Some Perturbations That Disturb the Circadian Melatonin Rhythm

The circadian melatonin rhythm is highly reproducible and generally not easily altered. The few perturbations that are capable of significantly changing either the amplitude or the pattern of the 24-h melatonin rhythm are summarized herein. Aging alters cyclic melatonin production by decreasing the amplitude of the nocturnal melatonin peak in all species in which it has been studied. The best known acute suppressor of nocturnal melatonin is light exposure. The brightness of light required to acutely depress pineal melatonin production is species dependent; of the visible wavelengths, those in the blue range (～500-520 nm) seem most effective in suppressing melatonin production. Nonvisible, nonionizing radiation in the extremely low frequency range (e.g., 60 Hz) seems also capable of altering pineal melatonin synthesis. Hormones have relatively little influence on the circadian production of melatonin, although either adrenalectomy or hypo-physectomy does attenuate the amplitude of the melatonin cycle. Exercise at the time of high melatonin production rapidly depresses pineal concentrations of the indole without influencing its synthesis; the mechanism of this suppression remains unknown.     

Some Perturbations That Disturb the Circadian Melatonin Rhythm

The circadian melatonin rhythm is highly reproducible and generally not easily altered. The few perturbations that are capable of significantly changing either the amplitude or the pattern of the 24-h melatonin rhythm are summarized herein. Aging alters cyclic melatonin production by decreasing the amplitude of the nocturnal melatonin peak in all species in which it has been studied. The best known acute suppressor of nocturnal melatonin is light exposure. The brightness of light required to acutely depress pineal melatonin production is species dependent; of the visible wavelengths, those in the blue range (∼500-520 nm) seem most effective in suppressing melatonin production. Nonvisible, nonionizing radiation in the extremely low frequency range (e.g., 60 Hz) seems also capable of altering pineal melatonin synthesis. Hormones have relatively little influence on the circadian production of melatonin, although either adrenalectomy or hypo-physectomy does attenuate the amplitude of the melatonin cycle. Exercise at the time of high melatonin production rapidly depresses pineal concentrations of the indole without influencing its synthesis; the mechanism of this suppression remains unknown.     

Melatonin Treatment Entrains the Rest-Activity Circadian Rhythm in Rats With Chronic Inflammation

We assessed the therapeutic effect of exogenous melatonin (MEL), dexamethasone (DEXA), and a combination of both on nociceptive response induced by chronic inflammation and on the rest-activity circadian rhythm in rats. A total of 64 animals were randomly divided into eight groups of eight rats each: one control group and seven groups with complete Freund’s adjuvant–inflamed animals (CFA; injection into the footpad). One of the CFA-inflamed groups did not receive any treatment; the other six were treated with melatonin (MEL), dexamethasone (DEXA), melatonin plus dexamethasone (MELDEXA), and their respective vehicles. Fifteen days after CFA injection, animals were treated with intraperitoneal injection of MEL (50?mg/kg) or its vehicle (8% ethanol in saline), DEXA (0.25?mg/kg) or its vehicle (saline), and MEL plus DEXA or their vehicles, for 8 days. The von Frey test was performed 24?h after the last administration of each treatment regimen. Hind paw thickness was measured using a pachymeter during the treatment days. The degree of swelling and histological findings were analyzed. All treated groups significantly reduced the severity of inflammation when compared with their vehicles (repeated-measures analysis of variance [ANOVA], p?<?0.05 for all analyses). Inflamed animals treated with dexamethasone alone or associated with melatonin showed marked inhibition of histological findings. On the other hand, the group treated with melatonin remained with moderate inflammation. The CFA group showed a decrease in the mean rest-activity circadian rhythm, determined by the number of touch-detections per hour during water intake in comparison with the control group; only the group treated with melatonin showed a synchronized rest-activity rhythm. At the end of treatment, a significant increase was observed in hind paw withdrawal threshold on the von Frey test in the treated groups (one-way ANOVA, p?<?0.05 for all). Our findings showed that melatonin (50?mg/kg) has strong chronobiotic and antinociceptive effects, but only mild anti-inflammatory effects. This evidence supports the hypothesis that melatonin can induce phase advance and circadian rhythm synchronization in rats with chronic inflammation.     

