-factors, were used to assess the association between the studied indicators. Multiple regression analysis showed that older adults with higher FMT consumption are more satisfied with life (FMTdinner: β = 0.107; ∆R² = 0.011; p = 0.020), have a lower level of depression (FMTday: β = −0.124; ∆R² = 0.015; p = 0.003), and higher scores in positive affect (FMTday: β = 0.169; ∆R² = 0.016; p = 0.007; FMTdinner: β = 0.136; ∆R² = 0.019; p = 0.003). Logistic regression analysis showed that older adults with higher FMT consumption are less likely to have depression (FMTday: OR, 0.614; 95% CI, 0.436–0.864; p = 0.005; FMTdinner: OR, 0.671; 95% CI, 0.476–0.945; p = 0.023), and they perform better on logical thinking tests (FMTday: OR, 2.066; 95% CI, 1.131–2.204; p = 0.013; FMTdinner: OR, 1.887; 95% CI, 1.183–2.138; p = 0.033). A greater life satisfaction as well as a decrease in the cognitive impairment and psychoemotional state of older adults is associated with a higher consumption of melatonin-containing foods.
... Furthermore, information on the daylight period is transmitted using neurohumoral signals to the underlying peripheral organs. Signal transduction from the SCN to peripheral organs is mediated by the hormone melatonin (MT), which is synthesized by the pineal gland in antiphase with daylight rhythm, thus defining the boundaries of "biological night" [5]. ...
... Food has been actively studied as a source of chronobiotics, a class of substances that regulate CS function [14]. One of the best-known chronobiotics is MT [5]. Knowledge has increased regarding the content of MT in foods of plant and animal origin [15]. ...
... This indicator is a quantitative measure of an individual's chronotype. Previously, MSFsc and dim light MT onset (DLMO) have been closely associated [38,39], representing a reliable marker of the endogenous rhythm in human CS [5]. In addition, we noted an inverse association between FMTday and SJL, a quantitative measure of circadian misalignment [6]. ...
Food is an important source of melatonin (MT), which belongs to a group known as chronobiotics, a class of substances that affect the circadian system. Currently, no studies have been conducted on how the consumption of foods containing MT (FMT) is associated with indicators characterizing the human circadian system. In this study, we tested the hypothesis that FMT consumption is associated with chronotype and social jetlag. A total of 1277 schoolchildren and university students aged M (SD) 19.9 (4.1) years (range: 16–25 years; girls: 72.8%) participated in a cross-sectional study. Each participant completed an online questionnaire with their personal data (sex, age, height, weight, waist circumference, and academic performance) and a sequence of tests to assess their sleep–wake rhythm (the Munich Chronotype Questionnaire), sleep quality (the Pittsburgh Sleep Quality Index), and depression level (the Zung Self-Rating Depression Scale). Study participants also completed a modified food frequency questionnaire that only included foods containing MT (FMT). They were asked how many foods containing MT (FMT) they had eaten for dinner, constituting their daily serving, in the past month. The consumption of foods containing MT (FMT) during the day (FMTday) and at dinner (FMTdinner) was assessed using this test. Multiple regression analyses were performed to assess the association between the studied indicators. We found that higher FMTday values were associated with early chronotype (β = −0.09) and less social jetlag (β = −0.07), better sleep quality (β = −0.06) and lower levels of depression (β = −0.11), as well as central adiposity (β = −0.08). Higher FMTdinner values were associated with a lower risk of central adiposity (β = −0.08). In conclusion, the data obtained confirm the hypothesis that the consumption of foods containing MT (FMT) is associated with chronotype and social jetlag in adolescents and young adults.
... Melatonin (MLT), a methoxy-indoleamine is a hormone that modifies the biological clock timing [33]. ...
... These changes are linked to diminished amplitude and the earlier timing of melatonin, cortisol, and core body temperature (cBT) rhythms, which demonstrate age-related alterations in the circadian system. This potential connection leads to the evaluation of exogenous melatonin as a treatment option [33]. Although it is not fully understood what causes these changes, it is possibly due to a combination of both internal (endogenous) and external (exogenous) factors. ...
Depression, which is emerging as one of the most widely prevalent neuropsychiatric disorders worldwide, has affected people across all age groups. However, it is currently primarily affecting adults aged 18 to 25. The condition is characterized by disrupted sleep cycles, diurnal variation, and disturbed core body temperature rhythms. Currently, the anti-depressant medications that are prescribed and authorized, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), benzodiazepines, anxiolytics, and antihistamines have demonstrated effective outcomes. However, the findings from the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study are disappointing. The results show that currently available antidepressants yield only minimal improvements in effectiveness for patients who did not respond to their initial medication. Melatonin has emerged as a promising option for tackling these issues. Moreover, due to its diverse abilities to regulate circadian rhythms and promote synchronization, melatonin offers an alternative therapeutic approach to alleviate the side effects and target the underlying causes of depression linked to an impaired circadian system. This review intends to provide a comprehensive overview of melatonin, including aspects such as its structural analysis, biosynthesis, regulation, catabolism, and involvement in various physiological processes, particularly highlighting its antidepressant activity.
... Melatonin (1 mg kg −1 per body weight for 21 days) considerably reduced these symptoms [197]. Melatonin is a feasible option for an anti-HD [218] medication because it was also discovered that melatonin worked in a HD model [219]. In mice exposed to 3 NP, melatonin improved social behavior and prevented damage to the dendritic spine [220]. ...
... The chronobiotic properties of melatonin have been successfully used in the treatment of numerous sleep disorders. There are no long-term safety data available, and it is still unclear what dosage and formulation are best for each use [218]. ...
A neurodegenerative disorder (ND) refers to Huntington's disease (HD) which affects memory loss, weight loss, and movement dysfunctions such as chorea and dystonia. In the striatum and brain, HD most typically impacts medium-spiny neurons. Molecular genetics, excitotoxicity, oxidative stress (OS), mitochondrial, and metabolic dysfunction are a few of the theories advanced to explicit the pathophysiology of neuronal damage and cell death. Numerous in-depth studies of the literature have supported the therapeutic advantages of natural products in HD experimental models and other treatment approaches. This article briefly discusses the neuroprotective impacts of natural compounds against HD models. The ability of the discovered natural compounds to suppress HD was tested using either in vitro or in vivo models. Many bioactive compounds considerably lessened the memory loss and motor coordination brought on by 3-nitropropionic acid (3-NP). Reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and enhanced mitochondrial energy generation have profoundly decreased the biochemical change. It is significant since histology showed that therapy with particular natural compounds lessened damage to the striatum caused by 3-NP. Moreover, natural products displayed varying degrees of neuroprotection in preclinical HD studies because of their antioxidant and anti-inflammatory properties, maintenance of mitochondrial function, activation of autophagy, and inhibition of apoptosis. This study highlighted about the importance of bioactive compounds and their semi-synthetic molecules in the treatment and prevention of HD.
... It is known that the consumption of high-calorie, high-fat foods leads to a decrease in the amplitude of the circadian rhythms of the central oscillator of the CS (Pendergast et al. 2013), which can lead to a mismatch of 24-h rhythms in individual organs and systems (internal desynchrony) and an increased risk of various diseases. At the same time, it is known that some foods are sources of chronobiotics, biologically active substances such as melatonin (MT), which have a direct effect on the function of the CS and thus can increase the synchronization of the circadian rhythms (Arendt and Skene 2005). Convincing experimental data have now been obtained on the positive effect of food MT or its precursor tryptophan on sleep function (Garrido et al. 2010;Pigeon et al. 2010;Lin et al. 2011;Howatson et al. 2012;Losso et al. 2018), well-being (Bravo et al. 2013), and health (Nagata et al. 2021) in young and elderly people. ...
... Therefore, potentially effective means of preventing SJL should increase the total sleep duration due to earlier falling asleep on work/school days. MT pills, used in the evening before going to bed, increase drowsiness and speed up falling asleep (Arendt and Skene 2005). The data obtained in this study on the relationship between SJL and FMT dinner are completely consistent with the mechanism of action of MT on sleep function. ...
The study examined eating timing, diet, and sleep phases in people with social jetlag (SJL). SJL was associated with a higher incidence rate of eating jetlag, eating phase delays, an increase in calorie intake after 9 p.m., a decrease in dietary fiber intake for brakfast, and melatonin-containing product consumption for dinner. People with SJL had a reduction in total sleep and light sleep phase duration by 60 and 36 min on work/school days and an increase in total sleep and rapid eye movement sleep duration by 66 and 60 min on weekends, respectively. People consuming foods with more melatonin for dinner showed a decrease in SJL by 54 min and an increase in total sleep and the deep sleep phase duration by 66 and 30 min, respectively. Thus, the consumption of melatonin-containing foods for dinner is associated with a decrease in circa-dian misalignment and an improvement in sleep quality. ARTICLE HISTORY
... It is known that the consumption of high-calorie, high-fat foods leads to a decrease in the amplitude of the circadian rhythms of the central oscillator of the CS [24], which can lead to a mismatch of 24-h rhythms in individual organs and systems (internal desynchrony) and an increased risk of various diseases. At the same time, it is known that some foods are source of chronobiotics, biologically active substances such as melatonin (MT), which have a direct effect on the function of the CS and thus can increase the synchronization of the circadian rhythms [25]. Convincing experimental data have now been obtained on the positive effect of food MT or its precursor tryptophan on sleep function [26][27][28][29][30], well-being [31], and health [32] in young and elderly people. ...
... Therefore, potentially effective means of preventing SJL should increase the total sleep duration due to earlier falling asleep on work/school days. MT pills, used in the evening before going to bed, increasing drowsiness and speeding up falling asleep [25]. The data obtained in this study on the relationship between SJL and FMTdinner are completely consistent with the mechanism of action of MT on sleep function. ...
The study examined eating timing, diet, and the ratio of sleep phases in people with social jetlag (SJL). The study involved 83 participants who filled out a questionnaire, and 21 of them took part in the study of sleep phases by electroencephalography during the week. SJL was associated with a higher incidence rate of eating jetlag, eating phase delays, an increase in calorie intake after 9 p.m., a decrease in dietary fiber intake for breakfast, and melatonin-containing product consumption for dinner. Young people with SJL had a reduction in total sleep and light sleep phase duration by 60 and 36 min on work/school days and an increase in total sleep and REM sleep phase duration by 66 and 60 min on weekends, respectively. Young people consuming foods with more than 4234.5 ng of melatonin for dinner, compared with their peers consuming less than 313.2 ng of melatonin, showed a decrease in SJL and sleep debt by 54 and 90 min and an increase in the total sleep and the deep sleep phase duration by 66 and 30 min, respectively. Thus, the consumption of melatonin-containing foods for dinner is associated with a decrease in circadian misalignment and a sleep quality improvement.
... Other circadian rhythm-related medications include melatonin, orexin, and circadian molecules. Melatonin is a natural neurohormone synthesized from tryptophan, produced by the pineal gland and keeps the circadian rhythm (Arendt and Skene, 2005). Melatonin has been demonstrated to entrain the circadian system, and has been found to possess sleep-promoting properties, improve glucose homeostasis, and reduce insulin resistance (Gooley et al., 2011;Forrestel et al., 2017;Vasey et al., 2021). ...
The circadian clock, an innate timing mechanism, governs a variety of physiological activities by producing near-24-h cycles in gene expression. These cycles are reflected in patterns of metabolism and behavior. This system consists of two parts: one is the central clock located in the suprachiasmatic nucleus of the hypothalamus, and the other is the peripheral clock located in tissues throughout the body. Glucokinase, also termed hexokinase 4, is a member of the hexokinase family. It acts as a glucose sensor, plays a pivotal role in glucose homeostasis. Here, we review the role of circadian rhythm in glucose metabolism across various tissues, look into the molecular mechanism of circadian disruption involvement in glucose metabolism and diabetic complications, with a particular focus on the role of glucokinase. Finally, we propose potential strategies for effectively treating metabolic disorders and diabetic complications by modulating circadian rhythm glucokinase.
... Once in the brain, melatonin modulates neurotransmitter systems, including serotonin and dopamine, contributing to mood regulation, cognitive function, and overall neuronal health. Melatonin is also known to be a key regulator of circadian rhythms, acting on receptors in the suprachiasmatic nucleus to synchronize sleep-wake cycles [177][178][179][180][181]. ...
Tumor necrosis factor (TNF) is a biomarker of inflammation whose levels are elevated in patients with several diseases associated with dysregulation of the immune response. The main limitations of currently used anti‐TNF therapies are the induction of immunodepression, which in many cases leads to serious adverse effects such as infection and cancer, and the inability to cross the blood‐brain barrier in neuroinflammatory conditions. Melatonin, in addition to being a chronobiotic compound, is widely known for its antioxidant and immunomodulatory capacity to control inflammatory processes in different pathological contexts. The aim of the present review is to address human‐based studies that describe the effect of melatonin on TNF production. The review includes all the articles published in PubMed databases until April 15, 2024. After depuration, 45 studies were finally included in the review, 23 related to the in vitro action of melatonin in human cells and 22 in vivo studies in humans. Most of the data reviewed support the idea that melatonin has an immunosuppressive effect on TNF levels, which, together with its low toxicity profile, low cost, and ability to cross the blood‐brain barrier, points to melatonin as a potential anti‐TNF therapy. Therefore, improving our knowledge of the action of melatonin in regulating TNF through appropriate clinical trials would reveal the true potential of this molecule as a possible anti‐TNF therapy.
