Melatonin acts at the suprachiasmatic nucleus to attenuate behavioral symptoms of infection.

In common with reproduction, immune function exhibits strong seasonal patterns, which are driven by annual changes in day length (photoperiod) and melatonin secretion. Whereas changes in melatonin communicate seasonal time into the reproductive axis via subcortical receptors, the relevant melatonin targets for communicating seasonal time into the immune system remain unspecified. The authors report that melatonin implants targeting the hypothalamic suprachiasmatic nuclei (SCN) induced a winter phenotype in the immune system. SCN melatonin implants attenuated infection-induced anorexia and cachexia, indicating that the SCN mediate the effects of melatonin on these behavioral and metabolic symptoms of infection. However, SCN melatonin implants failed to induce winter-like peripheral leukocyte concentrations or behavioral thermoregulatory responses to infection. In contrast, subcutaneous melatonin implants induced winter-like changes in all behavioral and immunological parameters. Melatonin acts directly at the SCN to induce seasonal changes in neural-immune systems that regulate behavior. The data identify anatomical overlap between neural substrates mediating the effects of melatonin on the reproductive and immune systems but also suggest that the SCN are not the sole mediator of photoperiodic effects of melatonin on immunity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of seasonal changes in daylength on human neuroendocrine function

The circadian pacemaker imposes stereotypic patterns of daily variation on the activity of human neuroendocrine systems. In a number of cases, these patterns exhibit waveforms that are characterized by distinct diurnal and nocturnal periods with relatively discrete transitions between them (corresponding to a biological day, a biological dusk, a biological night, and a biological dawn). In humans, for example, diurnal periods of absence of melatonin secretion, low prolactin secretion, and falling levels of cortisol alternate with nocturnal periods of active melatonin secretion, high prolactin secretion and rising levels of cortisol. In response to light, the circadian pacemaker synchronizes the timing of the biological day and night so that their timing and duration are appropriately matched with the timing and duration of the solar day and night. As the pacemaker carries out this function, it is able to adjust the duration of the biological day and night to match seasonal variation in the duration of the solar day and night. Thus, after humans have been chronically exposed to long nights (scotoperiods), the duration of nocturnal periods of active melatonin secretion, high prolactin secretion and rising levels of cortisol is longer than it is after they have been chronically exposed to short nights. Furthermore, the sleep-related peak of growth hormone secretion is half as high after exposure to long nights as it is after exposure to short nights. These responses to seasonal changes in duration of the natural scotoperiod are suppressed in most individuals - especially men - who live in modern urban environments in which they are exposed to artificial light after dark and artificial darkness during the daytime.     

Role of melatonin in mediating seasonal energetic and immunologic adaptations

Winter is energetically demanding and stressful; thermoregulatory demands increase when food availability usually decreases. Physiological and behavioral adaptations, including termination of breeding, have evolved among nontropical animals to cope with the energy shortages during winter. Presumably, selection for the mechanisms that permit physiological and behavioral anticipation of seasonal ambient changes have led to current seasonal breeding patterns for many populations. In addition to the well-studied seasonal cycles of mating and birth, there are also significant seasonal cycles of illness and death among field populations of mammals and birds. Energetically challenging winter conditions can directly induce death via hypothermia, starvation, or shock; surviving these demanding conditions likely puts individuals under great physiological stress. The stress of coping with energetically demanding conditions may increase adrenocortical steroid levels that could indirectly cause illness and death by compromising immune function. Individuals would enjoy a survival advantage if seasonally recurring stressors could be anticipated and countered by bolstering immune function. The primary environmental cue that permits physiological anticipation of season is daily photoperiod, a cue that is mediated by melatonin. However, other environmental factors may interact with photoperiod to affect immune function and disease processes. Immune function is compromised during the winter in field studies of birds and mammals. However, laboratory studies of seasonal changes in mammalian immunity consistently report that immune function is enhanced in short day lengths. To resolve this apparent discrepancy, we hypothesize that winter stressors present in field studies counteract short-day enhancement of immune function. Prolonged melatonin treatment mimics short days, and also enhances rodent immune function. Reproductive responsiveness to melatonin appears to affect immune function. In sum, melatonin may be part of an integrative system to coordinate reproductive, immunologic, and other physiological processes to cope successfully with energetic stressors during winter.     