Circadian Rhythm in Pineal Methionine S-Adenosyltransferase

Abstract: The circadian rhythm of methionine S -adenosyltransferase, which catalyzes the formation of S -adenosylmethionine, a cosubstrate for melatonin in the pineal gland, follows the pattern of hydroxyindole- O -methyltransferase. Around the middle of the dark period, methionine S -adenosyltransferase and hydroxyindole- O -methyltransferase appear to be elevated by 2.5- and 1.5-fold, respectively, and tend to fall back during the light period.     

The Circadian Body Temperature Rhythm in the Elderly: Effect of Single Daily Melatonin Dosing

The present study is part of a more extensive investigation dedicated to the study and treatment of age‐dependent changes/disturbances in the circadian system in humans. It was performed in the Tyumen Elderly Veteran House and included 97 subjects of both genders, ranging from 63 to 91 yrs of age. They lived a self‐chosen sleep‐wake regimen to suit their personal convenience. The experiment lasted 3 wks. After 1 control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen?) daily at 22:30 h for 2 wks. The other 34 subjects were given placebo. Axillary temperature was measured using calibrated mercury thermometers at 03:00, 08:00, 11:00, 14:00, 17:00, and 23:00 h each of the first and third week. Specially trained personnel took the measurements, avoiding disturbing the sleep of the subjects. To evaluate age‐dependent changes, data obtained under similar conditions on 58 young adults (both genders, 17 to 39 yrs of age) were used. Rhythm characteristics were estimated by means of cosinor analyses, and intra‐ and inter‐individual variability by analysis of variance (ANOVA). In both age groups, the body temperature underwent daily changes. The MESOR (36.38±0.19°C vs. 36.17±0.21°C) and circadian amplitude (0.33±0.01°C vs. 0.26±0.01°C) were slightly decreased in the elderly compared to the young adult subjects (p<0.001). The mean circadian acrophase was similar in both age groups (17.19±1.66 vs. 16.93±3.08 h). However, the inter‐individual differences were higher in the older group, with individual values varying between 10:00 and 23:00 h. It was mainly this phase variability that caused a decrease in the inter‐daily rhythm stability and lower group amplitude. With melatonin treatment, the MESOR was lower by 0.1°C and the amplitude increased to 0.34±0.01°C, a similar value to that found in young adults. This was probably due to the increase of the inter‐daily rhythm stability. The mean acrophase did not change (16.93 vs. 16.75 h), although the inter‐individual variability decreased considerably. The corresponding standard deviations (SD) of the group acrophases were 3.08 and 1.51 h (p<0.01). A highly significant correlation between the acrophase before treatment and the phase change under melatonin treatment indicates that this is due to a synchronizing effect of melatonin. Apart from the difference in MESOR, the body temperature rhythm in the elderly subjects undergoing melatonin treatment was not significantly different from that of young adults. The data clearly show that age‐dependent changes mainly concern rhythm stability and synchronization with the 24 h day. A single daily melatonin dose stabilizes/synchronizes the body temperature rhythm, most probably via hypothermic and sleep‐improving effects.     

动物内源褪黑素调控生物节律的研究进展

内源褪黑素对人类和其他哺乳动物的节律行为具有调控功能。生物节律是自然进化赋予生命的基本特征之一,生物体的生命活动受到生物节律的控制与影响。在哺乳动物中,节律调控中心是松果体,其主要功能是合成和分泌褪黑素。褪黑素广泛参与生物体节律行为的调节,本文从褪黑素的产生和作用机制,分别阐述褪黑素对昼夜节律行为和多种年节律行为的调控作用,同时明确褪黑素与生物钟及神经内分泌系统的直接作用和反馈互动的复杂集合,进一步揭示褪黑素调控生物节律的重要作用,以期为褪黑素的基础研究以及未来探究生物体的生物钟内源性发生机制提供参考。     

