Jet lag: therapeutic use of melatonin and possible application of melatonin analogs

Each year millions of travelers undertake long distance flights over one or more continents. These multiple time zone flights produce a constellation of symptoms known as jet lag. Familiar to almost every intercontinental traveler is the experience of fatigue upon arrival in a new time zone, but almost as problematic are a number of other jet lag symptoms. These include reduced alertness, nighttime insomnia, loss of appetite, depressed mood, poor psychomotor coordination and reduced cognitive skills, all symptoms which are closely affected by both the length and direction of travel. The most important jet lag symptoms are due to disruptions to the body's sleep/wake cycle. Clinical and pathophysiological studies also indicate that jet lag can exacerbate existing affective disorders. It has been suggested that dysregulation of melatonin secretion and occurrence of circadian rhythm disturbances may be the common links which underlie jet lag and affective disorders. Largely because of its regulatory effects on the circadian system, melatonin has proven to be highly effective for treating the range of symptoms that accompany transmeridian air travel. Additionally, it has been found to be of value in treating mood disorders like seasonal affective disorder. Melatonin acts on MT(1) and MT(2) melatonin receptors located in the hypothalamic suprachiasmatic nuclei, the site of the body's master circadian clock. Melatonin resets disturbed circadian rhythms and promotes sleep in jet lag and other circadian rhythm sleep disorders, including delayed sleep phase syndrome and shift-work disorder. Although post-flight melatonin administration works efficiently in transmeridian flights across less than 7-8 times zones, in the case longer distances, melatonin should be given by 2-3 days in advance to the flight. To deal with the unwanted side effects which usually accompany this pre-departure treatment (acute soporific and sedative effects in times that may not be wanted), the suppression of circadian rhythmicity by covering symmetrically the phase delay and the phase advance portions of the phase response curve for light, together with the administration of melatonin at local bedtime to resynchronize the circadian oscillator, have been proposed. The current view that sleep loss is a major cause of jet lag has focused interest on two recently developed pharmacological agents. Ramelteon and agomelatine are melatonin receptor agonists which, compared to melatonin itself, have a longer half-life and greater affinity for melatonin receptors and consequently are thought to hold promise for treating a variety of circadian disruptions.     

Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment.

Smith-Magenis syndrome (SMS) is a mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features and congenital anomalies ascribed to an interstitial deletion of chromosome 17p11.2. Severe sleep disturbances and maladaptative daytime behavior have been linked to an abnormal circadian secretion pattern of melatonin, with a diurnal instead of nocturnal secretion of this hormone. SMS provides a demonstration of a biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate the generation of the circadian rhythm, haploinsufficiency for a circadian system gene, mapping to chromosome 17p11.2 might cause the inversion of the melatonin circadian rhythm in SMS. The disorder of circadian timing in SMS might also affect the entrainment pathway (retinohypothalamic tract), pacemaker functions (suprachiasmatic nucleus) or synthesis and release of melatonin by the pineal gland. Elucidating pathophysiological mechanisms of behavioral phenotypes in genetic disease can provide an original therapeutic approach in SMS: blockade of endogenous melatonin production during the day combined with exogenous melatonin administration in the evening.     

Selectively filtering short wavelengths attenuates the disruptive effects of nocturnal light on endocrine and molecular circadian phase markers in rats

Various physiological processes exhibit a circadian rhythm synchronized to the geophysical light/dark cycle. Our study using a rat model demonstrated that exposure to light at night suppressed the expected nocturnal rise in melatonin, increased plasma corticosterone, and disrupted core clock gene expression in the hypothalamus and the adrenal gland. These effects were prevented by filtration of a 10-nm bandwidth of light between 470 and 480 nm, whereas filtration of light between 452 and 462 nm prevented the rise of corticosterone without restoring normal melatonin secretion or hypothalamic clock gene expression. This is the first demonstration of a wavelength dependency of glucocorticoid secretion and clock gene expression. Our results in an animal model suggest that filtering a narrow bandwidth of light from nocturnal lighting may efficiently attenuate overall disruption of circadian endocrine rhythms and clock gene expression in the hypothalamus and adrenal gland. Because a narrow bandwidth of light is filtered, the color distribution of the illumination source is not altered, and this may be of practical importance for potential future studies in shift workers.     