Effects of sympathicolytic and sympathicomimetic drugs on plasma immunoreactive melatonin in the domestic pig

Plasma immunoreactive melatonin was monitored for 110 hr in sexually immature female domestic pigs kept under 12L:12D light conditions and treated with two sympathicolytic (alpha-methyl-p-tyrosine, propranolol) and three sympathicomimetic (clorgyline, isoproterenol, dobutamine) drugs. Mean levels of plasma melatonin in the control pigs showed significant diurnal changes with the highest values during the scotophase. In the individual gilts the diurnal changes of plasma melatonin were markedly irregular; melatonin increases were not consistently noted at night, and melatonin levels during light and darkness varied considerably between days. The lack of consistency in the diurnal patterns of plasma melatonin in individual pigs during consecutive days explains the large inter-individual differences observed in previous short-term studies. Administration of alpha-methyl-p-tyrosine resulted in the decrease in both daytime and nighttime melatonin levels, compared with the control group, but it did not eliminate the increases in melatonin during the night. Treatment with other drugs did not significantly change the level of plasma melatonin compared with the control group, however they had modulatory effects on melatonin rhythm. The results suggest that the plasma melatonin in the domestic pig is controlled by the adrenergic nervous system, but the pharmacology of the secretion and/or metabolism of this pineal hormone is different than described in other species.     

Successful treatment of transient acquired factor X deficiency by plasmapheresis with concomitant intravenous immunoglobulin and steroid therapy

Many nontropical rodent species display seasonal changes in reproductive physiology and metabolism, as well as in immune function. Field studies of seasonal changes in immune function typically report decreased immune function in the short days of winter compared to summer; presumably, reduced immunity in winter reflects increased glucocorticoid secretion in response to environmental stressors. In contrast, laboratory studies of photoperiodic changes in immunity invariably demonstrate increased immune function in short compared to long days. Although the precise mechanisms regulating short-day enhancement of immune function are not known, it is hypothesized that increased immunity is due to the increased duration of melatonin secretion in short compared to long days. However, melatonin can act both directly (i.e, via melatonin receptors located on lymphatic tissue) and indirectly (i.e., via alterations in gonadal steroids) to affect immune function. The present study examined the effects of exogenous melatonin administration on both cell-mediated and humoral immune function in adult male deer mice (Peromyscus maniculatus), as well as the role of gonadal steroid hormones in mediating these effects. Mice either were castrated to remove circulating androgens or received sham operations and were implanted with empty capsules or capsules containing melatonin. Individual mice implanted with melatonin underwent reproductive regression and displayed enhanced splenocyte proliferation to the T-cell mitogen concanavalin A; antigen-specific serum immunoglobulin M production was unaffected by melatonin treatment. Castration had no effect on either cell-mediated or humoral immune function. Taken together, these results suggest that exogenous melatonin enhances cell-mediated, but not humoral, immune function in adult male deer mice and that this effect is independent of gonadal steroid hormones. These results are consistent with a direct effect of melatonin on immunity.     

Body temperature daily rhythms in the striped mouse Rhabdomys pumilio: the effects of alpha and beta blockade

