Preliminary Study on Changes of Sleep EEG Power and Plasma Melatonin in Male Patients With Major Depressive Disorder After 8 Weeks Treatment

Objective: To clarify the effects of escitalopram on sleep EEG power in patients with Major depressive disorder (MDD).Method: Polysomnography (PSG) was detected overnight, and blood samples were collected at 4 h intervals over 24 h from 13 male healthy controls and 13 male MDD patients before and after treatment with escitalopram for 8 weeks. The outcome measures included plasma melatonin levels, sleep architecture, and the sleep EEG power ratio.Results: Compared with healthy controls, MDD patients presented abnormalities in the diurnal rhythm of melatonin secretion, including peak phase delayed 3 h and a decrease in plasma melatonin levels at night and an increase at daytime, accompanied by sleep disturbances, a decrease in low-frequency bands and an increase in high-frequency bands, and the dominant right-side brain activity. Several of these abnormalities (abnormalities in the diurnal rhythm of melatonin secretion, partial sleep architecture parameters) persisted for at least the 8-week testing period.Conclusions: Eight weeks of treatment with escitalopram significantly improved subjective sleep perception and depressive symptoms of patients with MDD, and partially improved objective sleep parameters, while the improvement of circadian rhythm of melatonin was limited.

Melatonin-Mediated Colonic Microbiota Metabolite Butyrate Prevents Acute Sleep Deprivation-Induced Colitis in Mice

Radical cure colitis is a severe public health threat worldwide. Our previous studies have confirmed that melatonin can effectively improve gut microbiota disorder and mucosal injury caused by sleep deprivation (SD). The present study further explored the mechanism whereby exogenous melatonin prevented SD-induced colitis. 16S rRNA high-throughput sequencing and metabolomics analysis were used to explore the correlation between SD-induced colitis and intestinal microbiota and metabolite composition in mice. Fecal microbiota transplantation (FMT) and melatonin or butyrate supplementation tests verified the core role of gut microbiota in melatonin-alleviating SD-induced colitis. Further, in vitro tests studied the modulatory mechanism of metabolite butyrate. The results demonstrated that SD leads to reductions in plasma melatonin levels and colonic Card9 expression and consequent occurrence of colitis and gut microbiota disorder, especially the downregulation of Faecalibacterium and butyrate levels. The FMT from SD-mice to normal mice could restore SD-like colitis, while butyrate supplementation to SD-mice inhibited the occurrence of colitis, but with no change in the plasma melatonin level in both treatments. However, melatonin supplementation reversed all inductions in SD-mice. In intestinal epithelial cells, the inflammatory ameliorative effect of butyrate was blocked with pretreatments of HDAC3 agonist and HIF-1α antagonist but was mimicked by GSK-3β and p-P65 antagonists. Therefore, the administration of MLT may be a better therapy for SD-induced colitis relative to butyrate. A feasible mechanism would involve that melatonin up-regulated the Faecalibacterium population and production of its metabolite butyrate and MCT1 expression and inhibited HDAC3 in the colon, which would allow p-GSK-3β/β-catenin/HIF-1α activation and NF-κB/NLRP3 suppression to up-regulate Card9 expression and suppress inflammation response.

Testis development in the Japanese eel is affected by photic signals through melatonin secretion

Objective According to reported spawning characteristics of Japanese eel, Anguilla japonica, which exhibit spawning and migration patterns that are synchronized with lunar cycles and photoperiod, we hypothesized that a close association exists between specific photic signals (daylight, daylength, and moonlight) and endocrinological regulation. Given the photic control in melatonin secretion, this hypothesis was tested by investigating whether melatonin signals act as mediators relaying photic signals during testis development in the eel. Methods We examined changes in melatonin-secretion patterns using time-resolved fluorescence immunoassays in sexually immature and mature male Japanese eels under the condition of a new moon (NM) and a full moon (FM). Results The eye and plasma melatonin levels exhibited a nocturnal pattern under a 12-h light: dark cycle (12L12D) or under constant darkness (DD), but not with constant light (LL). Eye melatonin levels were similar under the 12L12D and short-day (9L15D) conditions. In the long-day condition (15L9D), secreted plasma melatonin levels were stable, whereas short-day melatonin secretion began when darkness commenced. Sexual maturation began at 8 weeks following intraperitoneal injection of human chorionic gonadotropin (hCG), and NM exposure led to significantly higher eye and plasma melatonin levels compared with those detected under FM exposure.