Melatonin rhythmicity: effect of age and Alzheimer's disease

The circadian rhythm of the pineal gland hormone, melatonin is generated within the hypothalamic suprachiasmatic nuclei (SCN), site of the circadian clock. The circadian clock and its output melatonin rhythm is synchronized to the 24h day by environmental light which is transmitted from the retina to the SCN primarily via the retinohypothalamic tract. Changes in both the amplitude and timing of the melatonin rhythm have been reported with aging in humans. Whether these age-related changes (reduced melatonin amplitude, earlier timing of melatonin rhythm) are a result of aging of the retina, the SCN clock, the pineal gland, their neural connections or a combination of some or all of these is not known. The fragmented sleep/wake patterns observed in the elderly and to a greater extent in patients with Alzheimer's disease have been shown to be partly related to an altered retina-SCN-pineal axis. Therapies designed to reinforce the circadian axis (for example, administration of melatonin or light) have been reported to alleviate the disturbed circadian rhythms and disrupted sleep. Future research needs to pinpoint the site(s) of age-related dysfunction so that therapies can be specifically tailored to correct the abnormality in addition to reinforcing any of the intact processes.     

Stability of sleep timing against the melatonin secretion rhythm with advancing age: clinical implications

Aging is often associated with decreased ability of sleep maintenance. It has been hypothesized that the elderly experience a delayed timing of sleep period relative to the circadian phase of various sleep-promoting physiological functions, possibly causing decreased sleep propensity in the latter part of their nocturnal sleep. We evaluated the relationship between the sleep timing and circadian phase of melatonin secretion, which is known as a possible human sleep modulator as well as a stable marker of biological clock phase (BCP). Actigraph sleep recordings were performed, followed by the evaluation of melatonin phase under dim light in 42 healthy elderly volunteers (mean age, 68.8 yr; male/female ratio, 16/26) and 27 healthy young male volunteers (22.5 yr). Elderly subjects showed remarkable clock time advances in both the midpoint of BCP and sleep timing, with a significant decrease in sleep maintenance ability. However, they showed no significant age-related changes in the sleep timing against the midpoint of BCP, suggesting that early morning awakening in the elderly appeared in a BCP for which sleep propensity remained sufficient to sustain sleep. The present findings do not support the hitherto known hypothesis that age-related delay in the sleep timing against the BCP induces the deterioration in sleep maintenance in the elderly.     

From the Cover: Evening use of light-emitting eReaders negatively affects sleep,circadian timing,and next-morning alertness

In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. This negative impact on sleep may be due to the short-wavelength–enriched light emitted by these electronic devices, given that artificial-light exposure has been shown experimentally to produce alerting effects, suppress melatonin, and phase-shift the biological clock. A few reports have shown that these devices suppress melatonin levels, but little is known about the effects on circadian phase or the following sleep episode, exposing a substantial gap in our knowledge of how this increasingly popular technology affects sleep. Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety.The use of electronic devices for reading, communication, and entertainment has greatly increased in recent years. Greater portability, convenience, and ease of access to reading materials in electronic form add to the popularity of these devices. The use of light-emitting devices immediately before bedtime is a concern because light is the most potent environmental signal that impacts the human circadian clock and may therefore play a role in perpetuating sleep deficiency (1). The circadian-timing system synchronizes numerous internal physiological and biochemical processes, including the daily rhythm of sleep propensity (2), to external environmental time cues. For optimal sleep duration and quality, the timing of the sleep episode must be appropriately aligned with the timing of the circadian clock. In humans, exposure to light in the evening and early part of the night, even at low intensity, suppresses the release of the sleep-facilitating hormone melatonin (3–5) and shifts the circadian clock to a later time (3, 6), both of which make it more difficult to fall asleep at night. Light exposure in the biological evening/night also acutely increases alertness (7, 8), but not much is known about its impact on alertness the following day. Here we present results from a randomized study comparing the effects of reading before bedtime using a light-emitting eReader (LE-eBook) with reading a printed book by reflected light. We examined circadian timing and suppression of melatonin, polysomnographic (PSG) recordings of sleep, and subjective and objective measures of sleepiness both in the evening while reading and the following morning.     