Body temperature (Tb) daily rhythms and the effects of alpha and beta blockade were studied in the South African diurnal striped mouse Rhabdomys pumilio. Eleven mice (8 males and 3 females) with a body mass of 42.7+/-7.8 g (mean +/- SD) were tested. Mice were acclimated to a 13 h:11 h light-dark photoperiod at an ambient temperature of 25 degrees C. To assess the daily rhythm of pineal melatonin secretion, urinary 6-sulfatoxymelatonin (6-SMT) was determined. Mice displayed a robust Tb daily rhythm with an acrophase in the dark period, which is unexpected for a diurnal species. The nocturnal increase in Tb was accompanied by a significant rise in urinary 6-SMT. The beta blocker propranolol (4.5 mg/kg), injected 1 h before lights-off, resulted in a higher Tb value, whereas the alpha blocker prazosin (1 mg/kg) blocked the increase of Tb during the dark period. Prazosin also significantly attenuated the nocturnal increase of urinary 6-SMT. These results are in agreement with those obtained from the golden spiny mouse Acomys russatus and support the idea that small diurnal mammals retain the Tb rhythm of a nocturnal rodent. They also suggest that pineal melatonin secretion in these rodents is regulated by alpha rather than by beta receptors.     

Nocturnal decreases in nitric oxide and cyclic GMP contents in the chick brain and their prevention by light

The diurnal variations in the contents of nitric oxide (NO) and cyclic GMP were studied in the chick brain. NO and cyclic GMP contents in the chick brain were lower at night than during the day and were inversely correlated with high night-time tissue melatonin levels. Furthermore, when animals were kept in light at night, tissue melatonin levels remained at low diurnal values, whereas NO and cyclic GMP contents remained high. Since we have previously shown that physiological concentrations of melatonin inhibit nitric oxide synthase (NOS) activity in different brain areas, the nocturnal decrease in brain NO and cyclic GMP contents may be, in part, a consequence of the nocturnal inhibitory effect of melatonin on NOS activity.     

Seasonal profiles of plasma luteinizing hormone, testosterone and estradiol in the ram

Plasma profiles of luteinizing hormone (LH), testosterone (T), and estradiol (E2) have been determined in five mature rams during the primary breeding season (September) and again when breeding activity was low (May). Blood samples collected every half h for 24 h during September or May showed that LH was released into the general circulation as distinct peaks. Although this secretory pattern was not the same for all rams and seasonal differences were noted in certain individuals, it is suggested that an inherent rhythm persists within each ram. With the exception of one ram in September, obvious T peaks were preceded by LH peaks greater than 2 ng/ml (LH-T interval less than 60 min). Season had no effect on the number and magnitude of LH peaks or on the mean concentrations; however, basal levels of LH were higher (P less than 0.01) in September than in May. Seasonal differences in peripheral T levels were more dramatic with mean, baseline, and peak concentrations elevated (p less than 0.01) during the fall. The number of T peaks, like those of LH, was not affected by season. Large variations in circulating levels of E2 made any possible relationship between this hormone and LH or T difficult to identify. Furthermore, a diurnal or seasonal rhythm could not be established for E2 in this study. It is concluded that seasonal differences occur in secretory patterns of LH and T and that a cause and effect relationship between these two hormones exists. Under conditions of this study, neither a consistent relationship between E2 and LH or T, nor a seasonal difference in mean E2 levels, was apparent.     

Endocrine effects of the pineal gland and neutralization of circulating melatonin and N-acetylserotonin

Adrenocortical function was studied in rats after shampinealectomy, pinealectomy, or immunization against melatonin and N-acetylserotonin (NAS). Pineals were stimulated to increase melatonin synthesis by blinding or exposure to 23 h of darkness daily. Blinding elevated morning corticosterone levels without altering the corticosterone response to novelty stimulation. Among blinded animals, pinealectomy partially reversed and immunization completely reversed the elevations in morning steroid levels. Exposure to short daily photoperiods flattened the diurnal corticosterone rhythm. Pinealectomy did not affect morning corticosterone levels but reduced evening corticosterone levels. More importantly, immunization resulted in reduced corticosterone levels throughout the diurnal cycle. These findings suggest that melatonin and (or) NAS may be involved in the regulation of resting diurnal adrenocortical function.     

