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Jiang Y, Shi J, Tai J, Yan L. Circadian Regulation in Diurnal Mammals: Neural Mechanisms and Implications in Translational Research. BIOLOGY 2024; 13:958. [PMID: 39765625 PMCID: PMC11727363 DOI: 10.3390/biology13120958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/16/2024] [Accepted: 11/19/2024] [Indexed: 01/15/2025]
Abstract
Diurnal and nocturnal mammals have evolved unique behavioral and physiological adaptations to optimize survival for their day- or night-active lifestyle. The mechanisms underlying the opposite activity patterns are not fully understood but likely involve the interplay between the circadian time-keeping system and various arousal- or sleep-promoting factors, e.g., light or melatonin. Although the circadian systems between the two chronotypes share considerable similarities, the phase relationships between the principal and subordinate oscillators are chronotype-specific. While light promotes arousal and wakefulness in diurnal species like us, it induces sleep in nocturnal ones. Similarly, melatonin, the hormone of darkness, is commonly used as a hypnotic in humans but is secreted in the active phase of nocturnal animals. Thus, the difference between the two chronotypes is more complex than a simple reversal, as the physiological and neurological processes in diurnal mammals during the day are not equivalent to that of nocturnal ones at night. Such chronotype differences could present a significant translational gap when applying research findings obtained from nocturnal rodents to diurnal humans. The potential advantages of diurnal models are being discussed in a few sleep-related conditions including familial natural short sleep (FNSS), obstructive sleep apnea (OSA), and Smith-Magenis syndrome (SMS). Considering the difference in chronotype, a diurnal model will be more adequate for revealing the physiology and physiopathology pertaining to human health and disease, especially in conditions in which circadian rhythm disruption, altered photic response, or melatonin secretion is involved. We hope the recent advances in gene editing in diurnal rodents will promote greater utility of the diurnal models in basic and translational research.
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Affiliation(s)
- Yirun Jiang
- Department of Otolaryngology, Head and Neck Surgery, Capital Institute of Pediatrics, Beijing 100020, China; (Y.J.); (J.T.)
| | - Jiaming Shi
- Department of Psychology, Michigan State University, East Lansing, MI 48824, USA;
| | - Jun Tai
- Department of Otolaryngology, Head and Neck Surgery, Capital Institute of Pediatrics, Beijing 100020, China; (Y.J.); (J.T.)
| | - Lily Yan
- Department of Psychology, Michigan State University, East Lansing, MI 48824, USA;
- Neuroscience Program, Interdisciplinary Science & Technology Building (ISTB), Michigan State University, East Lansing, MI 48824, USA
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Oldoni AA, Bacchi AD, Mendes FR, Tiba PA, Mota-Rolim S. Neuropsychopharmacological Induction of (Lucid) Dreams: A Narrative Review. Brain Sci 2024; 14:426. [PMID: 38790404 PMCID: PMC11119155 DOI: 10.3390/brainsci14050426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 04/19/2024] [Accepted: 04/22/2024] [Indexed: 05/26/2024] Open
Abstract
Lucid dreaming (LD) is a physiological state of consciousness that occurs when dreamers become aware that they are dreaming, and may also control the oneiric content. In the general population, LD is spontaneously rare; thus, there is great interest in its induction. Here, we aim to review the literature on neuropsychopharmacological induction of LD. First, we describe the circadian and homeostatic processes of sleep regulation and the mechanisms that control REM sleep with a focus on neurotransmission systems. We then discuss the neurophysiology and phenomenology of LD to understand the main cortical oscillations and brain areas involved in the emergence of lucidity during REM sleep. Finally, we review possible exogenous substances-including natural plants and artificial drugs-that increase metacognition, REM sleep, and/or dream recall, thus with the potential to induce LD. We found that the main candidates are substances that increase cholinergic and/or dopaminergic transmission, such as galantamine. However, the main limitation of this technique is the complexity of these neurotransmitter systems, which challenges interpreting results in a simple way. We conclude that, despite these promising substances, more research is necessary to find a reliable way to pharmacologically induce LD.
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Affiliation(s)
- Abel A. Oldoni
- Center for Mathematics, Computing and Cognition, Federal University of ABC, São Bernardo do Campo 09606-045, Brazil; (A.A.O.); (P.A.T.)
| | - André D. Bacchi
- Faculty of Health Sciences, Federal University of Rondonópolis, Rondonópolis 78736-900, Brazil;
| | - Fúlvio R. Mendes
- Center for Natural and Human Sciences, Federal University of ABC, São Bernardo do Campo 09606-045, Brazil;
| | - Paula A. Tiba
- Center for Mathematics, Computing and Cognition, Federal University of ABC, São Bernardo do Campo 09606-045, Brazil; (A.A.O.); (P.A.T.)
| | - Sérgio Mota-Rolim
- Brain Institute, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
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Cruz-Sanabria F, Carmassi C, Bruno S, Bazzani A, Carli M, Scarselli M, Faraguna U. Melatonin as a Chronobiotic with Sleep-promoting Properties. Curr Neuropharmacol 2023; 21:951-987. [PMID: 35176989 PMCID: PMC10227911 DOI: 10.2174/1570159x20666220217152617] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/26/2022] [Accepted: 02/10/2022] [Indexed: 11/22/2022] Open
Abstract
The use of exogenous melatonin (exo-MEL) as a sleep-promoting drug has been under extensive debate due to the lack of consistency of its described effects. In this study, we conduct a systematic and comprehensive review of the literature on the chronobiotic, sleep-inducing, and overall sleep-promoting properties of exo-MEL. To this aim, we first describe the possible pharmacological mechanisms involved in the sleep-promoting properties and then report the corresponding effects of exo-MEL administration on clinical outcomes in: a) healthy subjects, b) circadian rhythm sleep disorders, c) primary insomnia. Timing of administration and doses of exo-MEL received particular attention in this work. The exo-MEL pharmacological effects are hereby interpreted in view of changes in the physiological properties and rhythmicity of endogenous melatonin. Finally, we discuss some translational implications for the personalized use of exo-MEL in the clinical practice.
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Affiliation(s)
- Francy Cruz-Sanabria
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa - Italy
| | - Claudia Carmassi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa - Italy
| | - Simone Bruno
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa - Italy
| | - Andrea Bazzani
- Institute of Management, Scuola Superiore Sant’Anna, Pisa – Italy
| | - Marco Carli
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa - Italy
| | - Marco Scarselli
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa - Italy
| | - Ugo Faraguna
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa - Italy
- Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Pisa, Italy
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Beros A, Farquhar C, Nagels HE, Showell MG, Fernando A, Jordan V. Pharmacological interventions for jet lag. Hippokratia 2021. [DOI: 10.1002/14651858.cd014611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Angela Beros
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences; The University of Auckland; Auckland New Zealand
| | - Cindy Farquhar
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences; The University of Auckland; Auckland New Zealand
| | - Helen E Nagels
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences; The University of Auckland; Auckland New Zealand
| | - Marian G Showell
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences; The University of Auckland; Auckland New Zealand
| | | | - Vanessa Jordan
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences; The University of Auckland; Auckland New Zealand
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Mannino G, Pernici C, Serio G, Gentile C, Bertea CM. Melatonin and Phytomelatonin: Chemistry, Biosynthesis, Metabolism, Distribution and Bioactivity in Plants and Animals-An Overview. Int J Mol Sci 2021; 22:ijms22189996. [PMID: 34576159 PMCID: PMC8469784 DOI: 10.3390/ijms22189996] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/21/2022] Open
Abstract
Melatonin is a ubiquitous indolamine, largely investigated for its key role in the regulation of several physiological processes in both animals and plants. In the last century, it was reported that this molecule may be produced in high concentrations by several species belonging to the plant kingdom and stored in specialized tissues. In this review, the main information related to the chemistry of melatonin and its metabolism has been summarized. Furthermore, the biosynthetic pathway characteristics of animal and plant cells have been compared, and the main differences between the two systems highlighted. Additionally, in order to investigate the distribution of this indolamine in the plant kingdom, distribution cluster analysis was performed using a database composed by 47 previously published articles reporting the content of melatonin in different plant families, species and tissues. Finally, the potential pharmacological and biostimulant benefits derived from the administration of exogenous melatonin on animals or plants via the intake of dietary supplements or the application of biostimulant formulation have been largely discussed.