Circadian Rhythm in Plasma Noradrenaline of Healthy Sleep-Deprived Subjects

Under normal sleep-wake conditions, noradrenaline (NA) secretions in supine subjects exhibit a weak circadian variation with a peak that occurs around noon; the sleep span is characterized by reduced NA secretion. Some investigators have reported that the circadian NA rhythm is completely obliterated during sleep deprivation. In our laboratory, plasma NA was assayed every hour for 24 h in nine healthy men 20-23 years of age. All men were deprived of sleep and were required to eat and walk around every hour to prevent sleep. However, subjects remained supine for 20 min before blood samples were collected to eliminate the effect of activity. Persistence of a slight decrease in the night concentration in several subjects, despite sleep deprivation, suggests that NA secretion may be influenced by a biological clock whose activity becomes visible when the influence of posture is removed.     

大鼠下丘脑交叉上核中CREB的昼夜节律

利用凝胶迁移率变化的实验方法,对饲养在光照－黑暗循环的条件和持续黑暗的条件下Wistar雄性大鼠下丘脑交叉上核中CREB含量的昼夜间变化进行了分析,发现CREB在交叉上核中具有内源性的昼夜节律.     

Uncertainty in Health Risks from Artificial Lighting due to Disruption of Circadian Rhythm and Melatonin Secretion: A Review

Incandescent lighting in many domestic and commercial applications is in the process of replacement by more efficient light sources, such as the compact fluorescent light (CFL) and the light emitting diode (LED). For household use, both CFL and LED sources have a significant blue component in the emitted spectrum in comparison to the warmer incandescent globes and this has been the cause of emerging health concerns. Recent research suggests that the blue light bandwidth in the visible spectrum has a significant impact on physical health, including disruption of the internal body clock and suppression of melatonin secretion at night. This disruptive effect has been linked to a range of illnesses, including breast cancer, prostate cancer, heart disease, obesity, and diabetes. There have also been positive effects observed, including re-setting the body clock to the required sleep pattern, boosting mood, alertness, cognitive performance, and alleviating seasonal affective depression (SAD). In this article, an introduction and review of recent research is provided, relevant health issues are highlighted and discussed, and uncertainty analysis completed for the dose–response curve for melatonin suppression as a function of incident photon density.     

The Circadian Rhythm of Plasma Thyrotropin in Depression and Recovery

The 24-hr patterns of plasma thyrotropin have been observed in 12 endogenous depressed patients in both depressed and recovered states and in 13 normal subjects. A clear circadian rhythm was detected in controls with high values at night. In depression, the circadian rhythm was altered with amplitude reduction and blunted nocturnal secretion, abnormalities particularly relevant in bipolar patients. This flattened profile could be linked to the blunted response of TSH to TRH administration reported in depressed patients. Normal nyctohemeral patterns have been restored after recovery. These chronobiological abnormalities as well as their normalization under antidepressant drugs seem to be similar to those reported for various parameters (e.g. temperature, Cortisol, etc) in depression which could support the chronobiological hypothesis for affective disorders.     

The Circadian Rhythm of Plasma Thyrotropin in Depression and Recovery

The 24-hr patterns of plasma thyrotropin have been observed in 12 endogenous depressed patients in both depressed and recovered states and in 13 normal subjects. A clear circadian rhythm was detected in controls with high values at night. In depression, the circadian rhythm was altered with amplitude reduction and blunted nocturnal secretion, abnormalities particularly relevant in bipolar patients. This flattened profile could be linked to the blunted response of TSH to TRH administration reported in depressed patients. Normal nyctohemeral patterns have been restored after recovery. These chronobiological abnormalities as well as their normalization under antidepressant drugs seem to be similar to those reported for various parameters (e.g. temperature, Cortisol, etc) in depression which could support the chronobiological hypothesis for affective disorders.     

Circadian Rhythm Changes in Autotrophic Euglena Induced by Organic Carbon Sources*

SYNOPSIS. Acetate added to autotrophic Euglena cultures changed the period length of the circadian rhythm of phototaxis. Phase shifts were induced by acetate pulses. Since transition from one metabolic state to another (autotrophic/mixotrophic) caused a phase shift or a period change, such effects possibly result from switching metabolic pathways. As suggested (Brinkmann, K., 1966. Planta 70 , 344–89), differences in the temperature responses of the rhythm in mixotrophic and autotrophic cells might also be caused by participation of different metabolic pathways with different Q¹⁰ values, e.g. dark reactions vs photochemical reactions. However the Q¹⁰ of a given dark reaction, e.g. protein synthesis, can differ in the 2 states. Therefore temperature experiments alone do not suffice for deciding whether the pathways include photochemical reactions, dark reactions, or both.     