Prospects of the clinical utilization of melatonin

This review summarizes the present knowledge on melatonin in several areas on physiology and discusses various prospects of its clinical utilization. Ever increasing evidence indicates that melatonin has an immuno-hematopoietic role. In animal studies, melatonin provided protection against gram-negative septic shock, prevented stress-induced immunodepression, and restored immune function after a hemorrhagic shock. In human studies, melatonin amplified the antitumoral activity of interleukin-2. Melatonin has been proven as a powerful cytostatic drug in vitro as well as in vivo. In the human clinical field, melatonin appears to be a promising agent either as a diagnostic or prognostic marker of neoplastic diseases or as a compound used either alone or in combination with the standard cancer treatment. Utilization of melatonin for treatment of rhythm disorders, such as those manifested in jet lag, shift work or blindness, is one of the oldest and the most successful clinical application of this chemical. Low doses of melatonin applied in controlled-release preparation were very effective in improving the sleep latency, increasing the sleep efficiency and rising sleep quality scores in elderly, melatonin-deficient insomniacs. In the cardiovascular system, melatonin seems to regulate the tone of cerebral arteries; melatonin receptors in vascular beds appear to participate in the regulation of body temperature. Heat loss may be the principal mechanism in the initiation of sleepiness caused by melatonin. The role of melatonin in the development of migraine headaches is at present uncertain but more research could result in new ways of treatment. Melatonin is the major messenger of light-dependent periodicity, implicated in the seasonal reproduction of animals and pubertal development in humans. Multiple receptor sites detected in brain and gonadal tissues of birds and mammals of both sexes indicate that melatonin exerts a direct effect on the vertebrate reproductive organs. In a clinical study, melatonin has been used successfully as an effective female contraceptive with little side effects. Melatonin is one of the most powerful scavengers of free radicals. Because it easily penetrates the blood-brain barrier, this antioxidant may, in the future, be used for the treatment of Alzheimer's and Parkinson's diseases, stroke, nitric oxide, neurotoxicity and hyperbaric oxygen exposure. In the digestive tract, melatonin reduced the incidence and severity of gastric ulcers and prevented severe symptoms of colitis, such as mucosal lesions and diarrhea.     

Multiple sclerosis: the role of puberty and the pineal gland in its pathogenesis

Epidemiological studies demonstrate that the incidence of multiple sclerosis (MS) is age-dependent being rare prior to age 10, unusual prior to age 15, with a peak in the mid 20s. It has been suggested that the manifestation of MS is dependent upon having passed through the pubertal period. In the present communication, I propose that critical changes in pineal melatonin secretion, which occur in temporal relationship to the onset of puberty, are intimately related to the timing of onset of the clinical manifestations of MS. Specifically, it is suggested that the fall in melatonin secretion during the prepubertal period, which may disrupt pineal-mediated immunomodulation, may stimulate either the reactivation of the infective agent or increase the susceptibility to infection during the pubertal period. Similarly, the rapid fall in melatonin secretion just prior to delivery may account for the frequent occurrence of relapse in MS patients during the postpartum period. In contrast, pregnancy, which is associated with high melatonin concentrations, is often accompanied by remission of symptoms. Thus, the presence of high melatonin levels may provide a protective effect, while a decline in melatonin secretion may increase the risk for the development and exacerbation of the disease. The melatonin hypothesis of MS may explain other epidemiological and clinical phenomena associated with the disease such as the low incidence of MS in the black African and American populations, the inverse correlation with sun light and geomagnetic field exposure, the occurrence of relapses in relation to seasonal changes and fluctuations in mood, and the association of MS with affective illness and malignant disease. Therapeutically, this hypothesis implies that application of bright light therapy or the use of other major synchronizers of circadian rhythms such as sleep deprivation or application of external weak magnetic fields may be beneficial in the treatment and/or prophylaxis of relapses in the disease.     