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Affiliation(s)
- Giuseppe Mannino
- Department of Life Sciences and Systems Biology, Plant Physiology Unit, University of Turin, Via Quarello 15/A, 10135 Turin, Italy; (G.M.); (C.P.)
| | - Carlo Pernici
- Department of Life Sciences and Systems Biology, Plant Physiology Unit, University of Turin, Via Quarello 15/A, 10135 Turin, Italy; (G.M.); (C.P.)
| | - Graziella Serio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy;
| | - Carla Gentile
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy;
- Correspondence: (C.G.); (C.M.B.); Tel.: +39-091-2389-7423 (C.G.); +39-011-670-6361 (C.M.B.)
| | - Cinzia M. Bertea
- Department of Life Sciences and Systems Biology, Plant Physiology Unit, University of Turin, Via Quarello 15/A, 10135 Turin, Italy; (G.M.); (C.P.)
- Correspondence: (C.G.); (C.M.B.); Tel.: +39-091-2389-7423 (C.G.); +39-011-670-6361 (C.M.B.)
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Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorders. BMC Psychiatry 2020; 20:445. [PMID: 32912180 PMCID: PMC7488027 DOI: 10.1186/s12888-020-02847-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 08/31/2020] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Clinical evidence is required about the long-term efficacy and safety of melatonin treatment for sleep problems in children with neurodevelopmental disorders (NDDs) who underwent adequate sleep hygiene interventions. METHODS We conducted a 26-week, multicenter, collaborative, uncontrolled, open-label, phase III clinical trial of melatonin granules in children 6 to 15 years of age who had NDDs and sleep problems. The study consisted of the 2-week screening phase, the 26-week medication phases I and II, and the 2-week follow-up phase. Children received 1, 2, or 4 mg melatonin granules orally in the medication phases. Variables of sleep status including sleep onset latency (SOL), aberrant behaviors listed on the Aberrant Behavior Check List-Japanese version (ABC-J), and safety were examined. The primary endpoint was SOL in the medication phase I. RESULTS Between June 2016 and July 2018, 99 children (80 males and 19 females, 10.4 years in mean age) were enrolled at 17 medical institutions in Japan-74, 60, 22, 9, 6, and 1 of whom had autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disabilities, motor disorders, specific learning disorder, and communication disorders, respectively, at baseline. Fifteen children received the maximal dose of 4 mg among the prespecified dose levels. SOL recorded with the electronic sleep diary shortened significantly (mean ± standard deviation [SD], - 36.7 ± 46.1 min; 95% confidence interval [CI], - 45.9 to - 27.5; P < 0.0001) in the medication phase I from baseline, and the SOL-shortening effect of melatonin persisted in the medication phase II and the follow-up phase. Temper upon wakening and sleepiness after awakening improved significantly (P < 0.0001 each) in the medication phase I from baseline and persisted in the follow-up phase. The following subscales of the ABC-J improved significantly: stereotypic behavior (P = 0.0322) in the medication phase I; and irritability, hyperactivity, and inappropriate speech (P < 0.0001) in the medication phase II. Treatment-emergent adverse events did not occur subsequent to week 16 after medication onset, and NDDs did not deteriorate in the follow-up phase. CONCLUSIONS Long-term melatonin treatment in combination with adequate sleep hygiene interventions may afford clinical benefits to children with NDDs and potentially elevates their well-being. TRIAL REGISTRATION ClinicalTrils.gov , NCT02757066 . Registered April 27, 2016.
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Yang TH, Chen YC, Ou TH, Chien YW. Dietary supplement of tomato can accelerate urinary aMT6s level and improve sleep quality in obese postmenopausal women. Clin Nutr 2020; 39:291-297. [PMID: 30792141 DOI: 10.1016/j.clnu.2019.02.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 01/16/2019] [Accepted: 02/04/2019] [Indexed: 12/27/2022]
Abstract
The aim of this study was to investigate the effect of the ingestion of tomato before bed on obese postmenopausal women's urinary 6-sulphatoxymelatonin (aMT6s) level and sleep quality. We quantified melatonin concentrations in beefsteak tomato, black tomato, and two commercial tomato juices and found that beefsteak tomato contained the highest level of melatonin. In this 8-week open-label, randomized controlled dietary intervention trial, 36 subjects completed the entire trial. The tomato group ate 250 g of beefsteak tomatoes 2 h before sleep for 8 weeks. Blood and urine samples were collected at the baseline and in the 8th week and were analyzed. The Pittsburgh Sleep Quality Index (PSQI) in the tomato group significantly decreased with time (p for trend = 0.0297). After 8 weeks of the beefsteak intervention, all components of the PSQI in tomato group had significantly improved, and their aMT6s level was 10-fold significantly higher than that of the control group. Therefore, supplementation with beefsteak tomato before sleep can increase circulating melatonin and improve sleep quality in obese postmenopausal women.
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Affiliation(s)
- Ting-Hsuan Yang
- Department of Nutrition and Health Sciences, Taipei Medical University, Taipei, 11031, Taiwan
| | - Yi Chun Chen
- Department of Nutrition and Health Sciences, Taipei Medical University, Taipei, 11031, Taiwan
| | - Tzu-Hsuan Ou
- Department of Nutrition and Health Sciences, Taipei Medical University, Taipei, 11031, Taiwan
| | - Yi-Wen Chien
- Department of Nutrition and Health Sciences, Taipei Medical University, Taipei, 11031, Taiwan; Graduate Institute of Metabolism and Obesity, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan.
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Paulose JK, Wang C, O'Hara BF, Cassone VM. The effects of aging on sleep parameters in a healthy, melatonin-competent mouse model. Nat Sci Sleep 2019; 11:113-121. [PMID: 31496853 PMCID: PMC6697669 DOI: 10.2147/nss.s214423] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 06/24/2019] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Sleep disturbances are common maladies associated with human age. Sleep duration is decreased, sleep fragmentation is increased, and the timing of sleep onset and sleep offset is earlier. These disturbances have been associated with several neurodegenerative diseases. Mouse models for human sleep disturbances can be powerful due to the accessibility to neuroscientific and genetic approaches, but these are hampered by the fact that most mouse models employed in sleep research have spontaneous mutations in the biosynthetic pathway(s) regulating the rhythmic production of the pineal hormone melatonin, which has been implicated in human sleep. PURPOSE AND METHOD The present study employed a non-invasive piezoelectric measure of sleep wake cycles in young, middle-aged and old CBA mice, a strain capable of melatonin biosynthesis, to investigate naturally-occurring changes in sleep and circadian parameters as the result of aging. RESULTS The results indicate that young mice sleep less than do middle-aged or aged mice, especially during the night, while the timing of activity onset and acrophase is delayed in aged mice compared to younger mice. CONCLUSION These data point to an effect of aging on the quality and timing of sleep in these mice but also that there are fundamental differences between control of sleep in humans and in laboratory mice.
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Affiliation(s)
- Jiffin K Paulose
- Department of Biology, University of Kentucky, Lexington, KY 40515, USA
| | - Chanung Wang
- Department of Biology, University of Kentucky, Lexington, KY 40515, USA.,Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Bruce F O'Hara
- Department of Biology, University of Kentucky, Lexington, KY 40515, USA
| | - Vincent M Cassone
- Department of Biology, University of Kentucky, Lexington, KY 40515, USA
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Quera-Salva MA, Claustrat B. Mélatonine : aspects physiologiques et pharmacologiques en relation avec le sommeil, intérêt d’une forme galénique à libération prolongée (Circadin®) dans l’insomnie. Encephale 2018; 44:548-557. [DOI: 10.1016/j.encep.2018.06.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 05/15/2018] [Indexed: 12/15/2022]
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Cheikh M, Hammouda O, Gaamouri N, Driss T, Chamari K, Cheikh RB, Dogui M, Souissi N. Melatonin ingestion after exhaustive late-evening exercise improves sleep quality and quantity, and short-term performances in teenage athletes. Chronobiol Int 2018; 35:1281-1293. [PMID: 29846091 DOI: 10.1080/07420528.2018.1474891] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2022]
Abstract
The present study aimed to explore the effects of a single 10-mg dose of melatonin (MEL) administration after exhaustive late-evening exercise on sleep quality and quantity, and short-term physical and cognitive performances in healthy teenagers. Ten male adolescent athletes (mean ± SD, age = 15.4 ± 0.3 years, body-mass = 60.68 ± 5.7 kg, height = 167.9 ± 6.9 cm and BMI = 21.21 ± 2.5) performed two test sessions separated by at least one week. During each session, participants completed the Yo-Yo intermittent-recovery-test level-1 (YYIRT-1) at ~20:00 h. Then, sleep polysomnography was recorded from 22:15 min to 07:00 h, after a double blind randomized order administration of a single 10-mg tablet of MEL (MEL-10 mg) or Placebo (PLA). The following morning, Hooper wellness index was administered and the participants performed the Choice Reaction Time (CRT) test, the Zazzo test and some short-term physical exercises (YYIRT-1, vertical and horizontal Jumps (VJ; HJ), Hand grip strength (HG), and five-jump test (5-JT)). Evening total distance covered in the YYIRT-1 did not change during the two conditions (p > 0.05). Total sleep time (Δ = 24.55 mn; p < 0.001), sleep efficiency (Δ = 4.47%; p < 0.001), stage-3 sleep (N3 sleep) (Δ = 1.73%; p < 0.05) and rapid-eye-movement sleep (Δ = 2.15%; p < 0.001) were significantly higher with MEL in comparison with PLA. Moreover, sleep-onset-latency (Δ = -8.45mn; p < 0.001), total time of nocturnal awakenings after sleep-onset (NA) (Δ = -11 mn; p < 0.001), stage-1 sleep (N1 sleep) (Δ = -1.7%; p < 0.001) and stage-2 sleep (N2 sleep) (Δ = -1.9%; p < 0.05) durations were lower with MEL. The Hooper index showed a better subjective sleep quality, a decrease of the subjective perception of fatigue and a reduced level of muscle soreness with MEL. Moreover, MEL improved speed and performance but not inaccuracy during the Zazzo test. CRT was faster with MEL. Morning YYIRT-1 (Δ = 82 m; p < 0.001) and 5-JT (Δ = 0.08 m; p < 0.05) performances were significantly higher with MEL in comparison with PLA. In contrast, HG, VJ and HJ performances did not change during the two conditions (p > 0.05). The administration of a single dose of MEL-10 mg after strenuous late-evening exercise improved sleep quality and quantity, selective attention, subjective assessment of the general wellness state, and some short-term physical performances the following morning in healthy teenagers.
