Plasma Melatonin Profiles Research Articles

Plasma melatonin night‐time peak levels and 24‐hour area under the curve profile seem higher in AD patients with epileptiform activity than in those without

AbstractBackgroundPlasma melatonin levels drop in elderly, which might become more pronounced in Alzheimer’s disease (AD) as compared to controls.(1) Melatonin can serve as a potential biomarker for AD, given the inverse correlation between cerebrospinal fluid (CSF) melatonin levels and severity of neuropathology (Braak stages).(2) Due to suggested antiepileptic effects(6), melatonin can potentially slow down disease progression as epileptiform activity may contribute to AD disease progression.(3‐5). We here present a preliminary interim analysis of an ongoing study.Aims1. To evaluate melatonin’s potential as biomarker for AD by comparing blood melatonin levels between patients with mild cognitive impairment (MCI) and dementia due to AD and preclinical AD subjects.2. To study the link between melatonin levels and epileptiform activity in AD.MethodsAll subjects underwent a neuropsychological examination, and lumbar puncture for analysis of core AD CSF biomarkers or amyloid brain PET. Subjects belonging to the AD continuum (dementia [n = 7]; MCI [n = 4]; preclinical AD [n = 1]) were diagnosed according to the NIA‐AA research criteria. A subset of subjects (n = 6) underwent 50‐minute magnetoencephalography to detect epileptiform activity. Blood samples were taken multiple times during a 24‐hour period, in in‐hospital controlled circumstances, and were analysed by use of liquid chromatography‐mass spectrometry.ResultsAD patients with epileptiform activity (n = 2) tended to have a higher melatonin 24‐hour area under the curve (AUC) and peak concentration (AUC 517.9pg/ml.h [+/‐140.1pg/ml.h] versus 204.5pg/ml.h [+/‐115.5pg/ml.h]; peak 65.4pg/ml [+/‐14.6pg/ml] versus 25.8pg/ml [+/‐17.5pg/ml]) than AD patients without (n = 4) (p = 0.064 for both; MWU test). There was no statistical difference regarding the melatonin 24‐hour plasma AUC or peak levels between patients with dementia, MCI, preclinical AD subjects (p = 0.760 for both; Kruskall‐Wallis test). We have to interpret these data with caution since sample sizes are still small and more patients are being recruited.ConclusionOn the basis of very preliminary data, 24‐hour plasma melatonin profile and peak plasma melatonin concentration tended to be higher in AD patients with epileptiform activity than in those without. Whether this could be a potential compensatory mechanism against epileptiform activity in AD or whether melatonin could rather have pro‐epileptic effects, remains to be elucidated in future research.

Assessment of plasma melatonin profile in summer anestrous buffaloes exhibiting differential fertility following melatonin implants treatment

Plasma melatonin vis-a-vis anestrus or estrus status of buffaloes during summer or winter season (n=50 in each group) suggested its impact on reproductive axis as plasma melatonin activity tended to be higher (P>0.05) in buffaloes exhibiting estrus compared to their anestrous counterparts irrespective of season. The differential reproductive status of these buffaloes was confirmed by history as well as differences (P<0.05) in diameter of largest follicle and luteal profile. Further, for evaluating the impact of melatonin treatment during summer season on reproductive axis, 132 anestrous buffaloes were subcutaneously inserted 2x4 mm absorbable slow-release melatonin implants (18 mg/50 kg b wt) at the base of left ear and 60 buffaloes were used as control. In these buffaloes, ovarian ultrasonography and jugular vein blood sampling was carried out at 7-day interval till day 35 post-treatment or till ovulation, whichever was earlier. Control and implanted buffaloes were subjected to artificial insemination (AI) at overt or induced estrus followed by pregnancy diagnosis at day 90 post-AI. In treatment group, an increase (P<0.05) in plasma melatonin was recorded in all the buffaloes, exhibiting differential fertility status, during post-treatment study period compared to their pre-treatment and control group values. However, within treatment group, there was no difference (P>0.05) in plasma melatonin between ovulatory or non-ovulatory as well as between pregnant or non-pregnant counterparts. Moreover, plasma melatonin within control buffaloes remained similar (P>0.05) throughout the study period irrespective of differential exhibition of fertility. It can be concluded that factors other than circulating melatonin are also involved in the display of differential fertility in terms of initiation of ovarian cyclicity/ovulation or ability to conceive in summer anestrous buffaloes.