... However, they could estimate their children's full daily diet on weekends quite accurately. This limitation is also an advantage, since on weekdays, estimates of the daily diet were mainly based on what children ate in the afternoon, after attending kindergarten/school, and in fact, it is known that exogenous melatonin has a chronobiotic effect (advancing sleep phase) when taken in the afternoon (Arendt and Skene 2005). The design of the study did not allow us to strictly assess the relationship between FMT consumption by children aged 2-12 and the rate of development of gross motor skills in the postpartum period since gross motor skills are developed in the first year of a child's life. ...
The purpose of this study was to investigate the sleep characteristics, circadian rhythms, behavior, and postnatal development of children with and without language difficulties (LDs) and the association of these variables with melatonin-containing food (FMT) consumption. The study involved parents who anonymously and voluntarily provided their children's personal data and assessed LDs, bedtime, meal timing, behavioral problems, gross motor skill development, and FMT consumption. Multiple regression analysis was used to analyze the associations between study variables. A total of 587 children were examined, with mean age M (SD) 5.5 (2.4) years, (range: 2-12 years), and 44.2% were boys. Children with LD had delayed sleep onset (β = 0.09; R 2 = 0.007), increased sleep latency (β = 0.11; R 2 = 0.014), social jetlag (β = 0.10; R 2 = 0.009), screen time (β = 0.14; R 2 = 0.022), and behavioral problems (β = 0.13-0.35; R 2 = 0.016-0.142); decreased gestational age at birth (β =-0.09; R 2 = 0.007), and delayed development of gross motor skills in the post-partum period (β = 0.11-0.21; R 2 = 0.012-0.064). The children's average FMT consumption was 2087.6 ± 2401.3 ng/d. Children with the highest FMT consumption had lower rates of LDs (β =-0.11; R 2 = 0.010), social jetlag (β =-0.08; R 2 = 0.007), and eating jetlag (β =-0.12; R 2 = 0.013); fever behavioral problems (β =-0.09-−0.10; R 2 = 0.007-0.057); and less delayed eating phase (β =-0.11; R 2 = 0.012), and development of gross motor skills in the postpartum period (β =-0.10-−0.12; R 2 = 0.009-0.014). In summary, LDs in children were associated with higher rates of circadian misalignment, sleep, behavioral, and developmental dysfunctions, and higher FMT consumption was associated with lower rates of circadian misalignment, behavioral, and developmental dys-functions. The data obtained indicate the need for a detailed study of the state of the circadian system in preschool and primary school children with language difficulties, which will serve as a rationale for the use of chronotherapy principles for the treatment of this neurological dysfunction. ARTICLE HISTORY
... Diğer değişle bu maddenin üretimi, uyku-uyanıklık döngüsünü düzenlemeye yardımcı olan ve uyku zamanı geldiğinde vücuda sinyal veren ışığın varlığından veya yokluğundan etkilenir. Yapılan bir çalışma (Arendt & Skene, 2005), melatoninin sirkadiyen ritimlerin doğal gündüz-gece döngüsüyle senkronize edilmesinde çok önemli bir rol oynadığını göstermektedir. Senkronizasyonun sağlanması, istikrarlı bir uyku düzeni ve genel esenliği (iyi oluş) koruması için hayati önem taşımaktadır. ...
Çalışmada, uykunun çalışan sağlığı ve örgütsel performans açısından önemi vurgulanırken uykuya önem veren bir örgüt kültürün yaygınlaşması adına insan kaynakları yönetiminin (İKY) üstüne düşen görevlere dikkat çekilmektedir. Çalışma, çalışma ortamları, iş stresi ve işyeri standartları ile çalışanların uyku sağlığının kötü olması arasında genellikle göz ardı edilen bağlantıyı vurgulamaktadır. Sağlıksız uykunun daha geniş etkileri arasında daha yüksek kaza riski, sağlık harcamaları, devamsızlık ve iş performansı yer almaktadır. Çalışmada, bu sorunları ele almak için literatürden hareketle İKY stratejileri ve uygulamaları önerilmektedir. Bunlar arasında çalışma saatlerinin kontrol edilmesi, uyku dostu politikaların teşvik edilmesi, kişiselleştirilmiş uyku terapileri için yapay zekanın kullanılması ve uyku sağlığının örgütsel sağlıklı yaşam programlarına dahil edilmesi yer alıyor. Çalışma, ayrıca örgütlerin uykuyu bir tembellik ya da zayıflık belirtisi olarak görmemesi gerektiğini aksine çalışanların esenliğini ve örgütsel performansın önemli bir parçası olarak görülmesi gerektiğini savunmaktadır. Bu anlamda çalışanların uyku sağlığının iyileştirmesi adına önemli çıkarımlar adım adım gösterilmektedir. Bu çıkarımların hem yöneticilere ve hem de bu alanda çalışmayı düşünen araştırmacılara değerli içgörüler sunacağı düşünülmektedir.
... Melatonin, a pleiotropic neurohormone secreted by the pineal gland is an important component of the circadian clock machinery. Melatonin signals regulate the circadian organization of a plethora of physiological processes such as immune responses, antioxidant defence, glucose regulation and energy homeostasis 3,4 . As a potent chronobiotic, melatonin influences the circadian timing of metabolic processes, aligning them with the activity/ rest cycles 5 . ...
Melatonin, a neurohormone, improves hepatic function in diet and/or chronodisruption in Metabolic dysfunction Associated with Steatotic Liver Disease (MASLD). Nocturnin (Noct), a circadian clock output gene, putatively regulates hepatic lipid metabolism but the underlying mechanisms related to its regulation remain largely unknown. Herein, we hy-pothesise that melatonin-mediated improvement in liver function in MASLD is regulated via Noct and this study delves into Noct as a putative target of melatonin. Molecular docking studies (Autodock, Pyrx and PyMol) confirmed interactions between melatonin and mouse Noct (Binding affinity:-7kcal/mol; RMSD: 0). Further, studies on C57BL/6J mice comprised of experimental groups viz. high-fat-high-fructose (H) diet fed, photoperiodic shifts-induced chronodisruption (CD) or a combination of the two (HCD) wherein melatonin-mediated improvements in serum lipid profile (TGs, total lipids, VLDL-chol., LDL-chol. and total cholesterol) and liver function markers (ALT and AST) were recorded. Further, the fatty manifestations, hepatocyte ballooning, and steatotic score were significantly improved following exogenous melatonin. Likewise, the liver samples of H, CD and HCD mice recorded a marked increment in hepatic Noct mRNA expression whereas melatonin administration accounted for a significant improvement in the said expression. These findings were further validated in vitro in HepG2 cells treated with Oleic Acid (OA) cells wherein, melatonin supplementation improved Noct mRNA and protein expressions compared to the disease control. Taken together, this study provides insight into melatonin-mediated modulation in hepatic Noct that correlates with improved hepatic health in experimental models of MASLD.
... The excretion of melatonin is directly driven by the output of the SCN through a multi-synaptic pathway, which successively includes pre-autonomic neurons of the paraventricular nucleus (PVN), sympathetic pre-ganglionic neurons of the intermediolateral cell column of the spinal cord, noradrenergic sympathetic neurons of the superior cervical ganglion, and finally the pineal gland [1,18]. In conditions of diminished light, melatonin excretion starts in the evening (dim light melatonin onset -DLMO), close to bedtime, reaching its peak between 2:00 and 4:00 [19,20]. ...
This review attempts to analyze the relationship between the vestibular system and the circadian timing system. The activity of the biological clock allows an organism to optimally perform its tasks throughout the nychtemeron. To achieve this, the biological clock is subjected to exogenous factors that entrain it to a 24h period. While the most powerful synchronizer is the light-dark cycle produced by the Earth’s rotation, research has led to the hypothesis of the vestibular system as a possible non-photic time cue used to entrain circadian rhythms. Demonstrated neuroanatomical pathways between vestibular nuclei and suprachiasmatic nuclei could transmit this message. Moreover, functional evidence in both humans and animals has shown that vestibular disruption or stimulation may lead to changes in circadian rhythms characteristics. Vestibular stimulations could be considered to act synergistically with other synchronizers, such as light, to ensure the entrainment of biological rhythms over the 24-h reference period.
... Dozajul efectului supresor al radiației luminei asupra producției de melatonină este determinat de intensitatea iluminării, lungimea de undă, i.e. un anumit diapazon al spectrului de oscilații electromagnetice și durata expunerii în timpul nopţii [2,7,8]. ...
Synthesis paper revealing fundamental data on the epigenetic determination of the initiation and maintenance of neoplastic processes in the breast tissue of female workers in light industry enterprises. The primary importance of the synchronization of circadian rhythms in the environment and the biorhythms of the biological molecular, cellular and internal tissue clocks is noted. Preventive programs should be based on preventing the desynchronization of neuroendocrine mechanisms involving melatonin and hormone-dependent tissues of the internal environment with circadian light/dark cycles of the external environment. The forced nature of the work activity associated with the development of social jetlag requires the provision of recreation periods after the rotation period.
... phase of the photoperiod, signaling darkness to the body (Zisapel, 2018). During the night, melatonin reduces body temperature and alertness and induces sleep (Arendt and Skene, 2005). Additionally, melatonin exerts long-lasting effects, priming the body for the upcoming seasons (Cipolla-Neto and Amaral, 2018). ...
Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine secreted by the pineal gland during the dark phase of the photoperiod. Its main function is the synchronization of different body rhythms with the dark-light cycle. Research on melatonin has significantly advanced since its discovery and we now know that it has considerable significance in various physiological processes, including immunity, aging, and reproduction. Moreover, in recent years evidence of the pharmacological possibilities of melatonin has increased. Indoleamine, on the other hand, has antidepressant-like effects in rodents, which may be mediated by the activation of calcium-calmodulin-dependent kinase II (CaMKII) and are also related to the regulation of neuroplasticity processes, including neurogenesis, synaptic maintenance, and long-term potentiation. Remarkably, patients with major depression show decreased levels of circulating melatonin in plasma. This review presents evidence of the antidepressant-like effects of melatonin in preclinical models and the participation of CaMKII in these actions. CaMKII's role in cognition and memory processes, which are altered in depressive states, are part of the review, and the effects of melatonin in these processes are also reviewed. Furthermore, participation of CaMKII on structural and synaptic plasticity and the effects of melatonin are also described. Finally, the advantages of using melatonin in combination with other antidepressants such as ketamine for neuroplasticity are described. Evidence supports that CaMKII is activated by melatonin and downstream melatonin receptors and may be the common effector in the synergistic effects of melatonin with other antidepressants. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin causes antidepressant-like effects in mice through calmodulin kinase II stimulation of downstream melatonin receptors as well as the participation of this enzyme in neuroplasticity, memory, and cognition. Finally, we describe evidence about the effectiveness of antidepressant-like effects of melatonin in combination with ketamine.
... In fact, serotonin and tryptophan, direct precursors of melatonin, increased notably after intake of the cherry beverage. These results may have important health-related implications because of the wide spectrum of biological functions in which these molecules are involved [38,39]. ...
Cherry is a fruit which contains elevated amounts of antioxidant compounds, such as anthocyanins, pigments, and vitamins. Furthermore, it possesses high water, sugar, mineral, and indolamine contents. The general objective of this study was to characterise a cherry-based fermented beverage (the ‘sweetheart’ variety) and analyse the effects of its ingestion on (i) circulating serum levels of melatonin and serotonin, (ii) inflammatory response, and iii) serum total antioxidant capacity in rats (Rattus norvegicus). For cherry-based fermented beverage manufacturing, the cherries were washed, the stems and woody endocarps were removed, and ascorbic acid was added (to avoid enzymatic browning). After the homogenisation of the cherry fruit, lactic acid bacteria were inoculated, and the fermentation process was conducted for 36 h. The main bioactive compounds in the cherry beverage were characterised, as well as their total antioxidant capacity. Moreover, an in vivo assay was developed, in which rats ingested the fermented beverage ad libitum for seven days. The inflammatory mediators, the total antioxidant capacity, and the serum levels of melatonin and serotonin were measured. Based on these results, the intake of the cherry-based fermented beverage assayed in this study increased the total antioxidant status of rats, elevated the melatonin and serotonin levels in the serum, and improved the regulation of the inflammatory systemic processes.
... 14,95,96 Furthermore, melatonin may act as an effective cardiovascular system protector, reducing the likelihood of developing reperfusion injury following myocardial infarction. 97 After a myocardial infarction, melatonin receptors are also crucial in lowering the risk of heart failure and cardiomyopathy. According to Yeung et al., melatonin was found to be protective against CIH-induced myocardial fibrosis, inflammation, and ischemia-reperfusion injury. ...
Melatonin, a circardian biomolecule exerts cardioprotective effects through its ability to directly scavenge free radicals and to indirectly act as an antioxidant. It has biological functions such as anti-apoptosis, anti-inflammation, antioxidant activity, mitochondrial protection, and controlling the production of cytokines by target cells. Melatonin also showed blood pressure lowering, normalising lipid profiles, and anti-inflammatory characteristics. Melatonin plays critical roles in averting oxidative stress, enhancing autophagic cell repair, modulating immunological and inflammatory responses, improving mitochondrial function, and reducing endoplasmic reticulum stress in cardiomyocytes. The absence of these cardioprotective properties due to low melatonin levels may be linked to an array of cardiovascular diseases, including ischemic heart disease. As a result, administration of melatonin is anticipated to have a clinically important role in the management of ischemic heart disease; an assertion backed by melatonin's low toxicity and high safety. Therefore, the evidence gathered in this review should provide comprehensive information on melatonin's effect in cardioprotection and, perhaps, contribute to the planning of future experimental studies.
