Extraocular light exposure does not suppress plasma melatonin in humans.

Light affects the circadian axis in at least two ways. It can cause the acute suppression of pineal melatonin synthesis, and/or a phase-shift of the circadian oscillator. As recent evidence has suggested that extraocular light exposure may cause phase-shifts of the circadian clock, we have investigated whether suppression of melatonin can be induced by the same type of light exposure. In the first study subjects' eyes were exposed to white light (2250 lux for 30 mins) via a fibre optic cable. As expected, suppression of nighttime plasma melatonin levels (61 +/- 6%) was observed. In the second study, light of the same quality but higher intensity (14,000 or 67,500 lux for 180 mins) was delivered in the same manner to the popliteal region behind the subjects' knees, whilst shielding their eyes. No suppression of plasma melatonin levels (4 +/- 7%) was detected in any of the subjects. Thus, extraocular photoreception, if it exists in mammals, does not affect the suprachiasmatic nucleipineal pathway.

Circadian characteristics of sleep propensity function in healthy elderly: a comparison with young adults.

Changes in sleep-wake patterns are among the hallmarks of biological aging, Elderly persons complain of daytime drowsiness and difficulties in initiating and maintaining sleep. The question of whether age-related changes in sleep-wake distribution are the result of a dimunition in amplitude of the endogenous circadian pacemaker, resulting in a decline in nocturnal sleep tendency and an increase in diurnal sleep tendency, or a manifestation of the impact of the medical and psychosocial burden on sleep has not yet been fully determined. In the present study, we utilized a 7/13 ultrashort sleep-wake paradigm to investigate the 24-hour sleep propensity function (SPF) in healthy elderly persons. Seventeen healthy, elderly males, aged 65-78 years, and eight young males, aged 19-26, participated in the study. All elderly subjects were living independently in the community and were vigorous, physically active, and socially engaged. The young adult subjects were students living on campus, all with the same daily schedule. As anticipated, polysomnographic measures from the night prior to experimental periods differed between the elderly and young subjects. Specifically, the elderly had a reduction in percentage of sleep stage 3/4 and in sleep efficiency. The results of the 7/13 ultrashort sleep-wake paradigm showed that although aging did not affect the overall structure of the SPF, there was an age-related trend toward lower circadian amplitude and advanced phase. Our findings suggest that these age-related changes in sleep propensity may contribute to the difficulties in initiating sleep and to the early morning awakening.

Melatonin replacement therapy of elderly insomniacs.

Changes in sleep-wake patterns are among the hallmarks of biological aging. Previously, we reported that impaired melatonin secretion is associated with sleep disorders in old age. In this study we investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. The study comprised a running-in, no-treatment period and four experimental periods. During the second, third and fourth periods, subjects were administered tablets for 7 consecutive days, 2 hours before desired bedtime. The tablets were either 2 mg melatonin administered as sustained-release or fast-release formulations, or an identical-looking placebo. The fifth period, which concluded the study, was a 2-month period of daily administration of 1 mg sustained-release melatonin 2 hours before desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three 1-week periods revealed that a 1-week treatment with 2 mg sustained-release melatonin was effective for sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. Sleep maintenance and initiation were further improved following the 2-month 1-mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. Our findings suggest that for melatonin-deficient elderly insomniacs, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep.

The prevention and treatment of jet lag.

Travel across multiple time zones is a common feature of modern life. After transmeridian flights, the internal clocks are desynchronized from the external environment and it can take several days to readjust to the new external time cues. The time taken is related to the direction of the flight and to the number of time zones crossed as well as to individual variability. The result of this desynchronization between the human circadian system and the new environmental timing is described as "jet lag". Although the term "jet lag" refers to disturbances in a variety of symptoms, jet-lagged travellers mostly complain of loss of sleep and of its consequences (e.g., diurnal sleepiness, depressed mood, decreased efficiency, premature awakening, etc.). The direct reason for sleep disturbances after a multiple time-zone flight is that sleep is very sensitive to changes in its temporal setting. The present report reviews current data concerning the symptoms of jet lag, the approaches proposed for the alleviation of jet lag and the effectiveness of these strategies.

Hypnotic and hypothermic effects of melatonin on daytime sleep in humans: lack of antagonism by flumazenil.