Light intensity and suppression of nocturnal plasma melatonin in Arctic charr (Salvelinus alpinus)

The problem of early sexual maturation among farmed Arctic charr and other salmonids can be effectively reduced by 24 h light overwinter, provided it is bright enough to over-ride interference from the natural daylength cycle. To determine the threshold light intensity to suppress the nocturnal elevation of plasma melatonin, three groups of individually tagged fish (n = 26–28/group ca. 1040 g) were reared on 12 h light: 12 h dark (LD 12:12) and subjected to nighttime light intensities of either 50–65, 0.1–0.3 or 0 (control) lux for five months (November to April). Daytime light intensity was 720–750 lx. Diel plasma melatonin profiles in both November and April were similar; mean daytime levels ranged from 20 to 100 pg/ml, and nighttime levels were inversely proportional to light intensity. In the control group at 0 lx, plasma melatonin increased about four-fold after lights-off, ranging between 320 and 430 pg/ml. Nighttime light intensity of 0.1–0.3 lx halved plasma melatonin levels to 140–220 pg/ml, and 50–65 lx further reduced the levels to one quarter of the control group, 68–108 pg/ml. Among the lit groups, daytime plasma melatonin levels were about 20–30 pg/ml, significantly lower than the nocturnal levels suggesting the diel hormonal rhythm was not completely abolished. Fish grew steadily from about 1100 g to 1600 g between November and April, independent of light intensity (P = .67). Overall, the study demonstrated the sensitivity of pineal melatonin hormone to different light intensities in Arctic charr.

Meagre's melatonin profiles under captivity: circadian rhythmicity and light sensitiveness.

The present study reveals the first characterization of the plasma melatonin rhythms of the meagre (Argyrosomus regius) under aquaculture conditions. Melatonin levels were monitored during a 24h cycle under a photoperiod of 16L:8D and under constant darkness (DD), respectively to characterize the daily rhythm of this indoleamine and to test its endogenous origin. Besides, to identify which light intensities are perceived as night or day by this species, the degree of inhibition of nocturnal melatonin production caused by increasing intensities of light was tested (3.3, 5.3, 10.5, and 120μW/cm2), applying 1h light pulses at Mid-Dark. The result for melatonin daily rhythm in plasma showed a typical profile: concentration remained low during all daytime points, increasing greatly during dark points, with maximum values at 16:00 and 22:00h, zeitgeber time. Under DD conditions, the plasma melatonin profile persisted, with a similar acrophase but with a lower amplitude between subjective day and night periods, indicating this rhythm as being endogenously driven. Moreover, meagre seemed to be very sensitive to dim levels of illumination during the night, since an intensity of just 3.3μW/cm2 inhibited melatonin production. However, only the pulse of 5.3μW/cm2 caused a melatonin drop till daytime concentrations. Thus, the threshold of light detection by the pineal organ was suggested as being located between 3.3 and 5.3μW/cm2. Such results are an added value for this species biology knowledge, and in consequence to its adaptation to aquaculture conditions, allowing the improvement of culture husbandry protocols.

Profile and reproductive roles of seminal plasma melatonin of boar ejaculates used in artificial insemination programs.