... Accordingly, the time of the nocturnal rise in plasma (or saliva) melatonin determined in darkness or controlled dim light is commonly used as a phase marker of the master clock in human subjects. 34 The physiological role of melatonin in mammals is mediated by high-affinity G protein-coupled membranebound receptors, called MT 1 and MT 2 , encoded respectively by the Mtnr1a and Mtnr1b genes. MT 1 and MT 2 receptors are widely distributed in the brain and peripheral tissues, although with many species differences. ...
Melatonin is a neurohormone synthesized from dietary tryptophan in various organs, including the pineal gland and the retina. In the pineal gland, melatonin is produced at night under the control of the master clock located in the suprachiasmatic nuclei of the hypothalamus. Under physiological conditions, the pineal gland seems to constitute the unique source of circulating melatonin. Melatonin is involved in cellular metabolism in different ways. First, the circadian rhythm of melatonin helps the maintenance of proper internal timing, the disruption of which has deleterious effects on metabolic health. Second, melatonin modulates lipid metabolism, notably through diminished lipogenesis, and it has an antidiabetic effect, at least in several animal models. Third, pharmacological doses of melatonin have antioxidative, free radical‐scavenging, and anti‐inflammatory properties in various in vitro cellular models. As a result, melatonin can be considered both a circadian time‐giver and a homeostatic monitor of cellular metabolism, via multiple mechanisms of action that are not all fully characterized. Aging, circadian disruption, and artificial light at night are conditions combining increased metabolic risks with diminished circulating levels of melatonin. Accordingly, melatonin supplementation could be of potential therapeutic value in the treatment or prevention of metabolic disorders. More clinical trials in controlled conditions are needed, notably taking greater account of circadian rhythmicity.
... 11. FeG+CD/LDC: Rats exposed to Fe-D and DD for 15 days and then returned to the 12: 12 LDC. All groups are also listed in the Table 1. ...
Melatonin is a potent endogenously occurring antioxidant with the pleiotropic activities to neurodegenerative diseases associated with brain oxidative damage. In this study, we examined the prolonged photoperiodic alterations and iron (Fe) overload on melatonin production and brain oxidative stress in rats. The result showed that the 15 days of constant light (CL) exposure did not low the melatonin production but the 15 days of constant darkness (CD) significantly increased serum melatonin level in rats. The Fe treatment in both CL and CD conditions significantly reduced endogenous melatonin levels and increased brain tissue lipid peroxidation. Fe as a toxic transition metal can induce Fenton reaction to generated hydroxyl radical which can damage the neuronal cell membrane and impair the brain antioxidant system. In the current study, we observed the imbalanced antioxidant defense alterations upon Fe treatment in rat brain including the increased levels of alpha-tocopherol (α-T) and total thiols and the reduced melatonin level and catalase (CAT) activity. We speculated that the reduced melatonin level caused by Fe was due to its consumption since melatonin served as a metal chelator and antioxidant. Understanding these aspects enhances knowledge of brain Fe metabolism and its role in neurodegenerative disorders as well as the potential protective effects of melatonin on this metal.
... Although the C57Bl/6 mouse strain is deficient in pineal melatonin due to mutations affecting two enzymes involved in melatonin synthesis (Ebihara et al., 1986;Goto et al., 1989;Kasahara et al., 2010), several studies have detected low but measurable amounts of pineal hormone (Conti and Maestroni, 1996;Vivien-Roels et al., 1998;von Gall et al., 2000). Pineal melatonin is a signal of night and night length, and is also involved in the synchronization of biological rhythms (Arendt and Skene, 2005) and physiological processes, including reproductive function and ageing (Pierpaoli and Regelson, 1994;Vivien-Roels et al., 1998). While melatonin is thought to play a beneficial role in some sleep disorders in humans (Moon et al., 2022), an effect on the sleep of nocturnal rodents seems unlikely since it is released during their most active phase. ...
free access to the full article:
https://doi.org/10.1016/j.neuroimage.2024.120576
How the time-of-day, sex, and age affect functional connectivity (FC) in mice, a model of choice for neuroimaging studies, remains to be established. Our objective was to examine whether the mouse functional connectome varies with the day and night cycle as well as its possible dependency on sex and age. We explored C57Bl6/J mice (6♀ and 6♂) at a 9-month interval corresponding to completed cerebral maturation age (5 ± 1 months) and middle-age (14 ± 1 months). Each mouse underwent Blood Oxygen-Level-Dependent (BOLD) resting-state functional magnetic resonance imaging (rs-fMRI) at four different times of the day, two under light condition and two under dark condition. The rs-fMRI data were preprocessed using a home-made pipeline followed by group independent component analysis (ICA) and region level analysis using resting-state networks (RSNs) derived from literature. Mixed-effect models were used to assess the effects of sex, lighting condition and their interactions for each RSN obtained with group-ICA (RSNs-GICA) and RSNs adapted from literature (RSNs-LIT). Our study highlighted new RSNs in mice related to day and night alternation in addition to other networks already reported in the literature. In mature mice, we detected neither significant effect of lighting condition nor interaction of it with sex in any of the RSNs-GICA, but we found a sex-related difference in brain activation in one RSNs-GICA including the cortical, hippocampal, midbrain and cerebellar regions of the right hemisphere. Significant increases of brain activity were identified at the left side in the left hippocampus, the retrosplenial cortex, the superior colliculus, and the cerebellum in males regardless of lighting condition. This result is consistent with the role of these structures in memory formation and integration, sleep, and the sex-differences in memory processing. The effect of age could not be not assessed due to experimental constraints, however the impact of light and dark cycle on RSNs for middle-aged female was analyzed. We detected significant activation in the pineal gland during dark condition, a finding in line with the nocturnal activity of this gland, which is suppressed by light. Using RSNs-LIT, we identified neither an effect of lighting condition nor of a sex on FC between brain regions but we detected sex-related difference in FC as a function of lighting condition and RSNs-LIT in brain regions related to vision, memory and motor action.
We conclude that time-of-day and sex are independent variables that need to be considered when designing, analyzing, and interpreting functional imaging studies in rodents.
... This hormone, which is already reduced during older adults' sleep due to the aging process, is a chronobiotic that synchronizes the individual's intrinsic biological rhythm. Therefore, when secreted at times other than the physiological one, melatonin can lead to increased daytime sleepiness and/or insomnia 40 , and when decreased, it can result in poor sleep quality 41 . Table 4 Adjusted * association between neighborhood social environment characteristics and sleep problems in older adults (≥ 60 years). ...
This study aimed to investigate associations between neighborhood perception and sleep problems in older Brazilian adults. A cross-sectional study was conducted with 5,719 community-dwelling older adults (≥ 60 years) from the Brazilian Longitudinal Study of Aging (ELSI-Brazil, 2019-2021). The outcomes were self-reported sleep problems: poor sleep quality, daytime sleepiness, primary insomnia complaints, difficulty staying asleep, and waking up at dawn. The exposure variables were questions about the perception of participants about the physical and social environment of the neighborhood. Logistic regression was used in data analysis. Garbage, rubbish, or tall grass on the streets and the desire to move were associated with higher odds of poor sleep quality. Concern about falling due to damaged sidewalks, concern about having difficulties taking transportation, and concern about having difficulties crossing the street were associated with higher odds of all sleep problems. Sound/noise of buses and cars was associated with higher odds of some sleep problems. Perceiving the neighborhood as a good place to live was associated with lower odds of daytime sleepiness and primary insomnia complaints. Trusting most people in the neighborhood and perceiving that kids and younger people treat adults with respect were associated with lower odds of daytime sleepiness, primary insomnia complaints, and waking up at dawn. Being a good place for kids to play and raise teenagers was associated with lower odds of daytime sleepiness. These results can assist public administrators in creating urban planning policies aimed at improving neighborhood environments as a means of health promotion.
... Management: General approaches to treatment include sleep hygiene education, CBT, regular exercise, and planned light exposure. Drug treatment (melatonin) is usually also part of management [69][70][71]. ...
Biological, environmental, behavioral, and social factors can influence sleep and lead to sleep disorders or diseases. Sleep disorders are common, numerous, and heterogeneous in terms of their etiology, pathogenesis, and symptomatology. The management of sleep–wake circadian disorders (SWCDs) includes education on sleep hygiene, behavioral strategies, psychotherapy (cognitive behavioral therapy (CBT), particularly), instrument-based treatments (i.e., positive airway pressure therapy, hypoglossal nerve stimulation), and pharmacotherapy. Depending on the disease, therapy varies and is executed sequentially or can be a combination of several forms of therapy. Drugs used for SWCDs include traditional sleep- or wake-promoting agents and chronotherapeutic agents. Recently, novel medications, which more precisely act on specific neurochemical systems (i.e., the orexin system) important for sleep and waking, are also increasingly being used. In this review, the pharmacotherapy of common sleep disorders (insomnia, sleep-related breathing disorder, central disorders of hypersomnolence, circadian rhythm sleep–wake disorders, parasomnias, and sleep-related movement disorders) embedded in the overall therapeutic concept of each disorder is presented. There is also an outlook on possible future pharmacotherapies.
... Washout phases (which are 1 or 2 weeks or more in duration) may be inserted between each dose phase (e.g., A, B, C) to eliminate any effect of the prior dose. Melatonin, however, has a relatively short half-life of 4 to 8 hours, making washout unnecessary (Arendt & Skene, 2005). Some treatments, of course, may have a long half-life. ...
Treatment of patients who suffer from concurrent health conditions is not well served by (1) evidence-based clinical guidelines that mainly specify treatment of single conditions and (2) conventional randomized controlled trials (RCTs) that identify treatments as safe and effective on average. Clinical decision-making based on the average patient effect may be inappropriate for treatment of those with multimorbidity who experience burdens and obstacles that may be unique to their personal situation. We describe how the personalized (N-of-1) trials can be integrated with an automatic platform and virtual/remote technologies to improve patient-centered care for those living with multimorbidity. To illustrate, we present a hypothetical clinical scenario—survivors of both coronavirus disease 2019 (COVID-19) and cancer who chronically suffer from sleeplessness and fatigue. Then, we will describe how the four standard phases of conventional RCT development can be modified for personalized trials and applied to the multimorbidity clinical scenario, outline how personalized trials can be adapted and extended to compare the benefits of personalized trials versus between-subject trial design, and explain how personalized trials can address special problems associated with multimorbidity for which conventional trials are poorly suited.
... Melatonin was measured through collected saliva samples, as shown in Figure 1. Because melatonin is considered a "biological night" hormone, 31 the protocol was designed to allow larger numbers of salivary samples to be taken at nighttime. All participants were required to provide approximately 2 mL of saliva samples directly into an individual sterile tube at the specified time (a total of 15 time points). ...
With the inherent sleep and wake cycle regulated by natural sunlight, the human body has evolved over millennia to be active during the day and to rest at night. However, maintaining an optimal 24 h cycle has become increasingly problematic in modern society as more people spend the majority of the day indoors. Many research groups have reported that inadequate artificial lighting interferes with melatonin production and disrupts the circadian rhythm. This study considered biological functions for light-emitting diodes (LEDs) of next-generation illumination, and LED packages and spectra suitable for both daytime and nighttime applications were designed. The prepared daytime human-centric (HC)-LEDs had a melanopic/photopic (M/P) ratio that was up to 26% higher than that of conventional (c)-LEDs, whereas the nighttime HC-LEDs exhibited up to a 26% lower M/P ratio compared to the c-LEDs. Nevertheless, because the HC-LED is designed to have almost the same color coordinates as the c-LED having the same correlated-color temperature (CCT), there is no change in the perceived color. To substantiate the biological effect, melatonin level data were obtained from 22 voluntary participants in c- and HC-LED lighting environments. In the HC-LED lighting environment, melatonin was suppressed by 21.9% after waking, and nocturnal melatonin secretion was increased by up to 12.2%. As human-centric lighting, our HC-LEDs are expected to become an essential element for modern life, where people spend most of their time indoors.
... Additionally, a drop in endogenous melatonin concentrations is also observed following Antiparkinson therapy (38). Exogenous melatonin can effectively counteract these reductions, and its sleep-inducing effects (4,39,40), along with its safe profile, make it superior for addressing sleep disturbances compared to alternatives like Clonazepam, with undesirable hangover effects (41). Although, ample experimental evidence (18,19,31,33,42) supports melatonin use in Parkinson's disease, further evaluation is necessary to determine its real-world clinical applications. ...
Objective
Since its discovery as an antioxidant, melatonin has been increasingly recognized for its therapeutic potential beyond sleep disturbances in neurodegenerative disorders. This study aims to evaluate efficacy of various melatonin doses, treatment durations, and formulations, in alleviating motor symptoms and sleep disturbances in Parkinson’s disease, the second most common neurodegenerative disorder worldwide.