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Affiliation(s)
- Mohamed Cheikh
- a High Institute of Sport and Physical Education, Manouba University , Manouba , Tunisia
| | - Omar Hammouda
- b Research Center on Sport and Movement (Centre de Recherches sur le Sport et le Mouvement, CeRSM), UPL, Univ Paris Nanterre, UFR STAPS , Nanterre , France.,c Faculty of medicine of Sfax , Research Unit, Molecular Bases of Human Pathology, UR12ES17 , Sfax , Tunisia
| | - Nawel Gaamouri
- a High Institute of Sport and Physical Education, Manouba University , Manouba , Tunisia
| | - Tarak Driss
- b Research Center on Sport and Movement (Centre de Recherches sur le Sport et le Mouvement, CeRSM), UPL, Univ Paris Nanterre, UFR STAPS , Nanterre , France
| | - Karim Chamari
- d Athlete Health and Performance Research Ctr ASPETAR, Qatar Orthopaedic and Sports Medicine Hospital , Doha , Qatar
| | - Ridha Ben Cheikh
- e Functional Exploration of the Nervous System Service, CHU Sahloul , Sousse , Tunisia.,f Faculty of Medicine , Laboratory of Physiology , Monastir , Tunisia
| | - Mohamed Dogui
- e Functional Exploration of the Nervous System Service, CHU Sahloul , Sousse , Tunisia.,f Faculty of Medicine , Laboratory of Physiology , Monastir , Tunisia
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Dirani M, Nasreddine W, Melhem J, Arabi M, Beydoun A. Efficacy of the Sequential Administration of Melatonin, Hydroxyzine, and Chloral Hydrate for Recording Sleep EEGs in Children. Clin EEG Neurosci 2017; 48:41-47. [PMID: 26755506 DOI: 10.1177/1550059415621830] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 11/07/2015] [Indexed: 11/16/2022]
Abstract
Sedation of children for electroencephalography (EEG) recordings is often required. Chloral hydrate (CH) requires medical clearance and continuous monitoring. To try to reduce personnel and time resources associated with CH administration, a new sedation policy was formulated. This study included all children who underwent an EEG during a consecutive 3-month period following the implementation of the new sedation policy, which consists of the sequential administration of melatonin, hydroxyzine (if needed), and CH (if needed). The comparator group included all children with a recorded EEG during a consecutive 3-month period when the sedation policy consisted of the sole administration of CH. A total of 803 children with a mean age of 7.9 years (SD = 5.1, range = 0.5-17.7 years) were included. Sleep EEG recordings were obtained in 364 of 385 children (94.6%) using the old sedation policy and in 409 of 418 children (97.9%) using the new one. With the new sedation policy, the percentage of children requiring CH dropped from 37.1% to 6.7% (P < .001). Time to sleep onset and duration of sleep were not significantly different between the 2 policies. The new sedation policy was very well tolerated. The new sedation policy is very safe, is highly efficacious in obtaining sleep EEG recordings, and will result in substantial saving of time and personnel resources.
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Affiliation(s)
- Maya Dirani
- Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Wassim Nasreddine
- Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Jawad Melhem
- Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon
| | | | - Ahmad Beydoun
- Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon
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Block KI, Gyllenhaal C, Mead MN. Safety and Efficacy of Herbal Sedatives in Cancer Care. Integr Cancer Ther 2016; 3:128-48. [PMID: 15165499 DOI: 10.1177/1534735404265003] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Insomnia and other sleep disturbances are common in cancer patients. Insomnia is a multifactorial health concern that currently affects at least 1 in 3 cancer patients, and yet most insomnia sufferers do not consult their physician regarding pharmaceutical options for relief. Use of hypnotic drugs (primarily benzodiazepines) is associated with increasing tolerance, dependence, and adverse effects on the central nervous system. While hypnotic drug use declined substantially in the past decade, the use of herbal sedatives appeared to increase. Mostly self-prescribed by lay people, herbal sedatives hold widespread appeal, presumably because of their lower cost and higher margin of safety when compared to pharmaceuticals. Studies of better-known herbal sedatives, notably valerian and kava, showed moderate evidence for both safety and efficacy for valerian while revealing disturbing toxicity concerns for kava. Milder sedatives or anxiolytics in need of clinical study include German chamomile, lavender, hops, lemon balm, and passionflower; St. John’s wort may have anxiolytic effects with relevance to sleep. Herb-drug interactions are a possibility for some of these species, including St. John’s wort. Although sufficient evidence exists to recommend some of these agents for short-term relief of mild insomnia, long-term trials and observational studies are needed to establish the safety of prolonged use as well as overall efficacy in the context of cancer treatment and management.
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Affiliation(s)
- Keith I Block
- Block Center for Integrative Cancer Care, Evanston, Illinois 60201, USA
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Abstract
In this article, the effect of sleep and sleep disorders on endocrine function and the influence of endocrine abnormalities on sleep are discussed. Sleep disruption and its associated endocrine consequences in the critically ill patient are also reviewed.
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Affiliation(s)
- Dionne Morgan
- Department of Medicine, National Jewish Health, 1400 Jackson Street, A02, Denver, CO 80206, USA
| | - Sheila C Tsai
- Department of Medicine, National Jewish Health, 1400 Jackson Street, A02, Denver, CO 80206, USA; University of Colorado Denver, Aurora, CO 80045, USA.
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Shuboni DD, Agha AA, Groves TKH, Gall AJ. The contribution of the pineal gland on daily rhythms and masking in diurnal grass rats, Arvicanthis niloticus. Behav Processes 2016; 128:1-8. [PMID: 27038859 DOI: 10.1016/j.beproc.2016.03.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Revised: 03/12/2016] [Accepted: 03/14/2016] [Indexed: 10/22/2022]
Abstract
Melatonin is a hormone rhythmically secreted at night by the pineal gland in vertebrates. In diurnal mammals, melatonin is present during the inactive phase of the rest/activity cycle, and in primates it directly facilitates sleep and decreases body temperature. However, the role of the pineal gland for the promotion of sleep at night has not yet been studied in non-primate diurnal mammalian species. Here, the authors directly examined the hypothesis that the pineal gland contributes to diurnality in Nile grass rats by decreasing activity and increasing sleep at night, and that this could occur via effects on circadian mechanisms or masking, or both. Removing the pineal gland had no effect on the hourly distribution of activity across a 12:12 light-dark (LD) cycle or on the patterns of sleep-like behavior at night. Masking effects of light at night on activity were also not significantly different in pinealectomized and control grass rats, as 1h pulses of light stimulated increases in activity of sham and pinealectomized animals to a similar extent. In addition, the circadian regulation of activity was unaffected by the surgical condition of the animals. Our results suggest that the pineal gland does not contribute to diurnality in the grass rat, thus highlighting the complexity of temporal niche transitions. The current data raise interesting questions about how and why genetic and neural mechanisms linking melatonin to sleep regulatory systems might vary among mammals that reached a diurnal niche via parallel and independent pathways.