Melatonin (MLT) is present in seminal plasma (SP) of mammalian species, including pigs, and it is credited with antioxidant properties. This study aims to identify the sources of variation and the role of boar SP MLT on sperm quality and functionality and in vivo fertilizing ability of liquid-stored semen doses used in AI programs. The SP MLT was measured using an ELISA kit in a total of 219 ejaculates collected from 76 boars, and reproductive records of 5,318 AI sows were recorded. Sperm quality was assessed according to motility (computer-aided sperm analysis) and viability (cytometry evaluation). Sperm functionality was assessed according to the cytometric determination of intracellular HO generation, total and mitochondrial O production, and lipid peroxidation in liquid AI semen samples stored at 17°C over 144 h. The concentration of SP MLT differed among seasons ( < 0.01) and day length periods ( < 0.001) of the year, demonstrating that the ejaculates collected during the increasing day length period (9.80 ± 1.38 pg/mL, range: 2.75-21.94) had lower SP MLT concentrations than those collected during the decreasing day length period (16.32 ± 1.67 pg/mL, range: 5.02-35.61). The SP MLT also differed ( < 0.001) among boars, among ejaculates within boar, and among portions within the ejaculate, demonstrating that SP from the first 10 mL of sperm-rich ejaculate fraction (SRF) exhibited lower MLT concentrations than post-SRF. The SP MLT was negatively related ( < 0.001) to mitochondrial O production in viable sperm. The SP MLT did not differ among AI boars ( = 14) hierarchically grouped according to high and low fertility outcomes. In conclusion, SP MLT concentration in AI boars varies depending on the season of ejaculate collection and differs among boars, ejaculates within boar, and portions within ejaculate. The SP MLT may act at the mitochondrial level of sperm by reducing the generation of O. However, this antioxidant role of SP MLT was not reflected in sperm quality or in vivo fertility outcomes of AI semen doses.

Profile and reproductive roles of seminal plasma melatonin of boar ejaculates used in artificial insemination programs

Profile and reproductive roles of seminal plasma melatonin of boar ejaculates used in artificial insemination programs

Plasma Melatonin and Progesterone Profiles of Suffolk and Romney Marsh Ewes Implanted with Melatonin during Anoestrus Season at Lower Latitudes in Southern Hemisphere

Background: The subcutaneous implants of melatonin are stimulatory and mimic the positive effects of short photoperiod on reproduction in small ruminants. This study investigated the daily plasma melatonin profiles in ewes treated with melatonin implants and kept under natural photoperiod in Southeastern Brazil. The plasma progesterone concentrations were also investigated before and after melatonin implantation.Materials, Methods &amp; Results: Romney Marsh (n = 11) and Suffolk (n = 10) ewes, which had been isolated from rams for at least 2 months prior to the beginning of the trial, were randomly allocated in two groups based on melatonin implant treatment (with or without melatonin implant). For plasma melatonin concentration, 43 days after melatonin implantation and 3 days before the ram introduction blood samples were collected every 2 hours during 24 hours. For plasma progesterone concentrations, blood samples were collected every once to twice a week for 2 different periods: prior to melatonin implantation and 46 days after the melatonin implantation and at the same day of the introduction of rams. The hormonal concentrations were determined by the radioimmunoassay method (RIA). The data were analyzed according to MIXED procedure (SAS) as repeated measurements for random animal effects. The effect of melatonin treatment on plasma melatonin 24-h period varied according to the breed. At the dark-phase, there were no plasma melatonin differences (P &gt; 0.05) between implanted and no-implanted (228.02 ± 58.39 vs. 169.59 ± 48.39) Romney Marsh ewes whereas for Suffolk ewes the plasma melatonin levels were higher in implanted (305.61 ± 68.39 pg/mL) than no-implanted (151.26 ± 38.35 pg/mL) ones. At the light-phase, melatonin treatment effects could be evidenced and these differences (P &lt; 0.01) consisted of higher melatonin values for implanted ewes and basal values for no-implanted ones in both breed groups. Before the melatonin implantation, the plasma progesterone levels were ˂ 1 ng/mL for Romney Marsh (0.41 ± 0.02 ng/mL) and Suffolk (0.47 ± 0.02 ng/mL) ewes. During the ram introduction period, no melatonin treatment effect was observed on plasma progesterone concentrations in both breed groups, but 2 days after ram introduction the plasma progesterone concentrations increased the mean values &gt; than 1 ng/mL in implanted and no-implanted Suffolk ewes. In implanted Romney Marsh ewes the elevation of progesterone mean values was weak whereas in no-implanted Romney Marsh ewes the progesterone levels were maintained ˂ 1 ng/mL during all the blood sample collection times.Discussion: The melatonin treatment also produced a similar model of daily melatonin levels as reported previously by others, which is characterized by high plasma melatonin concentrations during the light phase of the day. The effect of melatonin implants on plasma melatonin profiles interacted with breed confirming an individual response to melatonin implantation which is proportional to genetic individual variation pattern of melatonin secretion. Before the melatonin implantation all Romney Marsh and Suffolk ewes were judged to be in non-ovulatory period (anoestrus) with plasma progesterone mean values lower than 1 ng/mL. The melatonin treatment helped to induce the ovulatory activity in most of the ewes that were in anestrous at the time of melatonin implantation and the efficacy of this treatment depends on the individual variation in ovulatory response to ram introduction. In Southeastern Brazil., melatonin implant altered the daily plasma melatonin profiles of Suffolk and Romney Marsh ewes by increasing the melatonin levels during the light-phase of the day. Melatonin implant also induced an ovulatory response in Suffolk and Romney Marsh after the introduction of the rams. For no-implanted Suffolk ewes, the male effect is sufficient to provoke an ovulatory response.