In this double-blind, placebo-controlled study we investigated whether 10 mg flumazenil, a pure benzodiazepine antagonist, can block the hypnotic and hypothermic effects of 3 mg melatonin. The design comprised four 7-h (1200-1900 h) testing periods, preceded by a 'no-treatment' adaptation period of the "7/13' sleep-wake paradigm. Six young healthy adult males were paid to participate. During each experimental period, tablets were administered at 1145 h (flumazenil or placebo) and at 1200 h (melatonin or placebo) in a randomized, double-blind, partially repeated Latin square design. Polysomnographic recordings and core body temperature recordings revealed that melatonin, either in combination with placebo or with flumazenil, significantly increased the amounts of sleep, and decreased core body temperature in comparison with placebo alone or the combination of flumazenil plus placebo. These results do not support the hypothesis that melatonin exerts its hypothermic and hypnotic effects via the central benzodiazepine receptors.

Melatonin rhythm abnormalities and sleep disorders in the elderly.

Biological aging is often associated with sleep problems and daytime napping. Complaints of difficulty in initiating and maintaining sleep, as well as daytime drowsiness, are more common in the elderly than in any other age group. This report reviews evidence that impaired melatonin secretion is associated with sleep disorders in old age. Circulating melatonin levels have been found to be significantly lower and onset and peak times have been delayed in elderly insomniacs as compared to age-matched control subjects. In view of these findings, we investigated the effects of melatonin treatment on melatonin-deficient insomnia in the elderly. From the results of our study, it seems likely that melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep in this population.

Melatonin - a chronobiotic and soporific hormone.

In this report we review evidence that melatonin, a hormone produced by the pineal gland during the hours of darkness, plays a major role in the synchronization of the sleep/wake cycle. The production of melatonin is regulated by a structure located in the hypothalamus called the suprachiasmatic nucleus (SCN). The activity of the SCN is strongly affected by changes in illumination and, as a consequence, melatonin levels are high during darkness and low in the light and it, therefore, reflects the cycle. Changes in sleep/wake patterns are among the hallmarks of biological aging. Complaints of difficulty in initiating and maintaining sleep, and daytime drowsiness, are more common in the elderly than in any other age group. In this report, we review evidence that impaired meltonin secretion is associated with sleep disorders in old age. Circulating melatonin levels have been found to be significantly lower in elderly insomniacs than in age-matched controls, and their onset and peak times delayed. In view of these findings, we investigated the effects of melatonin treatment on melatonin-deficient insomnia in the elderly. From the results of our study, it seems likely that melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep in this population.

Melatonin--the key to the gate of sleep.

This article reviews the evidence that melatonin, a hormone produced by the pineal gland during the dark hours, plays a major role in the regulation of the sleep-wake cycle. In recent years, our laboratory has been involved in a large-scale project aimed at investigating the role of endogenous melatonin in sleep-wake regulation and the effects of nonpharmacological levels of melatonin on sleep. Based on our finding on the precise coupling between the endogenous nocturnal increase in melatonin secretion and the opening of the nocturnal sleep gate, we propose that the role of melatonin in the induction of sleep does not involve the active induction of sleep, but is rather mediated by an inhibition of a wakefulness-producing mechanism in the central nervous system. Our studies also suggest that exogenously administered melatonin may be beneficial in certain types of insomnia that are related to disturbances in the normal secretion of the hormone.

Interleukin 6 induces DNA binding activity of AP1 in M1 myeloblastic cells but not in a growth resistant cell derivative.

The effects that three different growth inhibitory cytokines exert on expression and function of members of the Jun family were studied in this work. M1 myeloblastic cells were chosen for this purpose because of their high growth sensitivity to interleukin 6 (IL-6), transforming growth factor beta 1 and alpha- and beta-interferons. It is reported here that IL-6 elevated the junB and c-jun mRNA levels and induced the formation of a novel DNA-protein complex with high sequence specificity to 12-O-tetradecanoylphorbol-13-acetate response element (TRE) oligonucleotides. This IL-6 induced TRE binding complex was abolished by anti-Jun specific antibodies and was efficiently competed by an oligonucleotide that comprises the mouse homologue of a previously described human c-myc negative DNA element. It persisted in cells for at least 48 h after IL-6 treatment and failed to be induced by alpha- and beta-interferons or by transforming growth factor beta 1, which affected differently the pattern of jun mRNA expression. To further explore regulatory and functional aspects of this induced TRE binding activity, an IL-6 resistant M1 clone was isolated and further analyzed. This clone carried a postreceptor deficiency that abrogated completely the growth inhibitory responses to IL-6 but did not interfere with the induction of two differentiation related cell surface markers. Interestingly, the IL-6 resistant clone had lost two molecular responses to IL-6, induction of TRE binding activity and suppression of the c-myc gene. The data correlate the IL-6 induced AP1 activity with the suppression of c-myc and growth inhibition.