Methods
PubMed, Cochrane Library, ClinicalTrials.gov and other databases were systematically searched to retrieve randomized controlled trials (RCTs) administrating melatonin to Parkinson’s disease patients until June 10th, 2023. Outcomes including Unified Parkinson Disease Rating Scale (UPDRS) scores and Pittsburgh Sleep Quality Index (PSQI) scores, were pooled and reported as mean differences (MD) with 95% confidence intervals (CIs). Meta-analysis was performed using an inverse variance random-effects model in Review Manager 5.4 software. Trial Sequential Analysis was performed to avoid false-positive results from random errors.
Results
Five RCTs with a total of 155 patients were included. Statistically significant reductions in UPDRS total scores were observed in groups receiving Melatonin ≥10 mg/day (MD = −11.35, 95% CI: −22.35 to −0.35, I² = 0%, p = 0.04) and immediate release formulations (MD = −11.35, 95% CI: −22.35 to −0.35, I² = 0%, p = 0.04). No significant effects on individual UPDRS II, III, and IV scores were observed, regardless of melatonin dosage and treatment duration. Moreover, significant improvements in PSQI scores were observed with only immediate-release melatonin formulations (MD = −2.86, 95% CI: −4.74 to −0.97, I² = 0%, p = 0.003).
Conclusion
Melatonin ≥10 mg/day for a minimum duration of ≥12 weeks in immediate-release formulations consistently demonstrated significant therapeutic potential in improving motor symptom and sleep disturbances in Parkinson disease. However, further trials are warranted to investigate its impact when initiated early in the disease course to fully explore its true therapeutic potential.
Systematic review registration
Unique identifier: CRD42023427491 (PROSPERO).
... • Cir ka di nio rit mo pa lai ky mas ir mie go uþ tik ri nimas. Pa grin di në fi zio lo gi në en do ge ni nio me la to ni no funk ci ja yra uþ tik rin ti su tam sa su si ju sá el ge sá -fi zio lo gi ná po lin ká mie go ti [8]. Ka dan gi me la to ni no pro duk ci ja tie siogiai su si ju si su die nos ir nak ties kai ta, jo tiks las yra pa dë ti or ga niz mo bio lo gi niams pro ce sams pri si tai ky ti prie ap linkos ge o fi zi nës die nos ir nak ties po ky èiø. ...
Melatonin is a hormone secreted by the pineal gland that is important for various neurological and endocrine processes in the body. With age and various diseases, a decrease in the concentration of melatonin is observed, its antioxidant effect is reduced, therefore, the circadian rhythm is disturbed, mental disorders occur, and the risk of oncological, neurodegenerative and cardiovascular diseases increases. Due to its wide spectrum of action, melatonin can be used successfully and safely for the prevention and treatment of various diseases. In recent years, the antineoplastic, anti-inflammatory, and analgesic effects of melatonin have been increasingly investigated, as has the potential positive effects of melatonin on adjuvant therapy for COVID-19 infection. By adapting the natural properties of melatonin for therapeutic purposes, exogenous melatonin preparations can potentially be used in addition to, or even as a substitute for, other currently used drugs. However, it is important to weigh the benefits and the risks. Although current studies show relative safety with low doses of exogenous melatonin, it is necessary to further investigate and analyze the safety and efficacy of these agents in the short and long term.
... Therapeutical approaches to circadian rhythm disturbances in BD patients may include: bright light therapy, sleep deprivation or wake therapy-based treatments, dark therapy, melatonergic agonists and behavioral interventions (Gottlieb et al., 2019). The present study is focused on exogenous melatonin (exo-MEL), a potent chronobiotic (Arendt and Skene, 2005;Cruz-Sanabria et al., 2022) with proven efficacy in the treatment of DSWPD (van Geijlswijk et al., 2010). Studies on healthy subjects show that administering exo-MEL before the dim light melatonin onset (DLMO), a marker of the circadian phase that represents the onset of the endogenous melatonin release, induces a phase advance (Lewy et al., 1992). ...
The present study evaluates the effect of exogenous melatonin (exo-MEL) on sleep and circadian parameters in patients with bipolar disorder (BD) and delayed sleep-wake phase disorder (DSWPD). BD euthymic patients (n = 83, mean age = 45.13 ± 13.68, males 56%) were evaluated for chronotype (reduced Morningness-Eveningness Questionnaire [rMEQ]), sleep quality (Pittsburgh Sleep Quality Index), sleep and circadian parameters (actigraphic monitoring). Patients that fulfilled criteria for DSWPD (n = 25) were treated for three months with exo-MEL 2 mg administered approximately 4 h before the sleep onset time (SOT) actigraphically-determined at baseline. Sleep and circadian parameters at baseline (T0) and after the exo-MEL treatment (T1) were compared using paired Wilcoxon test. In patients that completed the treatment (n = 19), the rMEQ score increased between T0 (median = 8.0 [IQR = 7.0, 11.0]) and T1 (median = 13.5 [IQR = 9.3, 15.0], p-value = 0.006), the SOT was advanced between T0 (median = 00:55 [IQR = 00:25, 01:39] and T1 (median = 00:09 [IQR = 23:41, 01:04], p-value = 0.039), the sleep efficiency and total sleep time increased (T0: median = 84.4 [IQR = 81.3, 89.4]; T1 (median = 90.3 [IQR = 85.5, 92.9] %, p-value = 0.01, and T0: median = 7.20 [IQR = 6.15, 8.15]; T1: median = 7.7 [IQR = 7.0, 9.3] hours, p-value = 0.04, respectively). These results indicate that in BD with comorbid DSWPD, the self-reported chronotype, the sleep onset time, and sleep efficiency and duration were modified after a personalized treatment with exo-MEL, suggesting its potential efficacy in improving sleep patterns in BD. The absence of proper control groups and of treatment randomization constitute limitations of our study and further randomized controlled trials are required to confirm our results.
... The pineal gland, a neuroendocrine organ existing only in vertebrate species, is involved in the control and synchronisation of several behaviours and physiological processes through the circadian synthesis of its main hormone, melatonin [1]. This organ is found in all classes of vertebrates, from fish [2] to amphibians [3], reptiles [4], birds [5], and mammals [6]. ...
Simple Summary
The pineal gland, in conjunction with its hormone melatonin, possesses the capability to perceive and interpret the light signals from the environment, thereby regulating the physiology, metabolism, and behavior of avian species. This investigation aims to explore the associations between melatonin and immune system functioning. Through an exploration of the immune-pineal axis, our objective is to gain insight into various aspects, including the development of the pineal gland, the influence of light on pineal secretory activity, and the effects of melatonin on lymphoid organs. The findings of this study demonstrate that the utilization of green monochromatic light (560 nm) and blue monochromatic light (480 nm) leads to an increase in melatonin levels in the bloodstream. Furthermore, it ameliorates the inflammatory response, protected lymphoid organs against oxidative stress, and promotes a stronger immune response. In this case, melatonin should be considered a potent antioxidant and immunomodulator.
Abstract
It is well known that the pineal gland in birds influences behavioural and physiological functions, including those of the immune system. The purpose of this research is to examine the endocrine–immune correlations between melatonin and immune system activity. Through a description of the immune–pineal axis, we formulated the objective to determine and describe: the development of the pineal gland; how light influences secretory activity; and how melatonin influences the activity of primary and secondary lymphoid organs. The pineal gland has the ability to turn light information into an endocrine signal suitable for the immune system via the membrane receptors Mel1a, Mel1b, and Mel1c, as well as the nuclear receptors RORα, RORβ, and RORγ. We can state the following findings: green monochromatic light (560 nm) increased serum melatonin levels and promoted a stronger humoral and cellular immune response by proliferating B and T lymphocytes; the combination of green and blue monochromatic light (560–480 nm) ameliorated the inflammatory response and protected lymphoid organs from oxidative stress; and red monochromatic light (660 nm) maintained the inflammatory response and promoted the growth of pathogenic bacteria. Melatonin can be considered a potent antioxidant and immunomodulator and is a critical element in the coordination between external light stimulation and the body’s internal response.
The pineal gland synchronizes the body’s circadian rhythms by producing melatonin in response to changes in the light-dark cycle. Our study evaluated how prolonged exposure to constant lighting (LL) or darkness (DD) affects pineal physiology by monitoring the transcription of genes critical for rhythmic endocrine activity. To achieve this, rats were exposed to LL, DD, or LD (control) from P21 to P90. LL and DD impacted the rats’ physiology, as evidenced by the shift from a bimodal voluntary activity pattern to a free-running one. Serum melatonin and the transcription of genes encoding key enzymes involved in melatonin synthesis and adrenergic receptors changed their characteristic diurnal pattern observed in the LD group. The transcription of clock genes important for pineal rhythmicity was disturbed under both LL and DD: LL attenuated or flattened the expression of core clock genes, while DD showed a weaker effect and shifted the peak of expression. In LL, altered expression of clock genes was associated with increased transcription of regulators of mitochondrial biogenesis, and markers of mitophagy and mitochondrial dynamics, resulting in elevated ATP production. Oppositely, in DD conditions, ATP decreased. Principal Component Analysis (PCA) revealed distinct clusters comprising clock and mitochondria-related genes, indicating a close association between the circadian clock and mitochondrial function. These findings suggest that long-term exposure to LL environment poses more significant challenges to the pineal gland than DD. This might be associated with the heightened blood corticosterone levels observed in LL conditions, indicating potential chronobiological stress.
Introduction
Bipolar disorder (BD), characterized by extreme mood shifts between mania and depression, can manifest in childhood, and pose treatment challenges. Treatment for full‐criteria BD I or II in children has been partially described in the literature, but major uncertainties exist regarding non‐classic presentations, which were originally designated as bipolar “not otherwise specified” (BP‐NOS) in DSM‐IV and in DSM‐5 and ICD‐11 as either other specified or unspecified BD (S‐USBD). This review aims to provide literature‐based recommendations on the treatment of S‐USBD, with a focus on a fear of harm (FOH) subtype, now termed temperature and sleep dysregulation disorder (TSDD).
Methods
A broad systematic literature review with AI assistance was conducted to identify all articles in PubMed providing data on the treatment of children with either atypical BD, BD‐NOS, USBD, specified BD, rapid cycling BD, or a phenotype of BD.
Aims
Given the paucity of pharmacological treatment literature on any of the earliest forms of BD prior to their achieving a BP I or BP II diagnosis, it was felt that there was a critical need to review the existent literature on the earliest presentations and prodromes, which now fall under the rubric of specified (BD S‐USBD). Here, the focus is on the prevalent BP‐NOS subtype, which meets all the classical presentations of BP except for the brief durations of mania, and a more newly recognized form of S‐USBD called TSDD.
Results
Eleven family‐focused psychotherapy studies were identified, including nine randomized controlled trials (RCTs) with uniformly positive results versus the comparative group, which was treatment as usual (TAU) for unclear subtypes and subtypes of S‐USBD. Only three psychopharmacological RCTS were reported, and only one on aripiprazole in unspecified subtypes of S‐USBD in high‐risk children showed a significant difference from placebo. None of the controlled trials and only two case series provided separate outcome data on the S‐USBD subtypes, except for one that focused exclusively on the TSDD subtype. These two case series reports preliminarily defined the TSDD subtype and provided novel pharmacological treatment data, including lithium, clonidine, and ketamine, which led to good outcomes.
Conclusion
Good support was provided in the 11 studies for the use of adjunctive family‐focused psychotherapeutic approaches, and this approach should be considered an important part of any treatment regimen. The pharmacological treatment landscape for S‐USBD lacks a systematic research base, warranting further exploration with controlled clinical trials. Case series indicate promising treatment outcomes for TSDD with high‐dose lithium, clonidine, ketamine, and other cooling measures. Validation of this novel treatment strategy in controlled trials is needed to advance the management of the S‐USBD variants.
Throughout history, the development of new sleep medicines has been driven by progress in our understanding of the mechanisms underlying sleep. Ancient civilisations used their understanding of the sedative nature of natural herbs and compounds to induce sleep. The discovery of barbiturates and bromides heralded a new era of synthetic sleep medicine in the 19th century. This was followed by the development of benzodiazepines that were used to inhibit signalling throughout the brain by promoting gamma‐amino butyric acid release and thereby produce loss of consciousness. As our understanding of sleep has deepened, newer therapies have more specifically targeted the wake‐inducing neurotransmitter orexin with fewer side effects. Given the newly highlighted role of kinases in sleep/wake regulation, we predict that the next breakthroughs in sleep medicine will likely target these kinases. Given the fundamental role that sleep plays in maintaining brain health through processes such as glymphatic clearance, sleep medicine has therapeutic potential beyond just sleep. Recent evidence suggests that sleep disruptions directly contribute to the build‐up of pathological neuronal proteins in neurodegenerative disorders. Therefore, sleep medicine could improve prognosis in disorders such as these. Great attention must be paid to the mechanism of action of each sleep medicine, however, as sleep medicines which do not fully mimic sleep could actually worsen disease progression.
The pineal gland is located deep in the midline of the brain and is surrounded by critical structures. Therefore, open surgery for suspected tumor in this region is often challenging and might be associated with significant risks. For this reason, stereotactic biopsy is an alternative for diagnosing unclear findings in this region. Here we describe the features of stereotactic biopsies in the pineal region and discuss the diagnostic accuracy and complication rates of this neurosurgical procedure.