Bio-mimetic drug delivery systems designed to help the senior population reconstruct melatonin plasma profiles similar to those of the healthy younger population

The secretion of melatonin (MT) is obviously different in the younger and the senior sectors of the population, and the maximum plasma concentration of seniors is only half of that in the younger population group. If exogenous MT can be supplied to senior citizens based on the secretion rate and amount of endogenous MT in the younger population by a bio-mimetic drug delivery system (DDS), an improved therapeutic effect and reduced side effects can be expected. Based upon this hypothesis, the pharmacokinetic parameters of MT, namely, the absorption rate constant (ka), the elimination rate constant (ke), and the ratio of absorption rate (F) to the apparent volume of distribution (V) were obtained by a residual method depending on the plasma concentration curve of immediate release preparations in the healthy younger population. The dose-division method was applied to calculate the cumulative release profiles of MT achieved by oral administration of a controlled release drug delivery system (DDS) to generate plasma MT profiles similar to the physiological level-time profiles. The in vivo release of MT deduced from the healthy younger population physiological MT profiles as the pharmacokinetic output of the bio-mimetic DDS showed a two-phase profile with two different zero order release rates, namely, 4.919μg/h during 0–4h (r=0.9992), and 11.097μg/h during 4–12h (r=0.9886), respectively. Since the osmotic pump type of DDS generally exhibits a good correlation between in vivo and in vitro release behaviors, an osmotic pump controlled delivery system was designed in combination with dry coating technology targeting on the cumulative release characteristics to mimic the physiological MT profiles in the healthy younger population. The high similarity between the experimental drug release profiles and the theoretical profiles (similarity factor f2>50) and the high correlation between the predicted plasma concentration profiles and the theoretical plasma concentration profiles (r=0.9366, 0.9163, 0.9264) indicated that a prototype bio-mimetic drug delivery system of MT was established. The similarity factors between the experimental drug release profiles and the theoretical release profile were all larger than 50 both in periods of 0–4h and 4–12h, namely, 68.8 and 57.3 for the first batch (Batch No. 20131031), 76.7 and 50.2 for the second batch (Batch No. 20131101), and 73.7 and 51.1 for the third batch (Batch No. 20131126), respectively. The correlation coefficients between the predicted plasma concentration profiles based on the release profiles of the bio-mimetic DDS and physiological profiles were 0.9366 (Batch No. 20131031), 0.9163 (Batch No. 20131101), 0.9264 (Batch No. 20131126), respectively. Since the pharmacokinetic profile of MT in any kind of animal differs markedly from that of human beings, it is impossible to test the bio-mimetic DDS in animals directly. Therefore, the predicted pharmacokinetic profile based upon the in vitro release kinetics is an acceptable surrogate for the conventional animal test. In this research, a bio-mimetic DDS for replacement of MT was designed with in silico evaluation.

Effects of light regime on diurnal plasma melatonin levels and vertical distribution in farmed Atlantic cod (Gadus morhua L.)