Peripheral Clock System Abnormalities in Patients With Parkinson’s Disease

Objective: To evaluate the altered expression of peripheral clock genes, circulating melatonin levels, and their correlations with sleep-wake phenotypes including probable rapid eye movement sleep behavior disorder (pRBD) symptoms in a relatively large population of Parkinson’s disease (PD) patients.Methods: We determined the expression profiles of five principal clock genes, BMAL1, CLOCK, CRY1, PER1, and PER2, in the peripheral blood mononuclear cells (PBMCs) of PD patients (n = 326), and healthy controls (HC, n = 314) using quantitative real-time PCR. Melatonin concentration in the plasma of two groups was evaluated by enzyme-linked immunosorbent assay. Then we performed comprehensive association analyses on the PBMCs clock gene expression, plasma melatonin levels and sleep characteristics.Results: Our data showed that the expression levels of BMAL1, CLOCK, CRY1, PER1, and PER2 were significantly decreased in the PBMCs of PD as compared with that of HC (P < 0.05). PD patients had reduced plasma melatonin levels compared with HC (P < 0.0001). pRBD and excessive daytime sleepiness are common in these PD patients and are associated with the expression levels of all five clock genes (r = −0.344∼−0.789, P < 0.01) and melatonin concentration (r = −0.509∼−0.753, P < 0.01). Statistical analyses also revealed that a combination of five clock genes and melatonin could reach a high diagnostic performance (areas under the curves, 97%) for PD comorbid pRBD.Conclusion: This case-control study demonstrates that peripheral BMAL1, CLOCK, CRY1, PER1, PER2, and melatonin levels are altered in PD patients and may serve as endogenous markers for sleep and wakefulness disturbances of PD.

Effects of Duodenal 5-Hydroxytryptophan Perfusion on Melatonin Synthesis in GI Tract of Sheep

The purpose of this study is to investigate the potential effects of 5-hydroxytryptophan (5-HTP) duodenal perfusion on melatonin (MT) synthesis in the gastrointestinal (GI) tract of sheep. 5-hydroxytryptophan is a precursor in the melatonin synthetic pathway. The results showed that this method significantly increased melatonin production in the mucosa of all segments in GI tract including duodenum, jejunum, ileum, cecum and colon. The highest melatonin level was identified in the colon and this indicates that the microbiota located in the colon may also participate in the melatonin production. In addition, portion of the melatonin generated by the GI tract can pass the liver metabolism and enters the circulation via portal vein. The current study provides further evidence to support that GI tract is the major site for melatonin synthesis and the GI melatonin also contributes to the circulatory melatonin level since plasma melatonin concentrations in 5-HTP treated groups were significantly higher than those in the control group. In conclusion, the results show that 10–50 mg of 5-HTP flowing into the duodenum within 6 h effectively improve the production of melatonin in the GI tract and melatonin concentration in sheep blood circulation during the day.