Influence of the Amount of Light Received during the Day and Night Times on the Circadian Rhythm of Melatonin Secretion in Women Living Diurnally

The study investigated the relationship between the circadian variation of salivary melatonin and the amount of light received during the day and night. Forty one females served as subjects. An illuminance meter worn on the wrist of the non-dominant arm measured the amount of light which subjects leading a diurnal lifestyle received during two consecutive days. Light received from the time of rising to 18:00h was defined as ‘daytime light’, and that from 18:00h to the time of retiring as ‘nighttime light’. The average amount of light over the two days was 48 × 10 4 lx during the daytime and 11 × 10 4 lx during the nighttime. Saliva was collected every 4h in order to measure melatonin secretion. Peaks of melatonin secretion were observed at 14:00h and 18:00h in the subjects who had received lesser amounts of light during the daytime and nighttime. Melatonin secretion was high around 22:00h and peaked around 02:00h in the subjects who had received greater amounts of light during the daytime and lesser amounts of light during the nighttime. Nocturnal melatonin secretion was suppressed in the subjects who received greater amounts of light during the nighttime. Thus, the amount of light received during the daytime and the nighttime during the course of a diurnal lifestyle could have a profound influence on the circadian pattern of melatonin secretion.     

Diurnal Sensitivity of the Neuroendocrine-Reproductive Axis to the Antigonadotrophic Influence of Melatonin in Male Syrian Hamsters with Experimentally Altered Cortisol Rhythms

Two different experimental models were used to test if a temporal relationship exists between the rhythm of adrenal steroid secretion and the vulnerability of the hamster reproductive system to short photoperiod exposure or to the daily afternoon injection of melatonin. In the first experiment adrenalectomized hamsters were implanted with a Cortisol pellet to provide a sustained, rather than rhythmic, level of the hormone. The animals were either placed in short photoperiod or given a daily afternoon melatonin injection. In both cases the gonads underwent atrophy. In the second experiment adrenalectomized hamsters were given a Cortisol injection either in the morning (approx. 8 hr before the subsequent afternoon injection of melatonin) or in the afternoon (approx. 1 hr before the subsequent melatonin injection). Measurements of testicular and accessory organ weights 7 weeks later indicated regression of the reproductive system in both the groups when compared with their appropriate controls. Depressed levels of plasma LH. PRL, testosterone and thyroxine (T4) in these animals confirmed the melatonin induced gonadal collapse. The results suggest that apparently there is no temporal correlation between the rhythm of secretion of the adrenal steroids and the responsiveness of the reproductive system to late afternoon injection of melatonin. Interestingly, all the adrenalectomized Cortisol injected control animals (not receiving melatonin) had depressed plasma LH and PRL while the testicular weights and plasma testosterone titers remain unaffected.     

果蝇昼夜节律的分子机制研究进展

果蝇由于遗传易操作性而成为一个研究昼夜节律分子机制的理想模式生物 . 到目前为止,通过遗传学和生物化学方法已经鉴定到 10 多个时钟基因 (clock genes) 和许多时钟相关基因,包括时钟输入基因和钟控基因 . 这些时钟基因以及它们的相应产物组成两个互相依赖的转录 / 翻译反馈环路,从而调节行为和生理的昼夜节律 . 果蝇这种核心钟的工作原理同样见于哺乳动物 .     