Objective: Considering that inflammatory responses affect the nocturnal peak of melatonin and that sleep interruption activates inflammatory mechanisms that trigger changes in the effector systems that regulate the immune system, increasing the inflammatory response and pain, this study investigates the efficacy of melatonin as a treatment for the symptoms of the poor sleep quality and pain in the endometriosis. Methods: Endometriosis was diagnosed by medical history and imaging tests (ultrasound or magnetic resonance imaging). Pain intensity was assessed using a visual analogue scale (VAS). Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Patients were treated with exogenous melatonin and signs of inflammation were assessed before and after treatment. Results: There was an improvement in sleep quality with melatonin compared with the placebo group, with no evidence of side effects. The dose of 3g exogenous melatonin was not effective for the symptom of pain. Conclusion: The poor sleep quality associated with the inflammatory state of endometriosis was controlled by the exogenous use of melatonin, reinforcing the role of sleep induction in conditions associated with chronic inflammation. However, melatonin was not effective in the pain state during treatment. The mechanisms involved in the modulation of pain in relation to the functional mechanisms of melatonin should be further investigated.
While dynamic functional connectivity remains controversial in human neuroimaging, the transient nature of interareal coupling is considered a robust finding in other fields of neuroscience. Nevertheless, the origin and interpretation of these dynamics are still under debate. This letter argues that ongoing cognition is not sufficient to account for dynamic functional connectivity. Instead, it is proposed that the baseline state of the brain is inherently unstable, leading to dynamics that are of neural origin but not directly implicated in cognition. This perspective also reinforces the usefulness of conducting experiments during the resting state.
In the context of the escalating global health challenge posed by Alzheimer’s disease (AD), this comprehensive review considers the potential of melatonin in both preventive and therapeutic capacities. As a naturally occurring hormone and robust antioxidant, accumulating evidence suggests melatonin is a compelling candidate to consider in the context of AD-related pathologies. The review considers several mechanisms, including potential effects on amyloid-beta and pathologic tau burden, antioxidant defense, immune modulation, and regulation of circadian rhythms. Despite its promise, several gaps need to be addressed prior to clinical translation. These include conducting additional randomized clinical trials in patients with or at risk for AD dementia, determining optimal dosage and timing, and further determining potential side effects, particularly of long-term use. This review consolidates existing knowledge, identifies gaps, and suggests directions for future research to better understand the potential of melatonin for neuroprotection and disease mitigation within the landscape of AD.
Background:
Radiotherapy is a widely used treatment method in oncology, applied by delivering high-energy particles or waves to the tumor tissue. Although tumor cells are targeted with radiotherapy, it can cause acute or long-term damage to healthy tissues. Therefore, the preservation of healthy tissues has been an important subject of various scientific researches. Melatonin has been shown to have a radioprotective effect on many tissues and organs such as liver, parotid gland, brain, and testicles. This study aimed to evaluate the protective effect of melatonin against the radiation at various doses and rates administered to the lung tissue of healthy mice.
Methods:
This study was a randomized case-control study conducted with 80 rats comprising 10 groups with eight animals per group. Of the 10 groups, first is the control group, which is not given any melatonin, and second is the group that does not receive RT, which is given only melatonin, and the other eight groups are RT groups, four with melatonin and four without melatonin.
Results:
There was no statistical difference in terms of histopathological findings in the lung tissue between the second group, which did not receive radiotherapy and received only melatonin, and the control group. Lung damage due to radiotherapy was statistically significantly higher in the groups that did not receive melatonin compared to the groups that received melatonin.
Conclusions:
This study revealed that melatonin has a protective effect against the cytotoxic damage of RT in rats receiving RT.
Melatonin, an evolutionarily old molecule, is found in many living organisms. This neurohormone is known to control many physiological processes, including circadian rhythm, mood, and behavior. Melatonin was discovered to be a direct free radical scavenger. By activating its receptors, it stimulates a wide range of signaling pathways. It has been proven that melatonin exerts neuroprotective and antidepressant-like effects. Also, many researchers have found that melatonin plays an important role in various cardiovascular diseases. In the near future, melatonin will be a promising agent to control the fate of mesenchymal stem cells by regulating the generation of reactive oxygen species and the release of immune factors in regenerative medicine. Collectively, the studies link melatonin to a variety of outcomes and have a strong regulatory impact on numerous physiological processes in the body.
Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1‐knockout (KO) mice and MT1‐KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene‐expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species‐induced oxidative stress and activates the nuclear factor erythroid 2‐related factor 2/heme oxygenase‐1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1‐KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death.
Biological, environmental, behavioral, and social factors can influence sleep and lead to sleep disorders or diseases. Sleep disorders are common, numerous and heterogeneous in terms of their etiology, pathogenesis, and symptomatology. Management of sleep-wake circadian disorders (SWCD) includes education to sleep hygiene, behavioral strategies, psychotherapy (cognitive behavioral therapy (CBT), particularly), instrument-based treatments (i.e. positive airway pressure therapy, hypoglossal nerve stimulation), and pharmacotherapy. Depending on the disease, therapy varies and is executed sequentially, or can be a combination of several forms of therapy. Drugs used for SWCD include traditional sleep or wake-promoting agents, chronotherapeutic agents. Recently, novel medications, which are more precisely acting on specific neurochemical systems (i.e. orexin system) important for sleep and wake, are also increasingly being used. In this review, the pharmacotherapy of common sleep disorders (insomnia, sleep-related breathing disorder, central disorders of hypersomnolence, circadian rhythm sleep wake disorders, parasomnias, and sleep-related movement disorders) embedded in the overall therapeutic concept of each disorder is presented. There is also an outlook on possible future pharmacotherapies.
Cancer is the second major cause of disease-related dead worldwide, and its accurate early diagnosis and therapeutic intervention are fundamental for saving the patient’s life. Cancer, as a complex and heterogeneous disorder, results from disruption and alteration of a wide variety of biological entities, including genes, proteins, mRNAs, miRNAs, and metabolites that eventually emerge as clinical symptoms. Traditionally, diagnosis is based on clinical examination, blood tests for biomarkers, histopathology of biopsy, and imaging (MRI, CT, PET, US). Additionally, omics biotechnologies help to further characterize the genome, metabolome, microbiome traits of the patient that could have an impact on the prognosis and patient’s response to the therapy. The integration of all these data relies on gathering of several experts and may require considerable time, and, unfortunately, it is not without the risk of error in the interpretation and therefore in the decision. Systems biology algorithms exploit Artificial Intelligence (AI) combined with omics technologies to perform a rapid and accurate analysis and integration of patient’s big data and support the physician in making diagnosis and tailoring the most appropriate therapeutic intervention. However, AI is not free from possible diagnostic and prognostic errors in the interpretation of images or biochemical-clinical data. Here, we first describe the methods used by systems biology for combining AI with omics and then discuss the potential, challenges, limitations, and critical issues in using AI in cancer research.
Light pollution is now associated with an increased incidence of mental disorders in humans, and the unfixed light pattern (ULP) is a common light pollution that occurs in such as rotating shift work. However, how much contribution the ULP has to depression and its potential mechanism are yet unknown. Our study aimed to investigate the effect of the ULP on depressive-like behaviors in mice and to explore the links to the circadian-orexinergic system. Male C57BL/6 J mice were exposed to the ULP by subjecting them to an alternating light pattern every 6 days for 54 days. The tail suspension test (TST) and forced swimming test (FST) were conducted to assess depressive-like behaviors. The rhythm of locomotor activity and the circadian expression of cFOS in the suprachiasmatic nucleus (SCN), clock genes in the liver, and corticosterone (CORT) in serum were detected to observe changes in the circadian system. The circadian expression of orexin-A (OX-A) in the lateral hypothalamus area (LHA) and dorsal raphe nucleus (DRN) and serotonin (5-HT) in the DRN were measured to determine alterations in the orexinergic system. The results showed that mice exposed to the ULP exhibited increased immobility time in the TST and FST. The ULP significantly disrupted the circadian rhythm of locomotor activity, clock genes in the liver, and CORT in the serum. Importantly, when exposed to the ULP, cFOS expression in the SCN showed decreased amplitude. Its projection area, the LHA, had a lower mesor of OX-A expression. OX-A projection to the DRN and 5-HT expression in the DRN were reduced in mesor. Our research suggests that the ULP contributes to depressive-like behaviors in mice, which might be related to the reduced amplitude of circadian oscillation in the SCN and hypoactivity of the orexinergic system. These findings may provide novel insights into rotating shift work-related depression.
The biological rhythm is regulated through endogenous circadian clock and synchronizes with photoperiodic signal in an
environmental light-dark cycle. The hypothalamic suprachiasmatic nucleus (SCN) containing clock genes acts as a ‘time
keeper’ of the rhythmic functions as the environmental signal perceives through retino-hypothalamic tract and coordinates
with oscillators present in almost all organs throughout the body. This coordination with external environment is governed
by neuronal and hormonal cues. The pineal hormone melatonin (N-acetyl-5-methoxytryptamine) is synthesized rhythmically
in all vertebrates with a peak during dark phase and nadir during light phase. It is considered as a ‘hormone of darkness’
involved primarily in maintaining the zeitgeber in the central and peripheral clocks. Melatonin regulates gonadal growth
and maturation in fsh by acting directly and/or on hypothalamo-pituitary-gonadal (HPG) axis. Exogenous administration
of melatonin and/or altered photoperiods has a signifcant impact on the functions of gonads depending on the reproductive
status of several fsh species, particularly in carp. Seasonal fuctuations of ovarian melatonin concentration, high during the
spawning season and a sharp decline during the post-spawning, in an annual reproductive cycle in female carp also suggested
its involvement in the oocyte development. The hormone activates the structural components of maturation promoting factor
(MPF), cyclin B and Cdc2, to promote germinal vesicle breakdown (GVBD). Melatonin also up-regulates several antioxida-
tive enzymes in fsh ovary and reduces oxidative stress to augment the spawning process. Thus, present review focus on the
interactions of seasonal rhythmicity of melatonin secretions and gonadal functions for unravel its role in fsh reproduction.
In humans, the pineal hormone melatonin can phase shift a number of circadian rhythms (e.g., "fatigue," endogenous melatonin, core body temperature) together with the timing of prolactin secretion. It is uncertain, however, whether melatonin can fully entrain all human circadian rhythms. In this study, the authors investigated the effects of daily melatonin administration on sighted individuals kept in continuous very dim light. A total of 10 normal, healthy males were maintained in two separate groups in partial temporal isolation under constant dim light (< 8 lux) with attenuated sound and ambient temperature variations but with knowledge of clock time for two periods of 30 days. In these circumstances, the majority of individuals free run with a mean period of 24.3 h. In a double-blind, randomized crossover design, subjects received 5 mg melatonin at 20:00 h on Days 1 to 15 (Melatonin 1st) followed by placebo on Days 16 to 30 (Placebo 2nd) or vice versa (Placebo 1st, Melatonin 2nd) during Leg 1 with treatment reversed in Leg 2. The variables measured were melatonin (as 6-sulphatoxymelatonin), rectal temperature, activity, and sleep (actigraphy and logs). In the experiment, 9 of the 10 subjects free ran with Placebo 1st, whereas Melatonin 1st stabilized the sleep-wake cycle to 24 h in 8 of 10 individuals. In addition, 2 individuals showed irregular sleep with this treatment. In some subjects, there was a shortening of the period of the temperature rhythm without synchronization. Melatonin 2nd induced phase advances (5 of 9 subjects), phase delays (2 of 9 subjects), and stabilization (2 of 9 subjects) of the sleep-wake cycle with subsequent synchronization to 24 h in the majority of individuals (7 of 9). Temperature continued to free run in 4 subjects. Maximum phase advances in core temperature were seen when the first melatonin treatment was given approximately 2 h after the temperature acrophase. These results indicate that melatonin was able to phase shift sleep and core temperature but was unable to synchronize core temperature consistently. In the majority of subjects, the sleep-wake cycle could be synchronized.
Daytime sleepiness is a common complaint in blind subjects. Abnor mally timed melatonin has been invoked as a possible cause of both daytime sleepiness and nighttime awakening. In free-running blind individuals, there is an opportunity to assess the relationship between endogenous melatonin rhythms and subjective sleepiness and naps. The aim of this study was to characterize melatonin rhythms and simultaneously to evaluate subjective nap ping. A total of 15 subjects with no conscious light perception (NPL) were studied for 1 month. Prior to the study, sleep disorders were assessed using the Pittsburgh Sleep Quality Index. Cosinor and regression analysis revealed that 9 of the 15 NPL subjects had free-running 6-sulphatoxymelatonin (aMT6s) rhythms (period [τ] range = 24.34 to 24.79 h), 3 were entrained with an abnormal phase, and 3 were normally entrained. Most of the subjects (13 of 15) had daytime naps; the 2 individuals who did not made conscious efforts not to do so. Subjects with abnormal aMT6s rhythms had more naps of a longer duration than did those with normal rhythms. Free-running nap rhythms occurred only in subjects with free-running aMT6s rhythms. The 2 abnormally entrained subjects who napped did so at times that coincided with high levels of aMT6s (mean aMT6s acrophase [phi] ± SD = 14.30 ± 1.08 h, 20.30 ± 0.62 h; mean nap time ± SD = 14.01 ± 3.60 h, 18.23 ± 3.20 h, respectively). Regardless of aMT6s rhythm abnormality, signifi cantly more naps occurred within a 4-h period before and after the estimated aMT6s acrophase. In 4 free-running subjects, aMT6s acrophase (phi) passed through an entire 24-h period. When aMT6s was in a normal phase position (24:00 to 06:00 h), night-sleep duration tended to increase with a significant reduction in the number and duration of naps. Sleep onset and offset times tended to advance and delay as the aMT6s rhythms advanced and delayed. Our results show a striking relationship between the timing of daytime production of melatonin and the timing of daytime naps. This suggests that abnormally timed endogenous melatonin may induce sleepiness in blind subjects.