Sigma receptor modulation of noradrenergic-stimulated pineal melatonin biosynthesis in rats

Because sigma receptors are richly concentrated in the rat pineal gland, the present study was performed to investigate their possible role in the modulation of melatonin production. To this purpose, we assessed in vivo the effects of the sigma-receptor ligands 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine on the rat pineal gland activity during either the daytime or the nighttime. Compared with vehicle, 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine potentiated the enhancement of N-acetyltransferase activity and pineal melatonin content induced by isoproterenol administration during the daytime, whereas they did not affect the diurnal basal biosynthetic activity of the gland. Conversely, at night, 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine enhanced significantly the physiological increases in both pineal N-acetyltransferase activity and melatonin levels. This enhancement was prevented by pretreatment with rimcazole, a specific sigma-receptor antagonist. These findings suggest that, in rats, the activation of pineal sigma-receptor sites does not affect the biosynthetic activity of the pineal gland during daytime, whereas it potentiates the production of melatonin when the gland is noradrenergically stimulated either by isoproterenol administration or by the endogenously released norepinephrine at nighttime.     

The role of melatonin in the human fetus (review)

Melatonin, an indole amine, primarily derived from the pineal gland is secreted during the hours of darkness. Melatonin acts as a hormonal transduction of photoperiod influencing the timing of seasonal and daily (circadian) physiological rhythms. Maternal melatonin crosses the placenta and enters the fetal circulation providing photoperiodic information to the fetus influencing the subsequent circadian and seasonal rhythms of the offspring. The function of melatonin in humans is more obscure. However, melatonin has attained prominence as a treatment for disturbed circadian rhythms and sleep patterns which occur as a result of transmeridian travel, shift work or blindness. The biological clock, the hypothalamic suprachiasmatic nuclei (SCN), possesses melatonin receptors, in both the adult and fetal human. This concurs with the reported influence of melatonin on human circadian rhythmicity and indicates that this influence may begin in utero. Melatonin receptors are widespread in the human fetus and occur in both central and peripheral tissue from early in fetal development. Thus, the influence of melatonin on the developing human fetus may not be limited to entraining circadian rhythmicity. Considering the transplacental availability of melatonin to the fetus the ingestion of melatonin by pregnant women may be inadvisable.     

Effect of melatonin on 24-hour rhythms of ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis in submaxillary lymph nodes and spleen of young and aged rats

Young (50 days old) and old (18 months old) Sprague-Dawley rats were injected with mycobacterial Freund's adjuvant to produce an inflammatory disease of the joints and were studied the day before, and on days 6, 12 and 18 after injection. At every postinjection interval examined, old rats had significantly lower circadian amplitudes of pineal melatonin content. On day 18 of arthritis development, decreased levels of pineal melatonin were also seen in young rats. A second study, carried out 18 days after the injection of Freund's complete adjuvant and after 17 daily injections of 10 or 100 microg of melatonin in the evening, indicated that melatonin treatment restored the inflammatory response in old rats (assessed plethysmographically in hind paws) to the level found in young animals. In young rats, an inflammation-promoting effect of 100 microg melatonin could be demonstrated. As a consequence of the immune reaction, submaxillary lymph node and splenic ornithine decarboxylase activity (an index of lymph cell proliferation) augmented significantly, with acrophases of 24-hour rhythms in the afternoon for lymph nodes or in the morning for spleen. Mesor and amplitude of ornithine decarboxylase rhythm were lowest in old rats, while melatonin injection generally augmented its amplitude. Lymph node and splenic tyrosine hydroxylase activity (a presynaptic adrenergic marker) reached maximal values during early night hours while maximal values of [3H]acetylcholine synthesis (a presynaptic cholinergic marker) occurred during the afternoon in lymph nodes. Amplitude and mesor of these rhythms were lowest in old rats, an effect generally counteracted by melatonin treatment. The results suggest that inflammation is accompanied by an age-dependent, significant depression of pineal melatonin synthesis during adjuvant-induced arthritis and a decreased amplitude of the circadian rhythm of immune cell proliferation and autonomic activity in lymph nodes and spleen. These effects are counteracted by injection of melatonin, mainly in old rats.     