Two studies were performed to study the effect of different light intensities on melatonin secretory profiles in Atlantic cod (Gadus morhua L.). In an indoor tank study, plasma melatonin profiles were measured over a 24-hour cycle in juvenile Atlantic cod reared under a 12h light:12h dark photoperiod, having either a high or low daytime light intensity (15.5 or 0.16μE·cm−2·s−1). In a second study, plasma melatonin levels were measured in Atlantic cod kept in traps at three depths (4, 9 and 14m) in a large sea cage following exposure to the following five experimental light regimes: (1) natural light (NL), (2) NL+artificial constant light (LL) at 2, 7 and 12m depth, (3) NL+LL at 2 or 12m, (4) NL+LL at 2m and (5) NL+LL at 2m together with additional surface shading. The vertical distribution of free swimming Atlantic cod in the same sea cage was monitored using hydroacoustics. In the tank experiment, diurnal plasma melatonin profiles were similar under low and high light intensity, remaining low during the light period, then increasing rapidly within 15–30min of lights off, before peaking around midnight. In the sea cage experiment, fish under NL showed a similar diurnal rhythm in plasma melatonin levels, with high melatonin levels during the dark period, although at sunrise melatonin levels started to fall earlier in fish kept at 4m depth compared to fish kept at 9 and 14m. Overall, melatonin profiles were most effectively reduced, in terms of relative (day/night) plasma levels, in those fish sampled at the deepest depth (14m). Relative plasma melatonin levels were correlated to the distance from the artificial light source and the intensity of the ambient light. Dispersed light (lamps at 2, 7 and 12m) was the most effective light regime for inhibiting the nocturnal rise in plasma melatonin ratios in fish sampled at all three depths. Finally, exposure to the different light regimes did not influence the vertical distribution of Atlantic cod within the sea cage, which consistently remained close to the bottom of the cage.

Human phase response curve to a 1 h pulse of bright white light

The phase resetting response of the human circadian pacemaker to light depends on the timing of exposure and is described by a phase response curve (PRC). The current study aimed to construct a PRC for a 1 h exposure to bright white light (∼8000 lux) and to compare this PRC to a <3 lux dim background light PRC. These data were also compared to a previously completed 6.7 h bright white light PRC and a <15 lux dim background light PRC constructed under similar conditions. Participants were randomized for exposure to 1 h of either bright white light (n=18) or <3 lux dim background light (n=18) scheduled at 1 of 18 circadian phases. Participants completed constant routine (CR) procedures in dim light (<3 lux) before and after the light exposure to assess circadian phase. Phase shifts were calculated as the difference in timing of dim light melatonin onset (DLMO) during pre- and post-stimulus CRs. Exposure to 1 h of bright white light induced a Type 1 PRC with a fitted peak-to-trough amplitude of 2.20 h. No discernible PRC was observed in the <3 lux dim background light PRC. The fitted peak-to-trough amplitude of the 1 h bright light PRC was ∼40% of that for the 6.7 h PRC despite representing only 15% of the light exposure duration, consistent with previous studies showing a non-linear duration–response function for the effects of light on circadian resetting.

Pharmacokinetics of Melatonin in Preterm Infants

Background: There is strong experimental evidence of a neuroprotective effect of melatonin in immature animals. However, pharmacokinetic (PK) data on melatonin in preterm infants is lacking. The aim was to examine the preterm pharmacokinetic profile.Methods: We conducted a multi centre, open label study in infants < 31 weeks and < 7 days of age. A single intravenous melatonin infusion was given to successive groups. Melatonin and its primary urinary metabolite aMT6s were analysed by radioimmunoassay. Dosage was adjusted in subsequent groups until adult physiological levels were achieved (34.5-1185.3 pmol/L).Results: 18 preterms were enrolled. The results are summarized in table/graph below. Pre-infusion median plasma melatonin levels were 0pmol/L (range-0-165pmol/L). Blood melatonin levels closest to adult levels were achieved with a 2 hour infusion of 0.1mcg/kg/hr; the half life was 15.99 hours and Area under the curve-7234.74. Lower doses resulted in widely variable PK data. Figure [Plasma Melatonin Profile] Table Table Full size table Conclusion: Preterms have none or minimal circulating plasma melatonin. Urinary aMT6s levels are negligible in this gestational age group, probably because of immature liver metabolism. This melatonin PK data will be used in future clinical studies to test the hypothesis that melatonin has a neuroprotective effect.