Research on sleep, circadian rhythms and aging: applications to manned spaceflight

Disorders of sleep and circadian rhythmicity are characteristic of both advancing age and manned spaceflight. Sleep fragmentation, reduced nocturnal sleep tendency and sleep efficiency, reduced daytime alertness, and increased daytime napping are common to both of these conditions. Recent research on the pathophysiology and treatment of disrupted sleep in older people has led to a better understanding of how the human circadian pacemaker regulates the timing of the daily sleep-wake cycle and how it responds to the periodic changes in the light-dark cycle to which we are ordinarily exposed. These findings have led to new treatments for some of the sleep disorders common to older individuals, using carefully timed exposure to bright light and darkness to manipulate the phase and/or amplitude of the circadian timing system. These insights and treatment approaches have direct applications in the design of countermeasures allowing astronauts to overcome some of the challenges which manned spaceflight poses for the human circadian timing system. We have conducted an operational feasibility study on the use of scheduled exposure to bright light and darkness prior to launch in order to facilitate adaptation of the circadian system of a NASA space shuttle crew to the altered sleep-wake schedule required for their mission. The results of this study illustrate how an understanding of the properties of the human circadian timing system and the consequences of circadian disruption can be applied to manned spaceflight.     

The role of melatonin in glaucoma: implications concerning pathophysiological relevance and therapeutic potential

Glaucoma is a frequent ophthalmologic condition leading to chronic progressive optic neuropathy, which can result in visual impairment and blindness. In addition, glaucoma is associated with a dysregulation of circadian rhythms, as well as with a high incidence of sleep disorders, depression, and anxiety. However, because of their high comorbidity in older age, these conditions have not received much scientific attention and are often undertreated. In the current paper, we review the available literature on the role of melatonergic mechanisms in glaucoma, regulation of circadian rhythms, and depression. The literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications. Recently, there has been evidence for a progressive loss of intrinsically photosensitive retinal ganglion cells (ipRGC) because of oxidative stress in glaucoma. As ipRGC are responsible for the photic transduction to the circadian system and subsequent melatonin secretion, and melatonin is involved in the pathophysiology of circadian desynchronization, sleep disorder, and depression, an impairment of photo-dependent melatonergic signaling may be a common pathway connecting glaucoma with these comorbidities. This fact, as well as the proven retinal neuroprotective role of melatonin, suggests that melatonergic drugs provide a potentially promising treatment strategy supplementing the management of intraocular pressure by pharmacological and surgical measures. Additionally, multidisciplinary treatment focusing on depression and normalization of circadian rhythms might be beneficial for glaucoma patients. Furthermore, glaucoma might be a useful model for studying the pathophysiological interactions between the melatonergic, circadian, and mood systems.     

Behavior of the cardiovascular system in outer space

One of the important factors in outer space is the absence of gravity (OG). During longterm missions, this factor is responsible for the larger number of anatomical and physiological changes that astronauts experience. The cardiovascular system undergoes these changes with severe intensity, which is part of an adaptation process to the new environmental conditions. The modifications observed in both the anatomy of the cardiovascular system and its hemodynamics occur in two phases. The first phase begins when the astronauts enter into Earth orbit or in interplanetary trajectory and extends until the second or fourth day of the mission. It is characterized by an important shifting of fluids from the lower extremities to the cephalic regions which produces an increase of the venous return and the preload, the heart rate is increased, the blood volume in the thorax is also increased, the cardiac chambers become dilated, and by reflex action, the antidiuretic hormone diminishes, diuresis increases and leads to a virtual state of dehydration. Clinically, the first stage is manifested by headache, dizziness, space disorientation, nausea, anorexia, projectile vomiting, sweating and pallor. This constalation of data is known as "The Space Adaptation Syndrome". The second phase begins at the end of the first phase and finishes toward the fortieth or fiftieth day of the mission.(ABSTRACT TRUNCATED AT 250 WORDS)     

Melatonin regulates the rhythmic migration of neutrophils in live zebrafish

The circadian clock plays a vital role in physiology and behavior such as the sleep–wake cycle and blood pressure and hormone levels. Immune responses also display circadian rhythmicity and particularly pineal melatonin contributes to immunological processes. Little attention, however, is given to mechanisms underlying rhythmic neutrophil responses to the injury. Here, we used a transgenic Tg(lyz:EGFP) zebrafish tail fin transection model to investigate whether the recruitment of neutrophils toward the injured site is regulated by the circadian clock. We found that migrating neutrophils display robust rhythmicity, peaking at darkness. Melatonin positively regulates rhythmic neutrophil migration, as evidenced that treatment with melatonin at low dosage can significantly enhance neutrophil recruitment toward the injured site, which is attenuated by luzindole treatment and in pinealectomized fish. Furthermore, using a transgenic zebrafish eyeball model, we observed that melatonin enhances secretion of two cytokines, TNF‐α and IL‐8, both of which markedly enhance neutrophil migration. Taken together, these results highlight a positive role of melatonin in rhythmic neutrophil migration and help obtain a better understanding of circadian regulation in immunology.     