There has been scant evidence for a phase-shifting effect of melatonin in shift-work or jet-lag protocols. This study tested whether melatonin can facilitate phase shifts in a simulated night-work protocol. Subjects (n = 32) slept in the afternoons/evenings before night work (a 7-h advance of the sleep schedule). They took melatonin (0.5 mg or 3.0 mg) or placebo before the first four of eight afternoon/evening sleep episodes at a time when melatonin has been shown to phase advance the circadian clock. Melatonin produced larger phase advances than placebo in the circadian rhythms of melatonin and temperature. Average phase advances (+/-SD) of the dim light melatonin onset were 1.7 +/- 1.2 h (placebo), 3.0 +/- 1.1 h (0.5 mg), and 3.9 +/- 0.5 h (3.0 mg). A measure of circadian adaptation, shifting the temperature minimum enough to occur within afternoon/evening sleep, showed that only subjects given melatonin achieved this goal (73% with 3.0 mg, 56% with 0.5 mg, and 0% with placebo). Melatonin could be used to promote adaptation to night work and jet travel.
The pineal gland participates in the internal temporal organization of the vertebrate organism by the rhythmic synthesis of its hormone melatonin. This hormone is considered the darkness hormone because of its unique feature of being synthesized exclusively at night, regardless of the organism activity pattern. The presence and absence of this indolamine help to mark, respectively, dark and light time, i.e., night and day, to the organism. Moreover, the daily duration of the secretory episode of melatonin, synchronized to the duration of the night in the environment, times the several physiological regulatory processes in order to adapt the organism to the annual seasonal environmental variation.
The mechanisms of melatonin production are different among the several classes of vertebrates. In fishes, amphibians, some reptiles and birds, the pineal gland is photosensitive, whereas in mammals the photosensitivity is absent. In this case, the light periodical information is conveyed to the gland through a neural pathway that originates in the retina, projects to the hypothalamic suprachiasmatic region, including the suprachiasmatic nuclei (the circadian biological clock in vertebrates) and, then, indirectly to the pineal gland.
The signal that stimulates melatonin synthesis during the dark period of the daily light/dark cycle, in mammals, is the neurotransmitter noradrenaline, which is released from the sympathetic terminals of neurons whose cell body are located in the superior cervical ganglia. This transmitter interacts with adrenoreceptors in the pinealocytes membrane, resulting in cAMP and calcium elevation that induces melatonin synthesis.
The signaling cascade that involves cAMP triggers and/or increases the arylalkylamine N-acetyltransferase transcription and translation, as well as its activation by phosphorylation and association with 14-3-3 protein. This enzyme converts serotonin into N-acetylserotonin that is then transformed by hydroxyindole-O-methyltransferase into melatonin. These two steps occur only at night.
Melatonin, immediately after being synthesized, is released to the systemic circulation and it influences almost every physiological function in the organisms. It regulates the circadian clock, rest-activity and wake-sleep cycles, immunological system, energy metabolism and many other functions. Melatonin also influences the seasonal rhythms through the variation observed in its plasmatic profile duration according to the length of night. Among the seasonal physiological functions modulated by melatonin are reproduction, immune response, and metabolic adaptations and weight.
Melatonin is an ancestral molecule as it appears soon in the evolutionary chain and it is ubiquitous in the living organisms. It seems that early in evolution melatonin could have had an anti-oxidative role, protecting the primitive life from the possible oxidation process mainly dependent on light and aerobiosis. This property is still conserved by its intracellular direct interaction with other molecules involved in oxidation. Besides, melatonin has its proper receptors, known as MT1, MT2 and MT3 which are found in the central nervous system and peripheral organs.
Thus, melatonin is part of a photo-neuroendocrine temporal system, which adapts the organisms to the external environmental cyclic fluctuations, like day and night and the seasons, regulating most of the physiological regulatory processes, including insulin synthesis and action, playing a putative role in the pathophysiology of diabetes mellitus.
Objectives: Elimination of endogenous melatonin by surgical removal of the pineal gland has been widely used in animal studies to examine the roles played by the hormone in physiology and behavior. In humans, pineal resection occurs during the removal of pineal neoplasms. It results in very low (<0.5 pg/ml plasma) or undetectable melatonin levels, generally without a discernible circadian rhythm. Pineal tumor resection thus provides a unique clinical model to assess the putative role of melatonin in sleep regulation, circadian rhythmicity and seasonality. We examined self-reported sleep characteristics, circadian chronotype, mood disturbance and seasonal variation in subjects who had undergone pineal tumor resection. Methods: Subjects (n=13; 62% male) ranged in age from 23.5 to 64.0 y (mean ± SD: 40.4 ± 12.2 y) and had undergone surgery 0.5 to 6.5 years earlier. Four patients had presented with pineal cysts and 9 with various tumors. Gross resection was performed in 11 cases, while 2 patients received an estimated 40% and 70-90% pineal excision, respectively. Seven did not require postoperative radiation or chemotherapy, while 4 received both, 1 received radiation treatment only, and 1 received chemotherapy without radiation. They received a battery of standardized self-assessment instruments including the Sleep Disorders Questionnaire (SDQ), the Morningness-Eveningness Questionnaire (MEQ), and the Personal Inventory for Depression and SAD (PIDS), which provides a global seasonality score and itemizes criteria for major depressive disorder in the past year. Overnight urine samples were collected to measure the concentration of 6-sulphatoxymelatonin (aMT6s) as an indicator of residual pineal function. Results: Three subjects were at high risk for sleep apnea (SA, n=2) or periodic leg movements (PLM, n=1), with scores above the 90 th %ile in the corresponding SDQ indices. Additionally, 10 SDQ items were extracted to obtain an estimate of insomnia (i.e., difficulty falling asleep, poor/disturbed sleep, and wakefulness during sleep) independent of other sleep disorders. Nine subjects (69%) reported at least one of these symptoms at least "sometimes", while 6 (46%) reported them at least "usually", and 5 (38%) "always". Four subjects (31%) reported sleeping less than 6 h (in one case, <5 h), while the longest wake episode during sleep was estimated at >20 min by 10 subjects (80%), >60 min by 7 (54%), and >120 min by 2 (15%). Two subjects used sleep medications, while 3 used melatonin supplements PRN (discontinued at least two days prior to urine collection). Seven subjects (58%) reported clinically significant symptoms of depression, although only 3 used antidepressants. The MEQ indicated that no one was an extreme circadian type: 6 subjects (46%) were rated as moderate morning types, 1 (8%) as a moderate evening type, and 6 (46%) as neither type. The global seasonality score averaged 5.0 ± 3.1, which indicates negligible seasonal mood variation similar to that of the nonseasonal subgroup of a random sample of New York City residents, and well below the overall population mean 1. In all subjects, nocturnal urinary concentration of aMT6s, assessed using the ELISA method (Bühlmann Laboratories, Switzerland), showed abnormally low nighttime levels of the metabolite, below the detection limit of the assay (0.3 ng/ml). Conclusions: These results suggest a moderate incidence of sleep and mood disturbance in pineal surgery patients, with little seasonal variation in mood and behavior and no extreme chronotypes. A larger sample, using direct measurement (polysomnography, psychiatric examination) of potential pathology or other abnormalities, and extra-pineal surgical controls, are needed to ascertain the reliability of these findings, the validity of the self-reports and their specificity to patients lacking endogenous melatonin.
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.
The purpose of this study was to test the phase-shifting and entraining effects of melatonin in human subjects. Five totally blind men were found in a previous study to have free-running endogenous melatonin rhythms. Their rhythms were remarkably stable, so that any deviation from the predicted phase was readily detectable. After determination of their free-running period and phase, they were given exogenous melatonin (5 mg) at bedtime (2200 hr) for 3 weeks, in a double-blind, placebo-controlled trial. The effects on the endogenous melatonin rhythm were assessed at intervals ranging from several days to 2 weeks. Exogenous administration of melatonin phase-advanced their endogenous melatonin rhythms. In three of the subjects, cortisol was shown to be phase-shifted in tandem with the melatonin rhythm. A sixth subject [one of the coauthors (JS)] was previously found to have free-running cortisol and temperature rhythms and was plagued by recurrent insomnia and daytime sleepiness. He had tried unsuccessfully to entrain his rhythms for over 10 years. After he took melatonin (7 mg at 2100 hr), his insomnia and sleepiness resolved. Determination of his endogenous melatonin rhythm after about a year of treatment demonstrated endogenous rhythms that appeared normally entrained. The treatment of blind people with free-running rhythms has many advantages for demonstrating chronobiological effects of hormones or drugs.
The hormone melatonin is currently proposed by some investigators to be an efficient means for decreasing the impairing effects of jet lag. Eight healthy male subjects, aged 20 to 32, underwent a 9-hr advance shift in the isolation facility of our institute during two periods each of 15 days' duration. In a double-blind, crossover design, subjects took either melatonin or placebo at 1800 hr local time for 3 days before the time shift and at 1400 hr for 4 days afterwards. The time shift was simulated on days 7 and 8 by shortening the sleep period by 6 hr and the following wake period by 3 hr. Body temperature was recorded every 90 min, and urine was collected at 3-hr intervals all day and night. Melatonin treatment enhanced the resynchronization speed of some, but not all, hormone and electrolyte excretion rates for several days after the time shift. The adaptation speed of the temperature rhythm significantly increased during one postshift day. In addition, the circadian temperature rhythm had a significantly higher amplitude under melatonin treatment than under placebo after the time displacement. For the placebo group, the rhythm of 6-hydroxymelatoninsulfate excretion exhibited an advance shift in five subjects, whereas the other three showed a delay shift, and adjustment did not achieve more than one-half of the expected value within 8 days. A significantly different adjustment could be observed in the melatonin-treated group: Seven subjects underwent an advance shift of the expected 9 hr within an average of 8 days. The results suggest that melatonin treatment can accelerate resynchronization of the melatonin excretion rhythm after eastward time zone transitions. The improvement is not, however, sufficiently great that we can recommend melatonin for the alleviation of jet lag.
Early morning rectal body temperature is lowest when melatonin levels are highest in humans. Although pharmacological doses of melatonin are hypothermic in humans, the relationship between endogenous melatonin and temperature level has not been investigated. We measured rectal body temperature in nine normal men whose melatonin levels were suppressed by all-night sleep deprivation in bright light and compared values with those seen in sleep in the dark, sleep deprivation in dim light (to control for the stimulatory effect of wakefulness on temperature), and sleep deprivation in bright light with an infusion of exogenous melatonin that replicated endogenous levels. Minimum rectal temperature, calculated from smoothed temperature data from 2300 to 0515 h, was greater in bright-light sleep deprivation, resulting in suppression of melatonin, than in conditions of sleep deprivation in dim light or sleep in the dark. An exogenous melatonin infusion in bright light returned the minimum temperature to that seen in dim-light sleep deprivation. A nonsignificant elevation in mean and minimum temperature was noted in all conditions of sleep deprivation relative to sleep. We conclude that melatonin secretion contributes to the lowering of core body temperature seen in the early morning in humans.
In most species daily and seasonal changes in the light-dark cycle are the most important synchronisers (zeitgebers) of daily and seasonal rhythms. In humans only bright light (2500 lux) appears to be an effective circadian zeitgeber. Seasonal effects of light on human physiology have not been investigated. We have exploited the low intensity illumination of the Antarctic winter to investigate the effects of bright- or dim-light treatment for an hour in the morning and in the evening (a 'skeleton' 12.5-h day) for 6 weeks on the plasma melatonin rhythm, together with mood and a number of behavioural variables. In parallel seasonal changes in melatonin were observed. Melatonin is known to convey daylength information in photoperiodic seasonal breeders through characteristics of its night-time secretion profile. Bright-, but not dim-, light treatment in winter induced a marked phase advance of the melatonin rhythm, similar to that found in the summer, without marked effect on the other variables. Thus at least one human seasonal change appears to be light-dependent.
The pineal gland hormone melatonin may play a role in synchronization of rat circadian rhythms. Free-running activity rhythms
of the rat were entrained by a daily melatonin injection, with entrainment occurring when the onset of activity coincided
with the time of daily injections. When injections were stopped, activity rhythms became free-running again. Thus in pharmacological
experiments, the time of day of melatonin administration is crucial.
We examined effects of very low doses of melatonin (0.1-10 mg, orally) or placebo, administered at 1145 h, on sleep latency and duration, mood, performance, oral temperature, and changes in serum melatonin levels in 20 healthy male volunteers. A repeated-measure double-blind Latin square design was used. Subjects completed a battery of tests designed to assess mood and performance between 0930 and 1730 h. The sedative-like effects of melatonin were assessed by a simple sleep test: at 1330 h subjects were asked to hold a positive pressure switch in each hand and to relax with eyes closed while reclining in a quiet darkened room. Latency and duration of switch release, indicators of sleep, were measured. Areas under the time-melatonin concentration curve varied in proportion to the different melatonin doses ingested, and the 0.1- and 0.3-mg doses generated peak serum melatonin levels that were within the normal range of nocturnal melatonin levels in untreated people. All melatonin doses tested significantly increased sleep duration, as well as self-reported sleepiness and fatigue, relative to placebo. Moreover, all of the doses significantly decreased sleep-onset latency, oral temperature, and the number of correct responses on the Wilkinson auditory vigilance task. These data indicate that orally administered melatonin can be a highly potent hypnotic agent; they also suggest that the physiological increase in serum melatonin levels, which occurs around 2100 h daily, may constitute a signal initiating normal sleep onset.