The effects of continuous photoperiod (24L:0D) on growth of juvenile barramundi (Lates calcarifer)

The efficacy of photoperiod manipulation to influence growth and developmental processes is well documented in a range of temperate aquaculture species. However, the application of such techniques with tropical species requires further investigation. This preliminary 20-day study investigated the influence of continuous photoperiod on growth of barramundi (Lates calcarifer). In addition, diel plasma melatonin profiles provided a physiological measure of how the endocrine system of barramundi responded to continuous photoperiod. Juvenile barramundi (1.33 ± 0.02 g) were held in recirculation systems under 12-h light: 12-h dark (12L:12D) or 24-h light (24L:0D) with a light intensity of 1,000 lux throughout the water column. Fish from both treatments grew to more than 14 times their original weight, with final weight (24L:0D = 21.59 ± 0.85 g; 12L:12D = 19.12 ± 0.55 g), total length (24L:0D = 12.67 ± 0.14 cm; 12L:12D = 11.96 ± 0.13 cm) and specific growth rate (24L:0D = 9.60 ± 0.05% bw day−1; 12L:12D = 9.14 ± 0.06% bw day−1) being significantly higher for fish grown on 24L:0D compared with 12L:12D. There were no significant differences in feed intake (24L:0D = 226.46 ± 6.27 g; 12L:12D = 219.02 ± 5.73 g) or feed conversion ratio (24L:0D = 0.71 ± 0.06; 12L:12D = 0.80 ± 0.07) between light treatments. Barramundi held under 12L:12D exhibited diel melatonin secretion, which peaked mid-dark phase (171.83 ± 4.81 pg ml−1) followed by a gradual decrease in base levels at the onset of illumination (68.61 ± 8.77 pg ml−1). When juvenile barramundi were subjected to 24L:0D, the amplitude of peak melatonin secretion was significantly suppressed during the subjective mid-dark phase (129.71 ± 2.36 pg ml−1). This preliminary study confirmed that barramundi respond to photoperiod manipulation in a similar manner to many temperate fish species, thus demonstrating the future potential use of artificial lighting to improve growth in this species commercially.

Rest-Activity Disturbances in Children with Septo-Optic Dysplasia Characterized by Actigraphy and 24-Hour Plasma Melatonin Profiles

A trial of melatonin treatment in children with septo-optic dysplasia (SOD) and sleep disruption is accepted clinical practice in many centers. However, no objective measurements of sleep/activity patterns with 24-h melatonin profiles have been published for these individuals, and the pathophysiological basis underlying sleep disorders in SOD remains largely unknown. We studied six children with rest-activity disturbances and SOD. All wore an Actiwatch-Mini (a noninvasive method of detecting and recording movement intensity) for 2 wk and were admitted to hospital for a 24-h period during which hourly measurements of serum melatonin were taken. Sleep data were analyzed in conjunction with a detailed sleep diary. Ethical approval was obtained for these studies. Two children produced virtually no melatonin throughout the 24-h period of measurement and had fragmented sleep patterns with no evidence of a non-24-h sleep-wake disorder or delayed sleep-phase disorder. One child had a normal melatonin profile despite actigraphy showing an arrhythmic sleep pattern. The remaining three children had fragmented sleep, with two having normal melatonin profiles and one having a modest increase in daytime melatonin concentrations, making the timing of dim-light melatonin onset difficult to discern. There is considerable variation in timing and amount of melatonin secretion in these children. Surprisingly, none of the children had either actigraphic or melatonin profile evidence of a non-24-h sleep-wake disorder or delayed sleep-phase disorder. Understanding the heterogeneous nature of underlying sleep disorders in this group of children is important and has implications for their management.

On the Origin and the Consequences of Circadian Abnormalities in Patients With Cirrhosis