Effects of intracellular free cholesterol accumulation on macrophage viability: a model for foam cell death

A prominent innervation of the pineal gland of the European hamster with nerve fibres containing neuropeptide Y (NPY) and tyrosine hydroxylase (TH) was demonstrated by means of immunohistochemistry. Nearly all the TH- and NPY-immunoreactive nerve fibres in the superficial pineal gland disappeared after bilateral superior cervical ganglionectomy, showing that the majority of NPY- and TH-immunoreactive nerve fibres belonged to the sympathetic nervous system. Since, in the European hamster, preliminary studies of the NPY-fibre density in the pineal gland had indicated seasonal changes, the density of NPY-immunoreactive nerve fibre profiles was ascertained in the superficial pineal gland in a series of animals between the first part of November and late April. The highest density of NPY-immunoreactive nerve fibre profiles was observed during midwinter. On the other hand, during the same period of the year, the number of sympathetic TH-immunoreactive sympathetic nerve fibre profiles did not exhibit seasonal variation, nor did substitution of testosterone, during the sexually inactive period, affect the density of NPY-containing nerve fibres in the gland. Our results show the presence of a testosterone-independent annual variation in the content of NPY in the sympathetic nerve fibres innervating the pineal gland of the European hamster. This variation can be correlated with the changes in the daily pattern of melatonin production observed by others in the same species at this period of the year.     

Melatonin binding sites in the harderian gland of the rat and Syrian hamster

Specific melatonin binding sites in the harderian gland of both rat and Syrian hamster were studied using [125I]melatonin. In both species, binding of [125I]melatonin by harderian gland membranes exhibited properties such as dependence on time, temperature, membrane concentration, saturability, and high specificity. Only one class of high-affinity binding sites was found with a Kd of 0.19 and 6.47 nM for the rat and Syrian hamster, respectively. The binding capacity in the rat harderian gland was 4.00 fmol/mg protein; in the Syrian hamster it was 7.58 fmol/mg protein. In the rat, no sex differences were found in the binding of the tracer to the membranes. However, in the Syrian hamster, binding of [125I]melatonin by the harderian gland was twice higher in the female than in the male. No changes were found in the Kd values (6.47 vs. 6.94 nM), while binding capacity was significantly increased in the female (13.50 fmol/mg protein) when compared to the male hamster (7.58 fmol/mg protein). Binding of [125I]melatonin by the harderian gland of male hamsters was modified by castration but not by melatonin treatment. Castration induced an increase of binding up to the level of females. However, chronic melatonin administration did not alter the [125I]melatonin binding in either intact or gonadectomized male hamsters. Binding studies also showed diurnal variations. There was a diurnal rhythm of [125I]melatonin binding by Syrian hamster harderian glands with the peak at the end of the light period and the trough late in the dark period. This rhythm in the binding is observed in both male and female hamsters, although binding in females was always higher than that in males.(ABSTRACT TRUNCATED AT 250 WORDS)     

Photoperiod-melatonin relay in deer

Long-lived mammals from cold and temperate climates, including many species of deer, express overt cycles in reproduction, moulting, fattening and other characteristics. These cycles persist under constant conditions, but are normally induced and entrained by the annual cycle in daylength. The photoperiod-relay involves the eyes, the suprachiasmatic nuclei (SCN) of the hypothalamus and the pineal gland which secretes melatonin only at night. The duration of daily melatonin secretion varies with daylength and provides an internal endocrine signal for the time-of-year. In deer, treatments with melatonin induce phase-shifts in all overt seasonal rhythms. Melatonin is thought to act on specific target cells in the brain and pituitary gland which express high affinity melatonin receptors. In sheep, micro-implants of melatonin placed in the mediobasal hypothalamus (MBH) induce a complete spectrum of short-day responses, while surgical disconnection of the pituitary gland blocks all photoperiodic responses except for the regulation of prolactin. These observations support the 'dual-site hypothesis' that melatonin acts primarily in the MBH to control gonadotrophin secretion and the reproductive axis, but acts primarily in the pituitary gland via the pars tuberalis, to control prolactin secretion and the pelage axis. This differential regulation helps explains how prolactin can be 'the hormone of summer' in all photoperiodic ungulates irrespective of their seasonal breeding characteristics.     