Advancing human circadian rhythms with afternoon melatonin and morning intermittent bright light

CONTEXT: Both light and melatonin can be used to phase shift the human circadian clock, but the phase-advancing effect of the combination has not been extensively investigated. OBJECTIVE: The objective of the study was to determine whether phase advances induced by morning intermittent bright light and a gradually advancing sleep schedule could be increased with afternoon melatonin. PARTICIPANTS: Healthy adults (25 males, 19 females, between the ages of 19 and 45 yr) participated in the study. DESIGN: There were 3 d of a gradually advancing sleep/dark period (wake time 1 h earlier each morning), bright light on awakening [four 30-min bright-light pulses (approximately 5000 lux) alternating with 30 min room light < 60 lux] and afternoon melatonin, either 0.5 or 3.0 mg melatonin timed to induce maximal phase advances, or matching placebo. The dim light melatonin onset was measured before and after the treatment to determine the phase advance. RESULTS: There were significantly larger phase advances with 0.5 mg (2.5 h, n = 16) and 3.0 mg melatonin (2.6 h, n = 13), compared with placebo (1.7 h, n = 15), but there was no difference between the two melatonin doses. Subjects did not experience jet lag-type symptoms during the 3-d treatment CONCLUSIONS: Afternoon melatonin, morning intermittent bright light, and a gradually advancing sleep schedule advanced circadian rhythms almost 1 h/d and thus produced very little circadian misalignment. This treatment could be used in any situation in which people need to phase advance their circadian clock, such as before eastward jet travel or for delayed sleep phase syndrome.     

Circadian rhythm abnormalities in totally blind people: incidence and clinical significance.

When people are completely isolated from environmental time cues, their circadian rhythms free run with a nearly 24-h cycle, generated by an internal body clock. Free-running temperature, cortisol, and melatonin rhythms have also been described in totally blind people, even though they were living in normal society and had access to abundant time cues; thus an intact visual system may be essential for synchronization of the circadian system. However, because of the small numbers of subjects studied, the incidence and clinical significance of circadian rhythm abnormalities among the blind has remained uncertain. In this study, plasma melatonin (n = 20), cortisol (n = 4), and sleep propensity (n = 1) were measured in serial samples taken from totally blind subjects for 24 h. Most totally blind subjects had circadian rhythm abnormalities. In about half of the subjects, the rhythms were free-running. Some blind subjects suffered recurrent insomnia and daytime sleepiness that were maximal when the internal rhythms were out of phase with the preferred sleep times. The high incidence of abnormal circadian rhythms in blind people underscores the importance of the light-dark cycle as an important environmental synchronizer for the human circadian system.     

A unified model of melatonin, 6‐sulfatoxymelatonin,and sleep dynamics

A biophysical model of the key aspects of melatonin synthesis and excretion has been developed, which is able to predict experimental dynamics of melatonin in plasma and saliva, and of its urinary metabolite 6‐sulfatoxymelatonin (aMT6s). This new model is coupled to an established model of arousal dynamics, which predicts sleep and circadian dynamics based on light exposure and times of wakefulness. The combined model thus predicts melatonin levels over the sleep‐wake/dark‐light cycle and enables prediction of melatonin‐based circadian phase markers, such as dim light melatonin onset (DLMO) and aMT6s acrophase under conditions of normal sleep and circadian misalignment. The model is calibrated and tested against group average data from 10 published experimental studies and is found to reproduce quantitatively the key dynamics of melatonin and aMT6s, including the timing of release and amplitude, as well as response to controlled lighting and shift work.     