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Affiliation(s)
- Dorela D Shuboni
- Department of Psychology, Michigan State University, East Lansing, MI, USA.
| | - Amna A Agha
- Department of Psychology, Michigan State University, East Lansing, MI, USA
| | - Thomas K H Groves
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, USA
| | - Andrew J Gall
- Department of Psychology, Hope College, Holland, MI, USA
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Abstract
In this article, the effect of sleep and sleep disorders on endocrine function and the influence of endocrine abnormalities on sleep are discussed. Sleep disruption and its associated endocrine consequences in the critically ill patient are also reviewed.
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Galley HF, Lowes DA, Allen L, Cameron G, Aucott LS, Webster NR. Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis. J Pineal Res 2014; 56:427-38. [PMID: 24650045 PMCID: PMC4279949 DOI: 10.1111/jpi.12134] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 03/14/2014] [Indexed: 12/20/2022]
Abstract
Sepsis is a massive inflammatory response mediated by infection, characterized by oxidative stress, release of cytokines, and mitochondrial dysfunction. Melatonin accumulates in mitochondria, and both it and its metabolites have potent antioxidant and anti-inflammatory activities and may be useful in sepsis. We undertook a phase I dose escalation study in healthy volunteers to assess the tolerability and pharmacokinetics of 20, 30, 50, and 100 mg oral doses of melatonin. In addition, we developed an ex vivo whole blood model under conditions mimicking sepsis to determine the bioactivity of melatonin and the major metabolite 6-hydroxymelatonin at relevant concentrations. For the phase I trial, oral melatonin was given to five subjects in each dose cohort (n = 20). Blood and urine were collected for measurement of melatonin and 6-hydroxymelatonin, and symptoms and physiological measures were assessed. Validated sleep scales were completed. No adverse effects after oral melatonin, other than mild transient drowsiness with no effects on sleeping patterns, were seen, and no symptoms were reported. Melatonin was rapidly cleared at all doses with a median [range] elimination half-life of 51.7 [29.5-63.2] min across all doses. There was considerable variability in maximum melatonin levels within each dose cohort, but 6-hydoxymelatonin sulfate levels were less variable and remained stable for several hours. For the ex vivo study, blood from 20 volunteers was treated with lipopolysaccharide and peptidoglycan plus a range of concentrations of melatonin/6-hydroxymelatonin. Both melatonin and 6-hydroxymelatonin had beneficial effects on sepsis-induced mitochondrial dysfunction, oxidative stress, and cytokine responses at concentrations similar to those achieved in vivo.
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Affiliation(s)
- Helen F Galley
- Division of Applied Health, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK; Intensive Care Unit, Aberdeen Royal Infirmary, Aberdeen, UK
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Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: review and remarks. Aging Clin Exp Res 2013; 25:499-510. [PMID: 24046037 PMCID: PMC3788186 DOI: 10.1007/s40520-013-0118-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 04/24/2013] [Indexed: 01/24/2023]
Abstract
The aim of this article was to perform a systematic review on the role of melatonin in the prevention of cancer tumorigenesis--in vivo and in vitro--as well as in the management of cancer correlates, such as sleep-wake and mood disturbances. The International Agency for Research on Cancer recently classified "shift-work that involves circadian disruption" as "probably carcinogenic to humans" (Group 2A) based on "limited evidence in humans for the carcinogenicity of shift-work that involves night-work", and "sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)". The clinical implications and the potential uses of melatonin in terms of biologic clock influence (e.g. sleep and mood), immune function, cancer initiation and growth, as well as the correlation between melatonin levels and cancer risk, are hereinafter recorded and summarized. Additionally, this paper includes a description of the newly discovered effects that melatonin has on the management of sleep-wake and mood disturbances as well as with regard to cancer patients' life quality. In cancer patients depression and insomnia are frequent and serious comorbid conditions which definitely require a special attention. The data presented in this review encourage the performance of new clinical trials to investigate the possible use of melatonin in cancer patients suffering from sleep-wake and mood disturbances, also considering that melatonin registered a low toxicity in cancer patients.
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Oxidative stress and immunosenescence: therapeutic effects of melatonin. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2012; 2012:670294. [PMID: 23346283 PMCID: PMC3549369 DOI: 10.1155/2012/670294] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 12/13/2012] [Indexed: 02/02/2023]
Abstract
Age-associated deterioration in the immune system, which is referred to as immunosenescence, contributes to an increased susceptibility to infectious diseases, autoimmunity, and cancer in the elderly. A summary of major changes associated with aging in immune system is described in this paper. In general, immunosenescence is characterized by reduced levels of peripheral naïve T cells derived from thymus and the loss of immature B lineage cells in the bone marrow. As for macrophages and granulocytes, they show functional decline with advancing age as evidenced by their diminished phagocytic activity and impairment of superoxide generation. The indole melatonin is mainly secreted in the pineal gland although it has been also detected in many other tissues. As circulating melatonin decreases with age coinciding with the age-related decline of the immune system, much interest has been focused on melatonin's immunomodulatory effect in recent years. Here, we underlie the antioxidant and immunoenhancing actions displayed by melatonin, thereby providing evidence for the potential application of this indoleamine as a “replacement therapy” to limit or reverse some of the effects of the changes that occur during immunosenescence.
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Abstract
Circadian rhythms are ubiquitous in biological systems and regulate metabolic processes throughout the body. Misalliance of these circadian rhythms and the systems they regulate has a profound impact on hormone levels and increases risk of developing metabolic diseases. Melatonin, a hormone secreted by the pineal gland, is one of the major signaling molecules used by the master circadian oscillator to entrain downstream circadian rhythms. Several recent genetic studies have pointed out that a common variant in the gene that encodes the melatonin receptor 2 (MTNR1B) is associated with impaired glucose homeostasis, reduced insulin secretion, and an increased risk of developing type 2 diabetes. Here, we try to review the role of this receptor and its signaling pathways in respect to glucose homeostasis and development of the disease.
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MESH Headings
- Circadian Rhythm/genetics
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/genetics
- Female
- Genetic Variation
- Humans
- Insulin/blood
- Insulin/metabolism
- Insulin Secretion
- Insulin-Secreting Cells
- Male
- Melatonin/biosynthesis
- Receptor, Melatonin, MT1/blood
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT2/blood
- Receptor, Melatonin, MT2/genetics
- Risk Factors
- Signal Transduction
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Affiliation(s)
- Cecilia Nagorny
- Unit of Molecular Metabolism, Department of Clinical Sciences in Malmoe, Lund University Diabetes Centre, 20502, Malmoe, Sweden.
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21
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Abstract
INTRODUCTION Sleep is a vital neurochemical process involving sleep-promoting and arousal centers in the brain. Insomnia is a pervasive disorder characterized by difficulties in initiating or maintaining or non-refreshing (poor quality) sleep and clinically significant daytime distress. Insomnia is more prevalent in women and old age and puts sufferers at significant physical and mental health risks. This review summarizes published data on the current and emerging insomnia drug classes, rationale for development and associated risks/benefits. (Summary of Product Characteristics and Medline search on "hypnotic" or specific drug names and "Insomnia"). AREAS COVERED GABA(A) receptor modulators facilitate sleep onset and some improve maintenance but increase risk of dependence, memory, cognitive and psychomotor impairments, falls, accidents and mortality. Melatonin receptor agonists improve quality of sleep and/or sleep onset but response may develop over several days. They have more benign safety profiles and are indicated for milder insomnia, longer usage and (prolonged release melatonin) older patients. Histamine H-1 receptor antagonists improve sleep maintenance but their effects on cognition, memory and falls remain to be demonstrated. Late-stage pipeline orexin OX1/OX2 and serotonin 5HT2A receptor antagonists may hold the potential to address several unmet needs in insomnia pharmacotherapy but safety issues cast some doubts over their future. EXPERT OPINION Current and new insomnia drugs in the pipeline target different sleep regulating mechanisms and symptoms and have different tolerability profiles. Drug selection would ideally be based on improvement in the quality of patients' sleep, overall quality of life and functional status weighed against risk to the individual and public health.
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Affiliation(s)
- Nava Zisapel
- Tel Aviv University, Department of Neurobiology, The George S. Wise Faculty of Life Sciences and Neurim Pharmaceuticals, Tel Aviv 69978, Israel.