Melatonin and seasonal depression

Melatonin (MEL) hypothesis in seasonal affective disorders (SAD) is supported by: a) historical hint; b) circadian and seasonal MEL periodicity with evidence that the SAD is related to photoperiod; c) relationship between incidence and severity of SAD and latitude; d) the response to bright artificial light (ineffective in depression) which mimics summer time; e) MEL administration can induce some symptoms of the SAD; f) several antidepressant drugs increase MEL plasma levels. Several of these findings are disproved: the light acts independently from the MEL, some antidepressant agents act without modifying MEL levels; a consistent alteration in MEL secretion within SAD has not been convincingly demonstrated. Relationship between incidence and severity of SAD and latitude suggests a new potential implication of MEL in SAD. The daytime melatonin values reflect changes along the scale of a year in sunshine. Accordingly, the about-yearly periodicity, much larger in amplitude than the half-yearly component, yields ratios smaller than unity. By contrast during darkness an about-half-yearly component is more prominent. As the aurora zone is approached, the intensity of magnetic disturbances increases. Thus, the intensity of these two variables shows inverse relationships with latitude and geomagnetic field decreases plasma levels of MEL and inhibits MEL function.     

Differential pattern of the circadian rhythm of serum melatonin in young and elderly healthy subjects

The daily profile of serum level of melatonin was studied in 10 young and 13 elderly subjects. All of the subjects were physically and psychiatrically healthy and did not have any clinical symptoms related to rhythm disturbance. Blood samples were taken every 3 h for 1 day and serum melatonin levels were determined by RIA. All except for 1 of the elderly subjects exhibited a clear circadian rhythm of serum melatonin level with a nocturnal peak. In both subject groups, the melatonin rhythm showed significant diurnal variation. There was no significant difference in the total melatonin level per day between young and elderly groups, suggesting that there was no influence of aging on daily total melatonin secretion. However, there was a marked difference in the features of the melatonin rhythm between the two groups, i.e., a rapid decline of the melatonin level from the nocturnal peak in the elderly group, suggesting that the off-set time of melatonin secretion advances with aging. Our findings suggest that the pattern of melatonin rhythm alters significantly without clear clinical symptoms in the process of senescence.     

The effect of melatonin on aqueous humor flow in humans during the day

BACKGROUND: Aqueous humor flow through the anterior chamber of the eye undergoes a circadian cycle. The rate of flow during the day is twice as high as the rate of flow at night. The pineal hormone, melatonin, also undergoes a circadian cycle. Melatonin levels are high at night, whereas aqueous humor flow is low. The authors studied the effect of oral melatonin on aqueous humor flow in humans. METHODS: The effect of melatonin on aqueous humor flow was evaluated in 19 healthy human volunteers in a randomized, masked crossover study with a placebo control. The hormone or placebo was administered orally during the day when endogenous levels of melatonin are low. Aqueous flow was measured by fluorophotometry for 8 hours. RESULTS: The mean rate of flow during melatonin treatment was 2.71 +/- 0.64 microliters/minute (+/- standard deviation). The rate of flow during placebo treatment was 2.80 +/- 0.66 microliters/minute. There is no statistically significant difference between these two rates (P = 0.4). With a sample size of 19, the study has a power of 92% to detect at least a 15% difference in the rate of flow under the two conditions. Measurement of plasma concentration of melatonin in five subjects confirmed that concentrations after oral dosage reached peaks comparable with the normal endogenous nocturnal peaks. CONCLUSIONS: The authors conclude that melatonin concentrations during the day, comparable with plasma concentrations that occur spontaneously during sleep, do not suppress aqueous humor formation. The authors find no support for the idea that plasma melatonin, per se, can suppress aqueous formation or that the circadian rhythm of plasma melatonin is primarily responsible for the circadian rhythm of aqueous humor flow.