Melatonin in patients with reduced REM sleep duration: two randomized controlled trials

Recent data suggest that melatonin may influence human physiology, including the sleep-wake cycle, in a time-dependent manner via the body's internal clock. Rapid-eye-movement (REM) sleep expression is strongly circadian modulated, and the impact of REM sleep on primary brain functions, metabolic processes, and immune system function has become increasingly clear over the past decade. In our study, we evaluated the effects of exogenous melatonin on disturbed REM sleep in humans. Fourteen consecutive outpatients (five women, nine men; mean age, 50 yr) with unselected neuropsychiatric sleep disorders and reduced REM sleep duration (25% or more below age norm according to diagnostic polysomnography) were included in two consecutive, randomized, double-blind, placebo-controlled, parallel design clinical trials. Patients received 3 mg melatonin daily, administered between 2200 and 2300 h for 4 wk. The results of the study show that melatonin was significantly more effective than placebo: patients on melatonin experienced significant increases in REM sleep percentage (baseline/melatonin, 14.7/17.8 vs. baseline/placebo, 14.3/12.0) and improvements in subjective measures of daytime dysfunction as well as clinical global impression score. Melatonin did not shift circadian phase or suppress temperature but did increase REM sleep continuity and promote decline in rectal temperature during sleep. These results were confirmed in patients who received melatonin in the second study (REM sleep percentage baseline/placebo/melatonin, 14.3/12.0/17.9). In patients who received melatonin in the first study and placebo in the second, the above mentioned effects outlasted the period of melatonin administration and diminished only slowly over time (REM sleep percentage baseline/melatonin/placebo, 14.7/17.8/16.2). Our findings show that exogenous melatonin, when administered at the appropriate time, seems to normalize circadian variation in human physiology. It may, therefore, have a strong impact on general health, especially in the elderly and in shift workers.     

Human circadian melatonin rhythm phase delay during a fixed sleep-wake schedule interspersed with nights of sleep deprivation

The human circadian pacemaker, with an intrinsic period between 23.9 and 24.5 hr, can be reset by low levels of light. Biomathematical models of the human clock predict that light-dark cycles consisting of only approximately 3.5 lux during 16 hr of wakefulness and 0 lux during 8 hr of sleep should entrain approximately 45% of the population. However, under real-life conditions, sleep-wake schedules and the associated light-dark exposures are often irregular. It remains unclear whether the phase of the pacemaker would remain stable under such conditions. We investigated the stability of the circadian phase in dim light by assessing the plasma melatonin rhythm during nine consecutive circadian cycles. Ten subjects were scheduled to sleep for 8 hr (0.03 lux) and to be awake for 16 hr (5-13 lux) during all days except on days 4 and 8, during which the subjects were sleep deprived for 40 hr (5-13 lux), either in a sitting/standing or supine body posture. In all subjects, the phase of the melatonin rhythm occurred at a later clock time on day 9 than on day 2 (average delay: 1.4 hr). Largest delays in the melatonin onset were observed in subjects with low amplitude melatonin rhythms. The area under the curve during active melatonin secretion was significantly reduced when subjects were sleep deprived in the 40-hr supine body posture condition compared with either the 40-hr sitting/standing sleep deprivation (SD) or the ambulatory condition under non-SD conditions. Posture differences did not significantly affect the relative phase position of the melatonin profiles. The data indicate that under conditions of reduced zeitgeber strength, the phase of the human circadian pacemaker, using plasma melatonin as a marker, can be phase delayed by one night of SD and the associated dim light exposure.     

Circadian rhythm disorder in a rare disease: Smith-Magenis syndrome

Smith-Magenis syndrome (SMS) is a clinically recognizable contiguous gene syndrome, caused by interstitial deletion of chromosome 17p11.2. The SMS phenotype include distinctive facial features, developmental delay and neurobehavioral abnormalities. The patients present major sleep disturbances ascribed to a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Treatment with morning beta-blockers and evening melatonin reinstated a normally timed melatonin circadian rhythm, improved daytime behavior and restored normal sleep habits, resulting in a greatly improved quality of life for both SMS patients and their family. SMS is the demonstration of biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate generation of circadian rhythms, we suggest that haploinsufficiency for a circadian system gene mapping to chromosome 17p11.2 may cause the inversion of circadian rhythm in SMS.     

Cardiovascular deconditioning syndrome during space flight

Weightlessness results, in Man, in a redistribution of organic fluids from the lower half of the body to the thoraco-cephalic areas. This fluid transfer is responsible, in the course of the flight, for a series of subjective and objective disorders which the astronauts will experience. These disorders are related to venous stasis in the thoraco-cephalic area. Moreover, upon return of any space mission, regardless of its length, the astronauts will experience a disadaptation of their cardiovascular system indicated by hypotension with the possible occurrence of a presyncopal state, or even a syncope and a lowered stress capability. The haemodynamic consequences of this fluid transfer, from central and peripheral standpoint, and the mechanisms implicated in the cardiovascular deconditioning syndrome, are presented and discussed.