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Morris CJ, Aeschbach D, Scheer FAJL. Circadian system, sleep and endocrinology. Mol Cell Endocrinol 2012; 349:91-104. [PMID: 21939733 PMCID: PMC3242827 DOI: 10.1016/j.mce.2011.09.003] [Citation(s) in RCA: 260] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Revised: 08/19/2011] [Accepted: 09/01/2011] [Indexed: 11/23/2022]
Abstract
Levels of numerous hormones vary across the day and night. Such fluctuations are not only attributable to changes in sleep/wakefulness and other behaviors but also to a circadian timing system governed by the suprachiasmatic nucleus of the hypothalamus. Sleep has a strong effect on levels of some hormones such as growth hormone but little effect on others which are more strongly regulated by the circadian timing system (e.g., melatonin). Whereas the exact mechanisms through which sleep affects circulating hormonal levels are poorly understood, more is known about how the circadian timing system influences the secretion of hormones. The suprachiasmatic nucleus exerts its influence on hormones via neuronal and humoral signals but it is now also apparent that peripheral tissues contain circadian clock proteins, similar to those in the suprachiasmatic nucleus, that are also involved in hormone regulation. Under normal circumstances, behaviors and the circadian timing system are synchronized with an optimal phase relationship and consequently hormonal systems are exquisitely regulated. However, many individuals (e.g., shift-workers) frequently and/or chronically undergo circadian misalignment by desynchronizing their sleep/wake and fasting/feeding cycle from the circadian timing system. Recent experiments indicate that circadian misalignment has an adverse effect on metabolic and hormonal factors such as circulating glucose and insulin. Further research is needed to determine the underlying mechanisms that cause the negative effects induced by circadian misalignment. Such research could aid the development of novel countermeasures for circadian misalignment.
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Affiliation(s)
- Christopher J Morris
- Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, United States.
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23
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Boone PM, Reiter RJ, Glaze DG, Tan DX, Lupski JR, Potocki L. Abnormal circadian rhythm of melatonin in Smith-Magenis syndrome patients with RAI1 point mutations. Am J Med Genet A 2011; 155A:2024-7. [PMID: 21739587 PMCID: PMC3140606 DOI: 10.1002/ajmg.a.34098] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2011] [Accepted: 04/13/2011] [Indexed: 12/15/2022]
Affiliation(s)
- Philip M. Boone
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 77030
| | - Russel J. Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA 78229
| | - Daniel G. Glaze
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA 77030
- Department of Neurology, Baylor College of Medicine, Houston, TX, USA 77030
- Texas Children’s Hospital, Houston, TX, USA 77030
| | - Dun-Xian Tan
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA 78229
| | - James R. Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 77030
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA 77030
- Texas Children’s Hospital, Houston, TX, USA 77030
| | - Lorraine Potocki
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 77030
- Texas Children’s Hospital, Houston, TX, USA 77030
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24
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Clinical uses of melatonin in pediatrics. Int J Pediatr 2011; 2011:892624. [PMID: 21760817 PMCID: PMC3133850 DOI: 10.1155/2011/892624] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2010] [Revised: 03/31/2011] [Accepted: 04/08/2011] [Indexed: 11/29/2022] Open
Abstract
This study analyzes the results of clinical trials of treatments with melatonin conducted in children, mostly focused on sleep disorders of different origin. Melatonin is beneficial not only in the treatment of dyssomnias, especially delayed sleep phase syndrome, but also on sleep disorders present in children with attention-deficit hyperactivity, autism spectrum disorders, and, in general, in all sleep disturbances associated with mental, neurologic, or other medical disorders. Sedative properties of melatonin have been used in diagnostic situations requiring sedation or as a premedicant in children undergoing anesthetic procedures. Epilepsy and febrile seizures are also susceptible to treatment with melatonin, alone or associated with conventional antiepileptic drugs. Melatonin has been also used to prevent the progression in some cases of adolescent idiopathic scoliosis. In newborns, and particularly those delivered preterm, melatonin has been used to reduce oxidative stress associated with sepsis, asphyxia, respiratory distress, or surgical stress. Finally, the administration of melatonin, melatonin analogues, or melatonin precursors to the infants through the breast-feeding, or by milk formula adapted for day and night, improves their nocturnal sleep. Side effects of melatonin treatments in children have not been reported. Although the above-described results are promising, specific studies to resolve the problem of dosage, formulations, and length of treatment are necessary.
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Espino J, Pariente JA, Rodríguez AB. Role of melatonin on diabetes-related metabolic disorders. World J Diabetes 2011; 2:82-91. [PMID: 21860691 PMCID: PMC3158876 DOI: 10.4239/wjd.v2.i6.82] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Revised: 05/20/2011] [Accepted: 05/27/2011] [Indexed: 02/05/2023] Open
Abstract
Melatonin is a circulating hormone that is mainly released from the pineal gland. It is best known as a regulator of seasonal and circadian rhythms, its levels being high during the night and low during the day. Interestingly, insulin levels are also adapted to day/night changes through melatonin-dependent synchronization. This regulation may be explained by the inhibiting action of melatonin on insulin release, which is transmitted through both the pertussis-toxin-sensitive membrane receptors MT1 and MT2 and the second messengers 3’,5’-cyclic adenosine monophosphate, 3’,5’-cyclic guanosine monophosphate and inositol 1,4,5-trisphosphate. Melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion, but also by providing protection against reactive oxygen species, since pancreatic β-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. On the other hand, in several genetic association studies, single nucleotide polymorphysms of the human MT2 receptor have been described as being causally linked to an elevated risk of developing type 2 diabetes. This suggests that these individuals may be more sensitive to the actions of melatonin, thereby leading to impaired insulin secretion. Therefore, blocking the melatonin-induced inhibition of insulin secretion may be a novel therapeutic avenue for type 2 diabetes.
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Affiliation(s)
- Javier Espino
- Javier Espino, José A Pariente, Ana B Rodríguez, Department of Physiology, Neuroimmunophysiology and Chrononutrition Research Group, Faculty of Science, University of Extremadura, Badajoz 06006, Spain
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26
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Marrin K, Drust B, Gregson W, Morris CJ, Chester N, Atkinson G. Diurnal variation in the salivary melatonin responses to exercise: relation to exercise-mediated tachycardia. Eur J Appl Physiol 2011; 111:2707-14. [DOI: 10.1007/s00421-011-1890-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Accepted: 02/19/2011] [Indexed: 10/18/2022]
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Mulder H, Nagorny CLF, Lyssenko V, Groop L. Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene. Diabetologia 2009; 52:1240-9. [PMID: 19377888 DOI: 10.1007/s00125-009-1359-y] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2009] [Accepted: 03/16/2009] [Indexed: 12/13/2022]
Abstract
Melatonin is a circulating hormone that is primarily released from the pineal gland. It is best known as a regulator of seasonal and circadian rhythms; its levels are high during the night and low during the day. Interestingly, insulin levels also exhibit a nocturnal drop, which has previously been suggested to be controlled, at least in part, by melatonin. This regulation can be explained by the proposed inhibitory action of melatonin on insulin release. Indeed, both melatonin receptor 1A (MTNR1A) and MTNR1B are expressed in pancreatic islets. The role of melatonin in the regulation of glucose homeostasis has been highlighted by three independent publications based on genome-wide association studies of traits connected with type 2 diabetes, such as elevated fasting glucose, and, subsequently, of the disease itself. The studies demonstrate a link between variations in the MTNR1B gene, hyperglycaemia, impaired early phase insulin secretion and beta cell function. The risk genotype predicts the future development of type 2 diabetes. Carriers of the risk genotype exhibit increased expression of MTNR1B in islets. This suggests that these individuals may be more sensitive to the actions of melatonin, leading to impaired insulin secretion. Blocking the inhibition of insulin secretion by melatonin may be a novel therapeutic avenue for type 2 diabetes.
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Affiliation(s)
- H Mulder
- Unit of Molecular Metabolism, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Malmö, Sweden.
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28
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29
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Koch BCP, Nagtegaal JE, Kerkhof GA, ter Wee PM. Circadian sleep–wake rhythm disturbances in end-stage renal disease. Nat Rev Nephrol 2009; 5:407-16. [DOI: 10.1038/nrneph.2009.88] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Miyamoto M. Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther 2009; 15:32-51. [PMID: 19228178 PMCID: PMC2871175 DOI: 10.1111/j.1755-5949.2008.00066.x] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
An estimated one-third of the general population is affected by insomnia, and this number is increasing due to more stressful working conditions and the progressive aging of society. However, current treatment of insomnia with hypnotics, gamma-aminobutyric acid A (GABA(A)) receptor modulators, induces various side effects, including cognitive impairment, motor disturbance, dependence, tolerance, hangover, and rebound insomnia. Ramelteon (Rozerem; Takeda Pharmaceutical Company Limited, Osaka, Japan) is an orally active, highly selective melatonin MT(1)/MT(2) receptor agonist. Unlike the sedative hypnotics that target GABA(A) receptor complexes, ramelteon is a chronohypnotic that acts on the melatonin MT(1) and MT(2) receptors, which are primarily located in the suprachiasmatic nucleus, the body's "master clock." As such, ramelteon possesses the first new therapeutic mechanism of action for a prescription insomnia medication in over three decades. Ramelteon has demonstrated sleep-promoting effects in clinical trials, and coupled with its favorable safety profile and lack of abuse potential or dependence, this chronohypnotic provides an important treatment option for insomnia.