Circadian Rhythm in Muscarinic Receptor Subtypes in Rat Forebrain

The binding of different ligands to muscarinic receptors in the centra) nervous system is regulated by several factors. Among these are the administration of drugs, disease, ontogeny or aging. Studies carried out in rat brains have demonstrated changes in the density of the muscarinic receptors at different times of the day. These changes might be related to variations in the circadian rhythms. In this work we have studied the binding of the [3H]-N-methyl-escopolamine, the agonist carbachol and the antagonist pirenzepine to muscarinic receptors in rat forebrains at 10.00,14.00,18.00,22.00,02.00 and 06.00 hr. We have observed changes in the density of muscarinic receptors but not changes in affinity to the radioligand. The Bmax values obtained by saturation studies were maximum at 14.00 hr and minimum at 02.00 hr (p < 0.05 Mann-Whitney's test). Inhibition studies in the presence of the non-selective agonist carbachol and the selective antagonist pirenzepine, at the same time-points, did not show statistically significant changes in the Bmax values. These data indicate that changes in the Bmax values are only observed in the total population of muscarinic receptors and are not due to modifications in the subtypes of muscarinic receptors nor to the different affinity states of agonist binding.     

宽叶吊兰叶绿素生物合成的昼夜节律变化

在被子植物中,从谷氨酰-tRNA到叶绿素的生物合成是由许多酶催化的级联反应,其中间代谢产物具有较强的光反应活性和细胞毒性,因此这一过程在细胞内受到严格的调控。本研究通过检测宽叶吊兰叶片叶绿素生物合成途径的14种中间产物含量随昼夜节律的变化,探讨昼夜节律对宽叶吊兰叶绿素生物合成的影响。结果表明,中间产物ALA(δ-氨基乙酰丙酸)、PBG(胆色素原)、ProtoⅨ(原卟啉Ⅸ)、Heme(血红素)、Mg-ProtoⅨ(镁原卟啉Ⅸ)、Chlide a(叶绿素酸酯a)、Chlide b(叶绿素酸酯b)、Chl a(叶绿素a)、Chl b(叶绿素b)受光诱导,而UrogenⅢ(尿卟啉Ⅲ)、CoprogenⅢ(粪卟啉Ⅲ)和Pchlide(原叶绿素酸脂)受黑暗诱导,尤其是Pchlide在黑暗中的积累量显著增加;Mpe(镁原卟啉Ⅸ单甲酯)和Mpde(镁原卟啉Ⅸ二酯)具有2个积累峰值,分别出现在中午12∶00和夜间24∶00。说明叶绿素生物合成受昼夜节律的调控,但其中间代谢产物含量的变化规律与昼夜节律并不完全一致。     

The Daily Melatonin Pattern in Djungarian Hamsters Depends on the Circadian Phenotype

Djungarian hamsters (Phodopus sungorus) bred at the Institute of Halle reveal three different circadian phenotypes. The wild type (WT) shows normal locomotor activity patterns, whereas in hamsters of the DAO (delayed activity onset) type, the activity onset is continuously delayed. Since the activity offset in those hamsters remains coupled to “light-on,” the activity time becomes compressed. Hamsters of the AR (arrhythmic) type are episodically active throughout the 24?h. Previous studies showed that a disturbed interaction of the circadian system with the light-dark (LD) cycle contributes to the phenomenon observed in DAO hamsters. To gain better insight into the underlying mechanisms, the authors investigated the daily melatonin rhythm, as it is a reliable marker of the circadian clock. Hamsters were kept individually under standardized laboratory conditions (LD 14:10, T?=?22°C?±?2°C, food and water ad libitum). WT, DAO (with exactly 5?h delay of activity onset), and AR hamsters were used for pineal melatonin and urinary 6-sulfatoxymelatonin (aMT6s) measurement. Pineal melatonin content was determined at 3 time points: 4?h after “light-off” [D?+?4], 1?h before “light-on” [L???1], and 1?h after “light-on” [L?+?1]). The 24-h profile of melatonin secretion was investigated by transferring the animals to metabolic cages for 27?h to collect urine at 3-h intervals for aMT6s analysis. WT hamsters showed high pineal melatonin content during the dark time (D?+?4, L???1), which significantly decreased at the beginning of the light period (L?+?1). In contrast, DAO hamsters displayed low melatonin levels during the part of the dark period when animals were still resting (D?+?4). At the end of the dark period (L???1), melatonin content increased significantly and declined again when light was switched on (L?+?1). AR hamsters showed low melatonin levels, comparable to daytime values, at all 3 time points. The results were confirmed by aMT6s data. WT hamsters showed a marked circadian pattern of aMT6s excretion. The concentration started to increase 3?h after “light-off” and reached daytime values 5?h after “light-on.” In DAO hamsters, in contrast, aMT6s excretion started about 6?h later and reached significantly lower levels compared to WT hamsters. In AR animals, aMT6s excretion was low at all times. The results clearly indicate the rhythm of melatonin secretion in DAO hamsters is delayed in accord with their delayed activity onset, whereas AR hamsters display no melatonin rhythm at all. Since the regulatory pathways for the rhythms of locomotor activity and melatonin synthesis (which are downstream from the suprachiasmatic nucleus [SCN]) are different but obviously convey the same signal, we conclude that the origin of the phenomenon observed in DAO hamsters must be located upstream of the SCN, or in the SCN itself. (Author correspondence: weinert@zoologie.uni-halle.de)     