It is now well acknowledged that napping constitutes an inherent component of the human circadian system. To date, however, few studies have examined the effects of spontaneous napping on human free-running rhythms. This study investigated the free-running circadian periods of rest/activity and body core temperature in a group of young subjects who were permitted to nap during their time in isolation. Based on the frequency of self-reported sleep bouts, subjects were classified as Nappers or Nonnappers. Nappers exhibited free-running rhythms in both rest/activity and body core temperature that were not significantly different from 24 hours. Nappers showed a tendency for shorter free-running periods in both variables, when compared with Nonnappers. These findings emphasize the need for careful reassessment of data obtained from traditional free-run protocols.
The phase-shifting capacity and thermoregulatory effects of a single oral administration at 18 h of melatonin (5 mg) or S-20098, a melatonin agonist (5 or 100 mg), was investigated in eight healthy young men in a double-blind placebo crossover design. The unmasking conditions of a shortened constant-routine protocol (mini-CR) were used to collect evening phase markers of physiological parameters. In comparison to placebo, all three drug administrations induced an earlier dim-light melatonin onset (DLMO), an earlier increase in distal skin temperature, and an earlier decrease in core body temperature (CBT), heart rate, and proximal skin temperature. This indicates that administration at 18 h of both melatonin and S-20098 (more pronounced with 100 than 5 mg) induced an earlier regulation of the endogenous circadian nocturnal decline in CBT. On the posttreatment day a second mini-CR revealed persistent significantly phase-advanced circadian rhythms as estimated by DLMO, as well as by the midrange crossing time of CBT and heart rate decline. There were no significant differences between the two doses of S-20098. The data suggest that, in addition to immediate thermoregulatory changes, a phase advance of the circadian system had occurred and that the phase advance could still be measured on the posttreatment day.
The endogenous circadian rhythm of melatonin, driven by the suprachiasmatic nucleus, exhibits a close association with the endogenous circadian component of the sleep propensity rhythm and the endogenous circadian component of the variation in electroencephalogram (EEG) oscillations such as sleep spindles and slow waves. This association is maintained even when the sleep-wake cycle is desynchronized from the endogenous circadian rhythm of melatonin. Administration of melatonin during the day increases daytime sleep propensity as indexed by both the latency to sleep onset and sleep consolidation. The EEG during daytime sleep after melatonin administration exhibits characteristics reminiscent of the nocturnal sleep EEG, that is, increased sleep spindle activity and reduced slow-wave sleep and slow-wave activity as detected by quantitative EEG analysis. Administration of higher doses of melatonin (5 mg or more) prior to nocturnal sleep results in an increase in rapid eye movement (REM) sleep. These data demonstrate that melatonin exerts effects on the main characteristics of human sleep, that is, latency to sleep onset, sleep consolidation, slow waves, sleep spindles, an M sleep. There is a need for further studies using physioloRical doses and delivery systems that generate physiological plasma melatonin profiles to firmly establish the role of the endogenous circadian rhythm of melatonin in the circadian regulation of sleep.
Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The pres suggest, however, that although leep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.
Although the causes are different, totally blind people (without light perception) and night shift workers have in common recurrent bouts of insomnia and wake-time sleepiness that occur when their preferred (or mandated) sleep and wake times are out of synchrony with their endogenous circadian rhythms. In this article, the patterns of circadian desynchrony in these two populations are briefly reviewed with special emphasis on longitudinal studies in individual subjects that used the timing of melatonin secretion as a circadian marker. In totally blind people, the most commonly observed pattern is a free-running rhythm with a stable non-24-h circadian period (24.2-24.5 h), although some subjectively blind people are normally entrained, perhaps by residually intact retinoypothalamic photic pathways. Experiments at the cellular and behavioral levels have shown that melatonin can produce time dependent circadian phase shifts. With this in mind, melatonin has been administered to blind people in an attempt to entrain abnormal circadian rhythms, and substantial phase shifts have been accomplished; however, it remains to be demonstrated unequivocally that normal long-term entrainment can be produced. In untreated night shift workers, the degree and direction of phase shifting in response to an inverted sleepwake schedule appears to be quite variable. When given at the optimal circadian time, melatonin treatment appears to facilitate phase shifting in the desired direction. Melatonin given prior to a night worker's daytime sleep also may attenuate interference from the circadian alerting process. Because melatonin has both phase-shifting and sleep-promoting actions, night shift workers, who number in the millions, may be the most likely group to benefit from treatment.
Evidence obtained in animals has suggested a link of the pineal gland and its hormone melatonin with the regulation of core body temperature (CBT). Depending on the species considered, melatonin intervenes in generating seasonal rhythms of daily torpor and hibernation, in heat stress tolerance, and in setting the CBT set point. In humans, the circadian rhythm of melatonin is strictly associated with that of CBT, the nocturnal decline of CBT being inversely related to the rise of melatonin. Whereas there is inconsistent evidence for the suggestion that the decline of CBT may prompt the release of melatonin, conversely, stringent data indicate that melatonin decreases CBT. Administration of melatonin during the day, when it is not normally secreted, decreases CBT by about 0.3 to 0.4°C, and suppression of melatonin at night enhances CBT by about the same magnitude. Accordingly, the nocturnal rise of melatonin contributes to the circadian amplitude of CBT. The mechanisms through which melatonin decreases CBT are unclear. It is known that melatonin enhances heat loss, but a reduction of heat production cannot be excluded. Besides actions on peripheral vessels aimed to favor heat loss, it is likely that the effect of melatonin to reduce CBT is exerted mainly in the hypothalamus, where thermoregulatory centers are located.Recentobservationshaveshownthattheacutethermoregulatoryeffects induced by melatonin and bright light are independent of their circadian phase-shifting effects. The effect of melatonin ultimately brings a saving of energy and is reduced in at least two physiological situations: aging and the luteal menstrual phase. In both conditions, melatonin does not exert its CBT-lowering effects. Whereas in older women this effect may represent an age-related alteration, in the luteal phase this modification may represent a mechanism of keeping CBT higher at night to promote a better embryo implantation and survival.
This review discusses the issue of a dual effect of melatonin on sleep: acute sleep promotion that typically occurs within one hour of administration, and the ability to alter the phase of an underlying circadian pacemaker after a repeated melatonin treatment. The authors suggest that both mechanisms are at work, that they are complementary, and that they may manifest jointly or separately. The review provides some basic information on melatonin, an overview of the literature, and the authors' experience in studying the acute effects of melatonin treatment in humans of different age groups. This review also illustrates the authors' cautious attitude toward melatonin treatment that induces supraphysiologic circulating levels of the hormone.
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.
The homeostatic regulation of non-rapid eye-movement sleep (NREMS) consists of the changes in both duration and intensity, the latter being reflected by EEG slow-wave activity (SWA). In some species, the seasonal changes have a prominent effect on behavior and on physiological variables, and specific, seasonally recurring behaviors, such as breeding and torpor, are triggered by the photoperiod. During emergence from torpor, SWA rapidly increased to a level that significantly exceeded the baseline value. The increase of SWA and the spectral changes of the sleep EEG after emergence from torpor closely resembled the increase of SWA after 4-hour sleep deprivation. However, the effect of torpor was shorter lasting. To control for the metabolic exertion during the rise of body temperature, the emergence from torpor was promoted by heating the animal. The increase of SWA after this manipulation did not differ from the rise following the unaided termination of torpor. Taken together, these studies, as well as the hibernation experiments, strongly indicate that Process S builds up not only during waking but also in the course of other non-sleep states. They point to the exquisite role of sleep that alone can reduce the level of S.
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.
The effects of melatonin (MT) and placebo (P) on adaptation to a rapid 9-h advance phase shift, in the presence and absence of inappropriate bright light (BL) exposure were examined. Volunteers were initially subjected to a gradual 9-h delay phase shift over 5 days (D1–D5) using a combination of bright light and darkness/sleep. Readaptation to a subsequent rapid 9-h advance phase shift was studied using: 1) MT, 5 mg, 2300 h, D6–D8, 2) BL, 2,000 lx, 0800–1200 h, D7–D8, 3) MT + BL and 4) P, 2300 h, D6–D8. MT treatment was timed to phase advance and BL to phase delay. BL delayed the 6-sulphatoxymelatonin rhythm in five out of seven subjects. Two subjects delayed and five phase advanced with both MT and MT + BL. MT consistently improved subjective sleep, alertness, and performance even in the presence of inappropriate BL and before phase readaptation had occurred. BL improved alertness and performance transiently. The beneficial effects of MT are not wholly mediated through an effect on the biological clock.
Although melatonin treatment has been shown to phase shift human circadian rhythms, it still remains ambiguous as to whether exogenous melatonin can entrain a free-running circadian system. We have studied seven blind male subjects with no light perception who exhibited free-running urinary 6-sulphatoxymelatonin (aMT6s) and cortisol rhythms. In a single-blind design, five subjects received placebo or 5 mg melatonin p.o. daily at 2100 h for a full circadian cycle (35-71 days). The remaining two subjects also received melatonin (35-62 days) but not placebo. Urinary aMT6s and cortisol (n=7) and core body temperature (n=1) were used as phase markers to assess the effects of melatonin on the During melatonin treatment, four of the seven free-running subjects exhibited a shortening of their cortisol circadian period (tau). Three of these had taus which were statistically indistinguishable from entrainment. In contrast, the remaining three subjects continued to free-run during the melatonin treatment at a similar tau as prior to and following treatment. The efficacy of melatonin to entrain the free-running cortisol rhythms appeared to be dependent on the circadian phase at which the melatonin treatment commenced. These results show for the first time that daily melatonin administration can entrain free-running circadian rhythms in some blind subjects assessed using reliable physiological markers of the circadian system.
During time-zone travel, the endogenous melatonin rhythm is often out of phase with the new local time cues. Since endogenous melatonin could act as an endogenous zeitgeber, when its secretory rhythm is out of phase it may hinder adaptation by natural zeitgebers. It is possible that by temporarily suppressing the production of melatonin, by beta-blockers for example, adaptation may be facilitated. In a double-blind, crossover study eight healthy volunteers (aged 23-30 years) took 100 mg atenolol or placebo at 1900 h on Day (D) 1. Volunteers were then exposed to bright light (approx. 1000 lux) from 0000 to 0400 h during the following night and remained in dim light (<50 lux) or darkness until 1200 h on D3. Salivary melatonin (MT) and urinary 6-sulphatoxymelatonin (aMT6s) were measured every 30-60 min and every 2 h (except when asleep), respectively. Subjective alertness and core body temperature (cBT) were also measured. aMT6s and MT were significantly suppressed under atenolol treatment on the night of D1 only. Atenolol significantly phase delayed the salivary melatonin onset by 1.8+/-0.6 h and 1.28+/-0.35 h compared with the onsets on D1 placebo leg and D2 placebo leg (i.e. onset times before and after light treatment), respectively. There were no detrimental effects on cBT or alertness. Temporary suppression of melatonin by beta-blockers may facilitate adaptation to phase shifts.
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.
The actions of melatonin on the sleep-wake cycle were investigated by means of a randomised, double-blind, placebo-controlled trial in 8 subjects with a delayed sleep phase syndrome attending a sleep disorders clinic. In randomised order the subjects received placebo or melatonin 5 mg daily for 4 weeks with a 1 week washout period between the treatments. Drug or placebo was given at 2200 h, 5 h before the mean time of sleep onset determined by pretrial sleep logs. In all 8 subjects sleep onset time (mean advance 82 [range 19-124] min; p less than 0.01) and wake time (117 [10-187] min; p less than 0.01) were significantly earlier during melatonin treatment than during placebo. Mean total sleep time was slightly less on melatonin (8 h 12 min) than on placebo (8 h 46 min). Alertness acrophase calculated from the subjects' ratings of alertness made every 2 h while awake was unaltered. Melatonin may act as a phase-setter for sleep-wake cycles in subjects with a delayed sleep phase syndrome.
The geographic isolation and the prolonged absence of sunlight during winter make Antarctica an interesting environment for studying circadian rhythms. This study explored the effects of wintering on sleep, hormonal, and electrolyte rhythms in four human subjects living in a small Antarctic base. Up to the last sunset sleep, 6-sulfatoxymelatonin, cortisol, sodium, and potassium rhythms were synchronized within clock time. During the 126 days of winter, when there was no sunlight, the circadian rhythms of all measures free ran in each individual. For example, the free-running periods for the cortisol excretory rhythm were 24 h 29 min, 24 h 45 min, 25 h 7 min, and 25 h 14 min for subjects C, J, K, and G, respectively. The period lengths of C, J, and K were significantly different, whereas there was no significant difference between K and G. The phase relationships between each rhythm remained constant in three out of the four subjects. Total daily output and rhythm amplitude for 6-sulfatoxymelatonin, potassium, and sodium remained constant during the entrained and free-running stages of the study. Significant changes in total daily cortisol excretion were observed during the year with one subject producing less and two subjects more while the rhythms were free running. When the sun reappeared during spring, all rhythms again synchronized and entrained to the daylight. These results show that 1) circadian rhythms can free run, even when the subjects have knowledge of time; and 2) within a small communal group, individuals can maintain unique free-running periods.