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Affiliation(s)
- Masaomi Miyamoto
- Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, 4-1-1 Doshomachi, Chuo-ku, Osaka, Japan.
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Reilly T, Waterhouse J, Edwards B. Some chronobiological and physiological problems associated with long-distance journeys. Travel Med Infect Dis 2008; 7:88-101. [PMID: 19237142 DOI: 10.1016/j.tmaid.2008.05.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2008] [Accepted: 05/19/2008] [Indexed: 11/29/2022]
Abstract
Long-distance travel is becoming increasingly common. Whatever the means of transport, any long journey will be associated with "travel fatigue". The symptoms associated with this phenomenon result from a changed routine (particularly sleep lost and meals) and the general disruption caused by travel. Planning any trip well in advance will minimise many of these problems, but some factors are less easy to guard against. These problems include sitting in cramped and uncomfortable conditions and, with flights, the hypoxic environment in the cabin. After arrival at the destination in another country, there can be problems coping with the local language, alterations in food and different customs. If the flight has crossed the equator, then there is likely to be a change in season and natural lighting and, if it has crossed several time zones, there will also be the problem of "jet lag", caused by a transient desynchrony between the "body clock" and the new local time. Moreover, the new environment might differ from the place of departure with regard to ambient temperature and humidity, altitude, natural lighting (including ultraviolet radiation) and pollution. The traveller needs to be aware of these changes before setting off, so that appropriate preparations (clothing, for example) can be made.
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Affiliation(s)
- Thomas Reilly
- Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Henry Cotton Campus, 15-21 Webster Street, Liverpool L3 2ET, UK
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33
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Abstract
Many aspects of human physiology and behavior are dominated by 24-hour circadian rhythms that have a major impact on our health and well-being, including the sleep-wake cycle, alertness and performance patterns, and many daily hormone profiles. These rhythms are spontaneously generated by an internal "pacemaker" in the hypothalamus, and daily light exposure to the eyes is required to keep these circadian rhythms synchronized both internally and with the external environment. Sighted individuals take this daily synchronization process for granted, although they experience some of the consequences of circadian desynchrony when "jetlagged" or working night shifts. Most blind people with no perception of light, however, experience continual circadian desynchrony through a failure of light information to reach the hypothalamic circadian clock, resulting in cyclical episodes of poor sleep and daytime dysfunction. Daily melatonin administration, which provides a replacement synchronizing daily "time cue, " is a promising therapeutic strategy, although optimal treatment dose and timing remain to be determined.
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Affiliation(s)
- Steven W Lockley
- Division of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.
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Sanchez-Mateos S, Alonso-Gonzalez C, Gonzalez A, Martinez-Campa CM, Mediavilla MD, Cos S, Sanchez-Barcelo EJ. Melatonin and estradiol effects on food intake, body weight, and leptin in ovariectomized rats. Maturitas 2007; 58:91-101. [PMID: 17706901 DOI: 10.1016/j.maturitas.2007.06.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2007] [Revised: 06/22/2007] [Accepted: 06/28/2007] [Indexed: 11/29/2022]
Abstract
OBJECTIVE The study in ovariectomized (Ovx) rats, as a model of menopausal status, of the effects of melatonin (M) and/or estradiol (E), associated or not with food restriction, on body weight (BW) and serum leptin levels. METHODS Female SD rats (200-250 g) were Ovx and treated with E, M, E+M or its diluents. Control sham-Ovx rats were treated with E-M diluents. After 7 weeks being fed ad libitum, the animals were exposed for 7 more weeks to a 30% food restriction. We measured: food intake, BW, nocturnal and diurnal urinary excretion of sulphatoxymelatonin (aMT6s), leptin in midday and midnight blood samples, glucose, total cholesterol, LDL, HDL and triglycerides. RESULTS Day/night rhythm of aMT6s excretion was preserved in all cases. The increase of aMT6s excretion in M-treated animals basically affected the nocturnal period. In animals fed ad libitum, E fully prevented Ovx-induced increase of BW, leptin and cholesterol. Melatonin reduced food intake and partially prevented the increase of BW and cholesterol, without changing leptin levels. Under food restriction, M was the most effective treatment in reducing BW and cholesterol. Leptin levels were similar in M, E or E+M treated rats, and lower than in untreated Ovx rats. CONCLUSIONS Our result gives a preliminary experimental basis for a post-menopausal co-treatment with estradiol and melatonin. It could combine the effectiveness of estradiol (not modified by melatonin) with the positive effects of melatonin (improvement of sleep quality, prevention of breast cancer, etc.). The possible beneficial effects of melatonin which could justify its use, need to be demonstrated in clinical trials.
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Affiliation(s)
- S Sanchez-Mateos
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, 39011 Santander, Spain
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Abstract
The number of travellers undertaking long-distance flights has continued to increase. Such flights are associated with travel fatigue and jet lag, the symptoms of which are considered here, along with their similarities, differences, and causes. Difficulties with jet lag because of sleep loss and decreased performance are emphasised. Since jet lag is caused mainly by inappropriate timing of the body clock in the new time zone, the pertinent properties of the body clock are outlined, with a description of how the body clock can be adjusted. The methods, both pharmacological and behavioural, that have been used to alleviate the negative results of time-zone transitions, are reviewed. The results form the rationale for advice to travellers flying in different directions and crossing several time zones. Finally, there is an account of the main problems that remain unresolved.
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Affiliation(s)
- Jim Waterhouse
- Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Henry Cotton Campus, Liverpool L3 2ET, UK.
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36
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Steinhilber D. [Melatonin, melatonin receptor agonists and tryptophan as sleep aids]. PHARMAZIE IN UNSERER ZEIT 2007; 36:213-7. [PMID: 17555058 DOI: 10.1002/pauz.200600220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
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Abstract
Starting from fetal life, estrogens are crucial in determining central gender dimorphism, and an estrogen-induced synaptic plasticity is well evident during puberty and seasonal changes as well as during the ovarian cycle. Estrogens act on the central nervous system (CNS) both through genomic mechanisms, modulating synthesis, release and metabolism of neurotransmitters, neuropeptides and neurosteroids, and through non-genomic mechanisms, influencing electrical excitability, synaptic function and morphological features. Therefore, estrogen's neuroactive effects are multifaceted and encompass a system that ranges from the chemical to the biochemical to the genomic mechanisms, protecting against a wide range of neurotoxic insults. Clinical evidences show that, during the climacteric period, estrogen withdrawal in the limbic system gives rise to modifications in mood, behaviour and cognition and that estrogen administration is able to improve mood and cognitive efficiency in post-menopause. Many biological mechanisms support the hypothesis that estrogens might protect against Alzheimer's disease (AD) by influencing neurotransmission, increasing cerebral blood flow, modulating growth proteins associated with axonal elongation and blunting the neurotoxic effects of beta-amyloid. On the contrary, clinical studies of estrogen replacement therapy (ERT) and cognitive function have reported controversial results, indicating a lack of efficacy of estrogens on cognition in post-menopausal women aged >or=65 years. These findings suggest the presence of a critical period for HRT-related neuroprotection and underlie the potential importance of early initiation of therapy for cognitive benefit. In this review, we shall first describe the multiple effects of steroids in the nervous system, which may be significant in the ageing process. A critical update of HRT use in women and a discussion of possible prospectives for steroid use are subsequently proposed.
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Affiliation(s)
- Andrea Riccardo Genazzani
- Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy.
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Abstract
Ramelteon, a potent agonist for the melatonin MT1 and MT2 brain receptors, has recently been granted approval by the US FDA for the treatment of insomnia associated with sleep onset. The drug has not exhibited potential for abuse or dependency in laboratory tests, nor does it interact with neurotransmitter receptors most associated with these phenomena, hence it has the great advantage of being a nonscheduled drug. Few data have been published in peer-reviewed journals describing its efficacy and side effects in patients with insomnia; however, side effects noted to date appear minor. No comparison study has been performed to determine whether the recommended dose of ramelteon 8 mg has any advantage over physiologic doses of melatonin (0.3 mg), particularly for long-term use.
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Affiliation(s)
- Richard Wurtman
- Massachusetts Institute of Technology, Department of Brain & Cognitive Sciences, 46-5023B, 43 Vassar Street, Cambridge, MA 02139, USA.