Association of Worse Prognosis With an Aberrant Diurnal Cortisol Rhythm in Patients With Advanced Lung Cancer

A flatter diurnal rhythm of cortisol has been reported to be associated with early mortality in patients with metastatic breast cancer. The clinical stage of disease at the time of diagnosis and the patient's performance status (PS) are known to be important prognostic factors for lung cancer (LC) survival. The authors examined the relationship between diurnal cortisol rhythms and these prognostic factors in patients with advanced LC. Cortisol concentrations were measured in saliva samples collected from 52 patients (37 males/15 females) with advanced LC and from 56 healthy subjects (32 males/24 females) to characterize the diurnal cortisol rhythm, specifically the cortisol awakening response (CAR) and diurnal cortisol decline (DCD). Variations of CAR and DCD in the patients were analyzed according to their clinical disease stage and PS score, and the differences in CAR and DCD between patients and healthy controls were compared. The patient group showed significantly reduced diurnal cortisol secretory activity and rhythmicity, compared with healthy controls. When the patients were subgrouped according to their clinical disease stage, patients with stage 4 disease showed significantly reduced CAR and flatter DCD compared with the healthy controls. However, the CAR and DCD in patients with stage 3a and 3b disease were comparable to those of healthy controls. Neither the CAR nor the DCD showed stepwise changes as the disease stage worsened. When patients were subgrouped according to their Eastern Cooperative Oncology Group (ECOG) PS score, there was stepwise reduction in the CAR and flattening of the DCD as the PS score increased. Both an abolished CAR and a flattened DCD were common in patients with ECOG PS scores of 3 and 4. These results indicate that alteration of the diurnal cortisol rhythm in patients with advanced LC is more closely associated with their PS score than with their clinical disease stage. Gradual alteration of the CAR and DCD, indicative of loss of 24-h cortisol rhythm, in concert with increase in PS score implies that endogenous circadian rhythms may also be disintegrating as the PS score worsens in these patients. (Author correspondence: ryunsup@yahoo.co.kr)     

The Shape of the Endogenous Circadian Rhythm of Rectal Temperature in Humans

Fourteen healthy subjects have been studied in an isolation unit while living on a 30h “day” (20h awake, 10h asleep) for 14 (solar) days but while aware of real time. Waking activities were sedentary and included reading, watching television, and so forth. Throughout, regular recordings of rectal temperature were made, and in a subgroup of 6 subjects, activity was measured by a wrist accelerometer. Temperature data have been subjected to cosinor analysis after “purification,” a method that enables the endogenous (clock-driven) and exogenous (activity-driven) components of the circadian rhythm to be assessed. Moreover, the protocol enables effects due to the circadian rhythm and time-since-waking to be separated. Results showed that activity was slightly affected by the endogenous temperature rhythm. Also, the masking effects on body temperature exerted by the exogenous factors appeared to be less than average in the hours before and just after the peak of the endogenous temperature rhythm. This has the effect of producing a temperature plateau rather than a peak during the daytime. The implications of this for mental performance and sleep initiation are discussed. (Chronobiology International, 13(4), 261-271, 1996)