Plasma melatonin profile abnormalities have been described in patients with cirrhosis and generally attributed to impaired hepatic melatonin metabolism. The possibility that they might reflect circadian clock dysfunction has not been explored. In addition, the relationship between plasma melatonin profiles and the sleep disturbances observed in these patients remains unclear. The aims of this study were: (i) to evaluate circadian clock function and hepatic melatonin metabolism in cirrhotic patients, and (ii) to study the relationship between plasma melatonin profiles and sleep-wake behavior. The study population comprised 20 patients with cirrhosis (mean (range) age, 59 (39-77) years) and 9 healthy volunteers (60 (38-84) years). Plasma melatonin/cortisol concentrations were measured hourly, for 24 h, in light/posture-controlled conditions. Urinary 6-sulfatoxymelatonin, the main melatonin metabolite, was measured simultaneously to determine clearance. The ability of light to suppress nocturnal melatonin synthesis was assessed. Habitual sleep quality/timing was evaluated using a questionnaire, actigraphy, and sleep diaries. There was evidence of central circadian disruption in patients compared with healthy controls: peak plasma melatonin/cortisol times were delayed (04:48+/-02:36 vs. 02:48+/-00:54, P=0.01; 10:18+/-02:54 vs. 08:54+/-01:24, P=0.06) and the plasma melatonin response to light was reduced (12%+/-19% vs. 24%+/-15%, P=0.09). However, the mean 24 h plasma melatonin clearance did not differ significantly between patients and healthy volunteers (0.22+/-0.10 vs. 0.28+/-0.17 l/kg per h, P=0.36). Finally, although patients showed a degree of misalignment between sleep and circadian timings, there was no association between circadian abnormalities and impaired sleep quality. Plasma melatonin profile abnormalities, predominantly central in origin, are observed in patients with mild to moderately decompensated cirrhosis. However, they are substantially unrelated to the sleep disturbances prevalent in this population.

Interaction of chronic sleep restriction and circadian system in humans

Nocturnal sleep restriction and compensation with daytime naps is common in today's society. In a between-participants design, we examined the effects of chronic (10 nights) sleep restriction on 24 h plasma melatonin profiles in humans. Following a baseline period with 8.2 h time in bed (TIB) for sleep, participants were randomized to a control (8.2 h TIB) or sleep-restriction condition (4.2 h TIB), with and without diurnal naps. Sleep restriction was achieved via delaying bedtime and advancing wake time by 2 h each relative to the baseline sleep period. Participants were maintained in a controlled, time isolated laboratory environment throughout the protocol, with light levels below 40 lx at all times. Twenty-four hour plasma melatonin profiles were assessed at baseline and at the end of the sleep-restriction period, with subjects maintained in a constant posture protocol. Compared with the baseline assessment and the 8.2 h TIB control group, a significant phase delay in melatonin onset (1.2 +/- 0.9 h) occurred in all sleep-restriction (4.2 h TIB) groups (P < 0.05). There was no evidence of a phase advance or shortening of the period of melatonin secretion associated with the advanced waking time. These results suggest that nocturnal light and dark exposure may be more potent in effecting circadian phase shifts than exposure to morning light, at least in conditions of controlled, dim lighting in the laboratory.

Role of neuroendocrine pathways in cognitive decline during aging

The pineal and pituitary–adrenocortical secretions play an important role in adaptive responses of the organism acting as coordinating signals for both several biological rhythms and multiple neuroendocrine and metabolic functions. The more relevant neuroendocrine changes occurring with ageing affect the secretion of melatonin and of corticosteroids. These changes may be clearly appreciated by the study of their circadian rhythmicity. The circadian profile of plasma melatonin was clearly flattened in elderly subjects and even more in old individuals with dementia. Indeed, the impairment of melatonin signal occurring in aging was related either to age itself or to the cognitive performances of subjects. The biosynthetic dissociation between glucocorticoids and androgen secretion is responsible for the selective impairment of androgens, such as DHEA and DHEA-S, by comparison to cortisol. Due to the opposite effects of the two kinds of corticosteroids either in the periphery and in the CNS, the imbalance between glucocorticoids and androgens, well demonstrated by the evaluation of the cortisol/DHEA-S molar ratio, may be responsible for the occurrence in the CNS of a more neurotoxic steroidal milieu, already present in clinically healthy elderly subjects and especially in patients with dementia. The effects of that steroidal milieu are more prominent at the level of the hippocampal–limbic structure, involved both in the modulation of endocrine structures, such as the HPA axis, and in the control of cognitive, behavioral and affective functions.

Light–dark variations in plasma melatonin concentrations in the pot‐bellied seahorse Hippocampus abdominalis Lesson, 1827

A diel plasma melatonin profile measured in adult pot‐bellied seahorses Hippocampus abdominalis showed that this species produces elevated levels of melatonin during the scotophase, returning to basal levels during the photophase.