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Abstract
BACKGROUND Chronic insomnia is common among the elderly These elderly patients are often viewed as difficult to treat, yet they are among the groups with the greatest need of treatment. OBJECTIVE This article reviews the literature on the management of chronic insomnia in elderly persons. METHODS A search of MEDLINE was conducted for articles published in English between January 1966 and March 2006 using the terms insomnia, behavioral therapy, estsazolsam, fluvsazepsam, qusazepsam, teMsazepsam, tvisazolsam, eszopiclone, zaleplon, zolpidem, mirtazapine, nefazodone, trazodone, and ramelteon. Articles were selected if they were meta-analyses or evidence-based reviews of therapeutic modalities; randomized controlled trials of nonpharmacologic or pharmacologic treatment; or review articles covering the characteristics and management of insomnia. Preference was given to meta-analyses, evidence-based reviews, and articles that included relevant new information. RESULTS Available options for the treatment of insomnia include nonpharmacologic approaches, foremost among them cognitive behavioral therapy, and pharmacotherapies, including chloral hydrate, barbiturates, over-the-counter (OTC) and prescription antihistamines, OTC dietary supplements (including melatonin), sedating antidepressants, benzodiazepine and nonbenzodiazepine sedative-hypnotics, and melatonin agonists. There is considerable evidence to support the effectiveness and durability of nonpharmacologic interventions for insomnia in adults of all ages, yet these interventions are underutilized. With some recent exceptions, the majority of identified studies of pharmacotherapy were of short duration (< or =6 weeks) and did not exclusively enroll older adults. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. CONCLUSIONS Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.
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Melatonin and sleep in children with neurodevelopmental disabilities and sleep disorders. ACTA ACUST UNITED AC 2006. [DOI: 10.1016/j.cupe.2006.01.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Leproult R, Van Onderbergen A, L'hermite-Balériaux M, Van Cauter E, Copinschi G. Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol (Oxf) 2005; 63:298-304. [PMID: 16117817 DOI: 10.1111/j.1365-2265.2005.02341.x] [Citation(s) in RCA: 110] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Older adults are less responsive to the phase-shifting effects of light than younger subjects and may have difficulties adapting to abrupt time shifts. This study aims to determine whether the potent melatonin agonist agomelatine (S-20098) is capable of phase-shifting overt circadian rhythms in older adults. SUBJECTS AND DESIGN Eight healthy elderly men participated in a double-blind, two-period, cross-over study of 15 days of daily administration of either agomelatine (50 mg) or placebo at 1830 h. MEASUREMENTS At the end of each treatment period, the 24-h profiles of body temperature and of the plasma levels of GH, PRL, cortisol and TSH were collected and sleep was monitored polygraphically. RESULTS Phase-advances, averaging nearly 2 h, were observed for the temperature profile and for the variables characterizing the temporal organization of cortisol secretion following agomelatine administration. A similar trend was observed for the circadian rise of plasma TSH. There was no effect of agomelatine on any of the sleep variables. Agomelatine stimulated GH secretion during the wake period and was associated with a transient elevation of PRL levels. CONCLUSIONS Melatonin agonists such as agomelatine may be useful to phase-shift at least some overt circadian rhythms in older adults.
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Affiliation(s)
- Rachel Leproult
- Centre d'Etude des Rythmes Biologiques (CERB) and Laboratoire de Physiologie, Université Libre de Bruxelles, Brussels, Belgium.
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Abstract
The physiological roles of melatonin are still unclear despite almost 50 years of research. Elevated melatonin levels from either endogenous nocturnal production or exogenous daytime administration are associated in humans with effects including increased sleepiness, reduced core temperature, increased heat loss and other generally anabolic physiological changes. This supports the idea that endogenous melatonin increases nocturnal sleep propensity, either directly or indirectly via physiological processes associated with sleep. The article "Melatonin as a hypnotic--Pro", also in this issue, presents evidence to support this viewpoint. We do not entirely disagree, but nevertheless feel this is an overly simplistic interpretation of the available data. Our interpretation is that melatonin is primarily a neuroendocrine transducer promoting an increased propensity for 'dark appropriate' behavior. Thus, it is our view that exogenous melatonin is only hypnotic in those species or individuals for which endogenous melatonin increases sleep propensity and is consequently a dark appropriate outcome. Evidence supporting this position is drawn primarily from studies of exogenous administration of melatonin and its varied effects on sleep/wake behavior based on dose, time of administration, age and other factors. From this perspective, it will be shown that melatonin can exert hypnotic-like effects but only under limited circumstances.
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Affiliation(s)
- Cameron J van den Heuvel
- Centre for Sleep Research, University of South Australia, Basil Hetzel Institute, The Queen Elizabeth Hospital, Woodville, SA 5011, Australia.
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Danilenko KV, Putilov AA. Melatonin treatment of winter depression following total sleep deprivation: waking EEG and mood correlates. Neuropsychopharmacology 2005; 30:1345-52. [PMID: 15714224 DOI: 10.1038/sj.npp.1300698] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Patients with winter depression (seasonal affective disorder (SAD)) commonly complain of sleepiness. Sleepiness can be objectively measured by spectral analysis of the waking electroencephalogram (EEG) in the 1-10 Hz band. The waking EEG was measured every 3 h in 16 female SAD patients and 13 age-matched control women throughout a total sleep deprivation of 30 h. Melatonin (or placebo) under double-blind conditions was administered subsequently (0.5 mg at 1700 h for 6 days), appropriately timed to phase advance circadian rhythms, followed by reassessment in the laboratory for 12 h. The increase in EEG power density in a narrow theta band (5-5.99 Hz, derivation Fz-Cz) during the 30 h protocol was significantly attenuated in patients compared with controls (difference between linear trends p=0.037). Sleepiness (p=0.092) and energy (p=0.045) self-ratings followed a similar pattern. Six patients improved after sleep deprivation (> or =50% reduction on SIGH-SAD(22) score). EEG power density dynamics was correlated with clinical response to sleep deprivation: the steeper the build-up (as in controls), the better the improvement (p<0.05). There was no differential effect of melatonin or placebo on any measure; both treatments stabilized the improvement. Overall, patients with winter depression manifest similar wake EEG characteristics as long sleepers or late chronotype with respect to an insufficient build-up of homeostatic sleep pressure. Sleep deprivation was an effective antidepressant treatment for some patients, but evening melatonin was not more efficacious than placebo in sustaining this antidepressant effect.
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Affiliation(s)
- Konstantin V Danilenko
- Institute of Internal Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, Russia.
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Yukuhiro N, Kimura H, Nishikawa H, Ohkawa S, Yoshikubo SI, Miyamoto M. Effects of ramelteon (TAK-375) on nocturnal sleep in freely moving monkeys. Brain Res 2005; 1027:59-66. [PMID: 15494157 DOI: 10.1016/j.brainres.2004.08.035] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2004] [Indexed: 12/15/2022]
Abstract
We investigated the effects of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4]furan-8-yl)ethyl]propionamide (ramelteon, TAK-375), a novel MT1/MT2 receptor agonist, on nocturnal sleep in freely moving monkeys and compared these results with those of melatonin and zolpidem. Treatment with ramelteon (0.03 and 0.3 mg/kg, p.o.) significantly shortened latency to sleep onset and significantly increased total duration of sleep. Treatment with melatonin (0.3, 1, and 3 mg/kg, p.o.) also decreased sleep latency, but the effect was weak; the only significant reduction was seen with the 0.3 mg/kg dose on latency to light sleep. Melatonin had no significant effects on the duration of sleep. Zolpidem had no significant effects on latency to sleep onset in this study at any dose (1, 3, 10, and 30 mg/kg, p.o.). The highest dose (30 mg/kg) of zolpidem had a tendency to increase slow wave sleep; however, it also induced apparent sedation and myorelaxation. Treatment with ramelteon and melatonin had no evident effect on the general behavior of the monkeys. Spectral analysis (fast Fourier transform, FFT) of both ramelteon and melatonin revealed sleep patterns that were indistinguishable from those of naturally occurring sleep. The EEG power spectra of zolpidem were qualitatively different from that of naturally occurring physiological sleep. Results of the present study support the investigation of ramelteon as a sleep-promoting agent in humans.
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Affiliation(s)
- Nobuhito Yukuhiro
- Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Osaka 532-8686, Japan
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Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology 2005; 48:301-10. [PMID: 15695169 DOI: 10.1016/j.neuropharm.2004.09.007] [Citation(s) in RCA: 259] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2004] [Revised: 09/06/2004] [Accepted: 09/16/2004] [Indexed: 12/15/2022]
Abstract
Ramelteon (TAK-375) is a novel melatonin receptor agonist currently under investigation for the treatment of insomnia. This study describes the neurochemical and receptor binding characteristics of ramelteon in vitro. Ramelteon showed very high affinity for human MT1 (Mel1a) and MT2 (Mel1b) receptors (expressed in Chinese hamster ovary [CHO] cells), and chick forebrain melatonin receptors (consisting of Mel1a and Mel1c receptors) with Ki values of 14.0, 112, and 23.1 pM, respectively, making the affinities of ramelteon for these receptors 3-16 times higher than those of melatonin. The affinity of ramelteon for hamster brain MT3 binding sites was extremely weak (Ki: 2.65 microM) compared to melatonin's affinity for the MT3 binding site (Ki: 24.1 nM). In addition, ramelteon showed no measurable affinity for a large number of ligand binding sites (including benzodiazepine receptors, dopamine receptors, opiate receptors, ion channels, and transporters) and no effect on the activity of various enzymes. Ramelteon inhibited forskolin-stimulated cAMP production in the CHO cells that express the human MT1 or MT2 receptors. Taken together, these results indicate that ramelteon is a potent and highly selective agonist of MT1/MT2 melatonin receptors.