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At two different times of year (spring and autumn) an oral preparation of the pineal neurohormone melatonin, or placebo, was administered to 12 healthy volunteers (10 men and two women in spring: the same group minus one man in autumn) daily at 1700 h for 1 month (spring), or 3 weeks (autumn) using a double-blind cross-over protocol. The daily dose was 2 mg melatonin in 5 ml corn-oil, and placebo consisted of the vehicle only. In spring the anterior pituitary hormones LH, PRL, GH together with T4, cortisol, testosterone and melatonin were measured at 1- to 6-h intervals for 24 h in plasma on the day following the last dose. In autumn PRL, cortisol and melatonin levels were measured on the last day of treatment. Subjective fatigue, mood and sleep records were kept throughout the studies. Melatonin increased early evening fatigue and actual sleep, but had no effect on mood: these results are reported in full elsewhere. Melatonin administration had no effect on the levels or 24-h rhythm of LH, GH, T4, testosterone or cortisol. An earlier fall in the nocturnal PRL was observed on both occasions. Overall PRL levels were higher in spring than in autumn. In five of the subjects, the secretion of endogenous melatonin was advanced by 1-3 h in the presence of exogenous melatonin. These observations suggest that the potential therapeutic use of melatonin as a hypnotic or in the treatment of jet lag is unlikely to be complicated by undesirable endocrine effects.
Importance of the pineal and melatonin in human physiologyAdministration of melatonin to healthy volunteers without environmental controlAdministration of melatonin to healthy volunteers in environmental isolationMelatonin metabolitesStudies on the control of melatonin secretion in humans using a novel assay for a MT6sConclusions
ReferencesDiscussionReferences
In a double-blind cross-over study, melatonin (2 mg) or placebo, was administered daily for 4 weeks to 12 volunteers (10 men and 2 women) at 17.00 h during February and March. Self-rated fatigue (tiredness) was significantly increased in the evening during melatonin treatment. No other consistent effects on sleep ratings or mood parameters were observed and the dose was well tolerated.
The effect of melatonin, para-chlorophenyl alanine (PCPA), gamma-aminobutyric acid (GABA) and dibutyryl-cAMP (d-cAMP) on the photoentrainment of the circadian adrenocortical rhythm was studied by the intrahypothalamic (near the SCN) implantation of a paraffin pellet mixed with each agent, in the rat. 2 weeks after implantation, the rats were moved to a room with a reversed lighting cycle (from LD to DL). Blood samples were taken from individual rats at 4-hour intervals for 24 h, and 2, 4, 6 and 10 days after movement, by the tail tip incision method. The effects of implantation of PCPA, GABA and d-cAMP on the reentrainment to the illumination cycle reversed were indistinguishable from those due to implantation of a pellet of paraffin alone. In these groups, more than half of the rats did not reentrain to the light cycle reversed in 4 (less than 18.1%) and 6 days (less than 36.3%), but did reentrain in 10 days. However, melatonin caused reentrainment of the circadian adrenocortical rhythm to reversed illumination between 4 (45.4%) and 6 days (72.7%). Pinealectomized rats receiving a melatonin pellet also exhibited an accelerated reentrainment to the light cycle reversed, when compared with the rat which received a pellet of paraffin alone. However, pinealectomized rats which received a pellet of paraffin alone did not require more time than intact rats to reentrain to the light cycle reversed. These results indicate that melatonin accelerates the reentrainment of the circadian adrenocortical rhythm to the light cycle reversed.
Serum melatonin concentrations were determined by RIA in 81 healthy humans, aged 1-92 yr. The daytime (0900-1100) serum levels of melatonin decreased progressively with advancing age. No sex difference was noted. The nocturnal rise of serum melatonin in the aged group was significantly reduced compared with that in the young group. These results suggest that serum melatonin may be secreted under the age-related neural control of pineal metabolism.
A single physiological dose of melatonin (20 micrograms for 3 h given intravenously at different times of the day (04.00-12.00, 16.00 and 20.00 h) was able to shift the endogenous plasma melatonin profile of healthy volunteers under entrained conditions according to a phase-response curve (PRC). ANOVA showed an effect of the time of administration on the onset, the acrophase or the offset of the melatonin profiles. These profiles were significantly delayed when the infusion was administered at 12.00 h and advanced when the infusion was given at 20.00 h. Further, the AUCs evaluated on the nocturnal melatonin profiles were increased after the 04.00 h infusion (+20.5%, p < 0.05), whereas they were decreased after the 12.00 h infusion (-20%, p < 0.05). Lastly, no alteration was observed for cortisol rhythm, whatever the time of melatonin administration. These results, which show that according to a PRC the system regulating melatonin secretion is sensitive to a single short-term administration of the hormone given at a low dose, support the paradigm of the endogenous synchronizer melatonin.
In animals, circadian pacemakers respond to seasonal changes in day length by making corresponding adjustments in the durations of diurnal and nocturnal periods of circadian rhythms; these adjustments mediate effects of photoperiod on breeding and other seasonally recurring phenomena. Little is known about photoperiod responses of human circadian pacemakers. To investigate this question, we recorded and compared circadian rhythm profiles of 15 individuals after chronic exposures to short (8 h) and long (14 h) nights. As occurs in animals, durations of nocturnal periods of active melatonin secretion (11.9 +/- 1.6 vs. 10.3 +/- 1.3 h, df = 14, t = 4.583, P < 0.0005, paired t test), high prolactin secretion (12.9 +/- 2.1 vs. 9.9 +/- 2.2 h, df = 11, t = 2.917, P < 0.01), and sleep (10.6 +/- 0.8 vs. 7.6 +/- 0.4 h, df = 14, t = 17.122, P < 0.0005) were longer after exposure to long nights than after short ones. Durations of nocturnal periods of low rectal temperature (11.6 +/- 2.3 vs. 9.5 +/- 1.6 h, df = 12, t = 3.912, P < 0.001) and rising cortisol secretion (10.8 +/- 1.6 vs. 9.3 +/- 1.9 h, df = 14, t = 3.130, P < 0.005) were also longer. Some of these differences persisted during 24-h periods of enforced wakefulness in constant dim light, indicating that prior exposure to the two regimes induced abiding changes in the timing of internal processes, such as circadian pacemaker oscillations, that control the durations of nocturnal and diurnal periods of the rhythms.
The pineal hormone melatonin is potentially useful in the treatment of disorders, especially sleep disorders, associated with circadian rhythm disturbance. We have examined its effects on sleep, mood, and behaviour in a double-blind, placebo-controlled study of a small group of police officers working spans of seven successive night shifts. Compared to placebo, and to no treatment, melatonin (5 mg) taken at the desired bedtime improved problems related to sleep and increased alertness during working hours, especially during the early morning. In letter-target performance tests visual search speed and accuracy were either unchanged or slightly improved. Memory scanning speed and perception of mental load were adversely affected. This preliminary study suggests that melatonin has beneficial effects on sleep and alertness, but that its effects on performance need careful evaluation.
Melatonin is able to phase-shift the endogenous circadian clock and can induce acute temperature suppression. It is possible that there is a direct relationship between these phenomena. In a double-blind, placebo-controlled crossover study, 6 healthy volunteers maintained a regular sleep/wake cycle in a normal environment. From dusk until 24:00 h on days (D) 1-4 subjects remained in dim artificial lighting (< 50 lux) and darkness (< 1 lux) from 24:00-08:00 h. At 17:00 h on D3 either melatonin (0.05 mg, 0.5 mg or 5 mg) or placebo was administered. Melatonin treatment induced acute, dose-dependent temperature suppression and decrements in alertness and performance efficiency. On the night of D3, earlier sleep onset, offset and better sleep quality were associated with increasing doses of melatonin. The following day, a significant dose-dependent phase-advance in the plasma melatonin onset time and temperature nadir (D4-5) was observed with a trend for the alertness rhythm to phase-advance. A significant dose-response relationship existed between the dose of oral melatonin, the magnitude of temperature suppression and the degree of advance phase shift in the endogenous melatonin and temperature rhythms, suggesting that acute changes in body temperature by melatonin may be a primary event in phase-shifting mechanisms.
Melatonin's timekeeping function is undoubtedly related to the fact that it is primarily produced during nighttime darkness; that is, melatonin and light occur at opposite times. The human phase response curve (PRC) to melatonin appears to be about 12h out of phase with the PRC to light. These striking complementarities, together with light's acute suppressant effect on melatonin production, suggest that a function for endogenous melatonin is to augment entrainment of the circadian pacemaker by the light-dark cycle. The melatonin PRC also indicates correct administration times for using exogenous melatonin to treat circadian phase disorders.
Delayed sleep phase syndrome (DSPS) involves a mismatch between the usual daily schedule required by the individual's environment and his or her circadian sleep-wake pattern. Patients suffering from DSPS are treated with chronotherapy, light therapy, or melatonin administration. While chronotherapy and light therapy are demanding and difficult treatments that usually lead to compliance problems, melatonin administration is a relatively simple and easy treatment option. Previous studies carried out on relatively small samples of DSPS patients have shown that melatonin has a sleep-promoting and entraining action when taken in the evening. The present study, which accompanied routine treatment in our sleep clinic, examined the efficiency of melatonin treatment in a relatively large population of DSPS subjects by means of subjective reports. The 61 subjects, 37 males and 24 females, were diagnosed with DSPS by means of clinical assessment and actigraphy at our sleep clinic. Their mean pretreatment falling asleep and waking times were 03:09 (SD = 86.22 minutes) and 11:31 (SD = 98.58 minutes), respectively. They were treated with a 6-week course of 5 mg of oral melatonin taken daily at 22:00. A survey questionnaire was sent to the home of each subject 12-18 months after the end of the treatment; the survey investigated the efficiency of the melatonin treatment and its possible side effects. Of the patients, 96.7% reported that the melatonin treatment was helpful, with almost no side effects. Of these, 91.5% reported a relapse to their pretreatment sleeping patterns within 1 year of the end of treatment. Only 28.8% reported that the relapse occurred within 1 week. The pretreatment falling asleep and waking times of patients in whom the changes were retained for a relatively long period of time were significantly earlier than those of patients whose relapse was immediate (t = 2.18, p < .05; t = 2.39, p < .05, respectively), with no difference in sleep duration. The implications of these findings, as well as further research possibilities, are discussed.
In a double-blind placebo-controlled cross-over study, 30 patients with Delayed Sleep Phase Syndrome (DSPS) were included, of whom 25 finished the study. Melatonin 5 mg was administered during two weeks in a double-blind setting and two weeks in an open setting successively or interrupted by two week of placebo. The study's impact was assessed by measurements of the 24-h curves of endogenous melatonin production and rectal temperature (n = 14), polysomnography (n = 22), actigraphy (n = 13), sleep log (n = 22), and subjective sleep quality (n = 25). Mean dim light melatonin onset (DLMO) (+/- SD), before treatment, occurred at 23.17 hours (+/- 138 min). Melatonin was administered five hours before the individual DLMO. After treatment, the onset of the nocturnal melatonin profile was significantly advanced by approximately 1.5 hour. Body temperature trough did not advance significantly. During melatonin use, actigraphy showed a significant advance of sleep onset and polysomnography, a significant decreased sleep latency. Sleep architecture was not influenced. During melatonin treatment patients felt significantly more refreshed in the morning. These results show that analysis of DLMO of patients suffering from DSPS is important both for diagnosis and therapy. These results are discussed in terms of the biochemistry of the pineal.
The contribution of the circadian timing system to the age-related advance of sleep-wake timing was investigated in two experiments. In a constant routine protocol, we found that the average wake time and endogenous circadian phase of 44 older subjects were earlier than that of 101 young men. However, the earlier circadian phase of the older subjects actually occurred later relative to their habitual wake time than it did in young men. These results indicate that an age-related advance of circadian phase cannot fully account for the high prevalence of early morning awakening in healthy older people. In a second study, 13 older subjects and 10 young men were scheduled to a 28-h day, such that they were scheduled to sleep at many circadian phases. Self-reported awakening from scheduled sleep episodes and cognitive throughput during the second half of the wake episode varied markedly as a function of circadian phase in both groups. The rising phase of both rhythms was advanced in the older subjects, suggesting an age-related change in the circadian regulation of sleep-wake propensity. We hypothesize that under entrained conditions, these age-related changes in the relationship between circadian phase and wake time are likely associated with self-selected light exposure at an earlier circadian phase. This earlier exposure to light could account for the earlier clock hour to which the endogenous circadian pacemaker is entrained in older people and thereby further increase their propensity to awaken at an even earlier time.
Fifteen human subjects were exposed to natural outdoor summer light from 0415 h until 2000 h for 4 days and then from 0800 h until 1600 h for another 4 days. Following shortening of the natural summer photoperiod, times of the morning salivary melatonin decline and cortisol rise did not change whereas the time of the evening melatonin rise phase advanced by about 1.5 h within 1 day and further did not change significantly. Consequently, the melatonin signal duration extended markedly within 1 day. The data show that the compressed melatonin rhythm waveform in humans experiencing a long natural summer photoperiod from sunrise until sunset may change rapidly following a shortening of the photoperiod.