Daytime light intensity affects seasonal timing via changes in the nocturnal melatonin levels

Daytime light intensity can affect the photoperiodic regulation of the reproductive cycle in birds. The actual way by which light intensity information is transduced is, however, unknown. We postulate that transduction of the light intensity information is mediated by changes in the pattern of melatonin secretion. This study, therefore, investigated the effects of high and low daytime light intensities on the daily melatonin rhythm of Afro-tropical stonechats (Saxicola torquata axillaris) in which seasonal changes in daytime light intensity act as a zeitgeber of the circannual rhythms controlling annual reproduction and molt. Stonechats were subjected to light conditions simulated as closely as possible to native conditions near the equator. Photoperiod was held constant at 12.25 h of light and 11.75 h of darkness per day. At intervals of 2.5 to 3.5 weeks, daytime light intensity was changed from bright (12,000 lux at one and 2,000 lux at the other perch) to dim (1,600 lux at one and 250 lux at the other perch) and back to the original bright light. Daily plasma melatonin profiles showed that they were linked with changes in daytime light intensity: Nighttime peak and total nocturnal levels were altered when transitions between light conditions were made, and these changes were significant when light intensity was changed from dim to bright. We suggest that daytime light intensity could affect seasonal timing via changes in melatonin profiles.

Increased REM Sleep Associated with Melatonin Deficiency after Pinealectomy: A Case Study

The objectives of the investigation were to assess hypersomnia, which progressively appeared in a young patient after a pinealectomy, chemotherapy, and radiotherapy for a typical germinoma, as well as the potential benefit of melatonin administration in the absence of its endogenous secretion. 24 h ambulatory polysomnography and the Multiple Sleep Latency Test (MSLT) were performed; in addition, daily plasma melatonin, cortisol, growth hormone, prolactin, and rectal temperature profiles were determined before and during melatonin treatment (one 2 mg capsule given nightly at 21:00 h for 4 weeks). MSLT showed abnormal sleep latency and two REM sleep onsets. Nighttime total sleep duration was lengthened, mainly as a consequence of an increased REM sleep duration. These parameters were slightly modified by melatonin replacement. Plasma melatonin levels, which were constantly nil in the basal condition, were increased to supraphysiological values with melatonin treatment. The plasma cortisol profile showed nycthemeral variation within the normal range, and the growth hormone profile showed supplementary diurnal peaks. Melatonin treatment did not modify the secretion of either hormone. The plasma prolactin profile did not display a physiological nocturnal increase in the basal condition; however, it did during melatonin treatment, with the rise coinciding with the nocturnal peak of melatonin concentration. A 24 h temperature rhythm of normal amplitude was persistent, though the mean level was decreased and the rhythm was dampened during melatonin treatment. The role of radiotherapy on the studied parameters cannot be excluded; the findings of this case study suggest that the observed hypersomnia is not the result of melatonin deficiency alone. Overall, melatonin treatment was well tolerated, but the benefit on the sleep abnormality, especially on daytime REM sleep, was minor, requiring the re‐introduction of modafinil treatment.

Effects of Melatonin Feeding on Smoltification in Masu Salmon (Oncorhynchus masou)

Influences of photoperiod on plasma melatonin profiles and effects of melatonin administration on long-day-induced smoltification in masu salmon (Oncorhynchus masou) were investigated in order to reveal the roles of melatonin in the regulation of smoltification in salmonids. Under light-dark (LD) cycles, plasma melatonin levels exhibited daily variation, with higher values during the dark phase than during the light phase. The duration of nocturnal elevation under short photoperiod (LD 8:16) was longer than that under long photoperiod (LD 16:8). Melatonin feeding (0.01, 0.1 and 1 mg/kg body weight) elevated plasma levels of melatonin in a dose-dependent manner for at least 7 h but not for 24 h. When masu salmon reared under short photoperiod were exposed to long photoperiod (LD 16:8) and fed melatonin (1 mg/kg body weight) 7 hours before the onset of darkness, a significantly smaller proportion of smolts appeared in the melatonin-fed group after 32 days than in the control group. However, after 59 days of the treatment, there was no difference in the proportion of smolts between the control and melatonin-treated groups. Thus, melatonin feeding mimicked the effects of short photoperiod, which delays but does not completely suppress smoltification. These results indicate that the day length is transduced into changes in the duration of nocturnal elevation in plasma melatonin levels, and that artificial modification of the plasma melatonin pattern possibly delays the physiological processes of smoltification induced by long-day photoperiodic treatment.