Effects Of Exogenous Melatonin On Sleep And Circadian Rhythms In Women With Premenstrual Dysphoric Disorder

We previously found normal polysomnographic (PSG) sleep efficiency, increased slow wave sleep (SWS) and a blunted melatonin secretion in women with premenstrual dysphoric disorder (PMDD) compared to controls. Here, we investigated the effects of exogenous melatonin in five patients previously studied. They took 2 mg of slow-release melatonin 1 hour before bedtime during their luteal phase (LP) for three menstrual cycles. At baseline, patients spent every third night throughout one menstrual cycle sleeping in the laboratory. Measures included morning urinary 6-sulfatoxymelatonin (aMt6), PSG sleep, nocturnal core body temperature (CBT), visual analogue scale for mood (VAS-Mood), Prospective Record of the Impact and Severity of Menstrual Symptoms (PRISM), and ovarian hormones. Participants also underwent two 24-hour intensive physiological monitoring (during the follicular phase and LP) in time-isolation/constant conditions to determine 24-hour plasma melatonin and CBT rhythms. The same measures were repeated during their third menstrual cycle of melatonin administration. In the intervention condition compared to baseline, we found increased urinary aMt6 (p<0.001), reduced objective SOL (p=0.01), reduced SWS (p<0.001) and increased Stage 2 sleep (p<0.001). Increased urinary aMt6 was associated with reduced SWS (r=-0.51, p<0.001). Circadian parameters derived from 24-hour plasma melatonin and CBT did not differ between conditions, except for an increased melatonin mesor in the intervention condition (p=0.01). Ovarian hormones were comparable between the conditions (p≥0.28). Symptoms improved in the intervention condition, as measured by the VAS-Mood (p=0.02) and the PRISM (p<0.001). These findings support a role for disturbed melatonergic system in PMDD that can be partially corrected by exogenous melatonin.

738 Effects of exogenous melatonin on sleep, circadian rhythms, and mood in women with premenstrual dysphoric disorder

Introduction Most women with premenstrual dysphoric disorder (PMDD) report sleep disturbances. Our group found normal polysomnographic (PSG) sleep efficiency and increased slow wave sleep (SWS) across the menstrual cycle in women with PMDD and insomnia compared to controls. Reduced melatonin levels were found in PMDD women compared to controls, with reduced secretion during their luteal phase (LP) compared to follicular phase (FP). Here, we investigated the effects of exogenous melatonin in the patients we previously studied. Methods Five patients (age, mean: 33.6, SD: 2.7) diagnosed prospectively with PMDD and insomnia participated in the study. Following a baseline assessment, patients took 2 mg of slow-release melatonin 1h before bedtime during their LP for three consecutive menstrual cycles. At baseline (treatment-free condition), patients spent every third night of their menstrual cycle sleeping in the laboratory. Measures included morning urinary 6-sulfatoxymelatonin (aMt6), PSG sleep, nocturnal core body temperature (CBT), visual analogue scale for mood (VAS-Mood), Prospective Record of the Impact and Severity of Menstrual symptoms (PRISM), subjective sleep and ovarian hormones (estrogen and progesterone). Participants also underwent two 24-hour intensive physiological monitoring (during the FP and LP) in time-isolation/constant conditions to determine 24-hour plasma melatonin and CBT rhythms. The same measures were repeated during their third menstrual cycle of melatonin administration. Results In the intervention condition compared to baseline, we found increased urinary aMt6 (p<0.001), reduced objective SOL (p=0.01), SWS (p<0.001) and increased Stage 2 sleep (p<0.001). Increased urinary aMt6 was associated with reduced SWS (r=-0.51, p<0.001). Circadian parameters derived from 24-hour plasma melatonin and CBT did not differ between conditions, except for an increased melatonin mesor in the intervention condition (p=0.01). Ovarian hormones were comparable between the conditions (p≥0.28). Symptoms improved in the intervention condition, as measured by the VAS-Mood (p=0.02) and the PRISM (p<0.001). Conclusion We have shown normalization of SWS and reduction in self-reported mood and somatic symptoms after administrating exogenous melatonin in women with PMDD. These findings support a role for disturbed melatoninergic system in PMDD that can be partially corrected by exogenous melatonin. Support (if any) This study was supported by the Canadian Institutes of Health Research (CIHR)