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Affiliation(s)
- Koki Kato
- Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Osaka 532-8686, Japan
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Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M, Thomas R, Thal LJ. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep 2004; 26:893-901. [PMID: 14655926 PMCID: PMC4418658 DOI: 10.1093/sleep/26.7.893] [Citation(s) in RCA: 240] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer's disease. DESIGN A multicenter, randomized, placebo-controlled clinical trial of 2 dose formulations of oral melatonin coordinated by the National Institute of Aging-funded Alzheimer's Disease Cooperative Study. Subjects with Alzheimer's disease and nighttime sleep disturbance were randomly assigned to 1 of 3 treatment groups: placebo, 2.5-mg slow-release melatonin, or 10-mg melatonin. SETTING Private homes and long-term care facilities. PARTICIPANTS 157 individuals were recruited by 36 Alzheimer's disease research centers. Subjects with a diagnosis of Alzheimer's disease were eligible if they averaged less than 7 hours of sleep per night (as documented by wrist actigraphy) and had 2 or more episodes per week of nighttime awakenings reported by the caregiver. MEASUREMENTS Nocturnal total sleep time, sleep efficiency, wake-time after sleep onset, and day-night sleep ratio during 2- to 3-week baseline and 2-month treatment periods. Sleep was defined by an automated algorithmic analysis of wrist actigraph data. RESULTS No statistically significant differences in objective sleep measures were seen between baseline and treatment periods for the any of the 3 groups. Nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. Trends for a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group, compared to placebo, were also seen. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5-mg sustained-release melatonin group relative to placebo. There were no significant differences in the number or seriousness of adverse events between the placebo and melatonin groups. CONCLUSIONS Based on actigraphy as an objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer's disease.
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Affiliation(s)
- Clifford Singer
- Department of Psychiatry, Oregon Health & Science University, Portland, USA.
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Abstract
Neurologic disorders may present or masquerade as pediatric sleep problems and fool the pediatrician, which may delay diagnosis and treatment. Many of the sleep problems in children with neurologic disorders arise directly from primary dysfunction or delayed maturation of their sleep-wake regulation systems. It is important to realize that nocturnal frontal lobe seizures or cluster headaches can be mistaken for night terrors, and craniopharyngiomas or myotonic dystrophy may present as narcolepsy-cataplexy. Hypothalamic dysfunction may explain not only the impaired circadian rhythm disorders in children with profound mental retardation but also excessive sleepiness and hyperphagia in Prader-Willi and Kleine-Levin syndromes. Intellectually challenged children perform better, learn more, and are better behaved with sufficient restorative sleep.
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Affiliation(s)
- Madeleine Grigg-Damberger
- Department of Neurology, University of New Mexico School of Medicine, MSC10 5620, Albuquerque, NM 87131-0001, USA.
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Uchikawa O, Fukatsu K, Tokunoh R, Kawada M, Matsumoto K, Imai Y, Hinuma S, Kato K, Nishikawa H, Hirai K, Miyamoto M, Ohkawa S. Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J Med Chem 2002; 45:4222-39. [PMID: 12213063 DOI: 10.1021/jm0201159] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
To develop a new therapeutic agent for sleep disorders, we synthesized a novel series of tricyclic indan derivatives and evaluated them for their binding affinity to melatonin receptors. In our previous paper, we proposed a conformation of the methoxy group favorable for the binding of the MT(1) receptor. To fix the methoxy group in an active conformation, we decided to synthesize conformationally restricted tricyclic indan analogues with the oxygen atom in the 6-position incorporated into a furan, 1,3-dioxane, oxazole, pyran, morpholine, or 1,4-dioxane ring system. Among these compounds, indeno[5,4-b]furan analogues were found to be the most potent and selective MT(1) receptor ligands and to have superior metabolic stability. The optimization of substituents led to (S)-(-)-22b, which showed very strong affinity for human MT(1) (K(i) = 0.014 nM), but no significant affinity for hamster MT(3)() (K(i) = 2600 nM) or other neurotransmitter receptors. The pharmacological effects of (S)-(-)-22b were studied in experimental animals, and it was found that a dose of 0.1 mg/kg, po promoted a sleep in freely moving cats, as demonstrated by a decrease in wakefulness and increases in slow wave sleep and rapid eye movement sleep, which lasted for 6 h after administration. Melatonin (1 mg/kg, po) also had a sleep-promoting effect, though it lasted only 2 h. A new chiral method for the synthesis of (S)-(-)-22b starting from 60, which was prepared from 59 employing asymmetric hydrogenation with the (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl-Ru complex, was developed. (S)-(-)-22b (TAK-375) is currently under clinical trial for the treatment of insomnia and circadian rhythm disorders.
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Affiliation(s)
- Osamu Uchikawa
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
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Yoon IY, Song BG. Role of morning melatonin administration and attenuation of sunlight exposure in improving adaptation of night-shift workers. Chronobiol Int 2002; 19:903-13. [PMID: 12405553 DOI: 10.1081/cbi-120014571] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The authors studied whether melatonin administration improves adaptation of workers to nightshift and if its beneficial effect is enhanced by attenuation of morning sunlight exposure. Twelve nightshift nurses received three treatments: Placebo (Pla), Melatonin (Mel), and Melatonin with Sunglasses (Mel-S). Each treatment procedure was administered for 2d of different 4d nightshifts in a repeated measures crossover design. In Pla, nurses were treated with placebo before daytime sleep and allowed exposure to morning sunlight. In Mel, 6mg of melatonin was similarly administered before daytime sleep with morning sunlight permitted. In Mel-S, 6 mg of melatonin was given as in Mel, with sunglasses worn in the morning to attenuate sunlight exposure. Placebo or melatonin was administered during days 2 and 3 when the first and second daytime sleep occurred. Nocturnal alertness and performance plus daytime sleep and mood states were assessed during all three treatments. The sleep period and total sleep times were significantly increased by melatonin treatments; yet, nocturnal alertness was only marginally improved. There were no differences between Mel and Mel-S. Performance tests revealed no difference between Pla and melatonin treatments. Melatonin exerted modest benefit in improving the adaptation of workers to nightshift, and its effect was not enhanced by attenuation of morning sunlight exposure.
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Affiliation(s)
- In-Young Yoon
- Yong-In Mental Hospital, Kusung-myun, Republic of Korea.
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Cagnacci A, Malmusi S, Zanni A, Arangino S, Cagnacci P, Volpe A. Acute modifications in the levels of daytime melatonin do not influence leptin in postmenopausal women. J Pineal Res 2002; 33:57-60. [PMID: 12121486 DOI: 10.1034/j.1600-079x.2002.01893.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Melatonin shows a clear circadian rhythm with peak values at night, and may act directly with fat cells. Leptin, the anorexic hormone synthesized mainly by adipocytes, is produced in a circadian fashion, similar to that of melatonin. Accordingly, in the present study, we investigated whether melatonin may contribute to the rise in circulating leptin. The study was performed in postmenopausal women with 2 months of treatment with placebo or estradiol (50 microg/day). Melatonin was administered in doses of 1 mg by mouth versus placebo. In experiment 1, melatonin was administered at 08:30 hr. In experiment 2, at 08:30 hr and 10:30 hr, and in experiment 3 at 15:30 hr. Three blood samples, one every 15 min, were collected prior to the administration of melatonin and 2 hr after the administration of the single melatonin dose or the second melatonin administration (experiment 2). Following its administration, circulating melatonin reached pharmacological levels. In the three experiments, levels of leptin were not modified by the daytime administration of melatonin. These data indicate that, at least in daytime hours, acute modifications in daytime melatonin levels do not influence levels of leptin of postmenopausal women either without or with estradiol replacement. Accordingly, the metabolic, endocrine, reproductive and biological modifications induced by acute daytime melatonin in women do not seem to be mediated by modifications in circulating leptin.
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Affiliation(s)
- Angelo Cagnacci
- Institute of Obstetrics and Gynecology, University of Modena, Modena, Italy.
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