|
1
|
Aiello G, Cuocina M, La Via L, Messina S, Attaguile GA, Cantarella G, Sanfilippo F, Bernardini R. Melatonin or Ramelteon for Delirium Prevention in the Intensive Care Unit: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Clin Med 2023; 12:jcm12020435. [PMID: 36675363 PMCID: PMC9863078 DOI: 10.3390/jcm12020435] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/29/2022] [Accepted: 12/31/2022] [Indexed: 01/06/2023] Open
Abstract
Melatonin modulates the circadian rhythm and has been studied as a preventive measure against the development of delirium in hospitalized patients. Such an effect may be more evident in patients admitted to the ICU, but findings from the literature are conflicting. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We assessed whether melatonin or ramelteon (melatonin agonist) reduce delirium incidence as compared to a placebo in ICU patients. Secondary outcomes were ICU length of stay, duration of mechanical ventilation (MV) and mortality. Estimates are presented as risk ratio (RR) or mean differences (MD) with 95% confidence interval (CI). Nine RCTs were included, six of them reporting delirium incidence. Neither melatonin nor ramelteon reduced delirium incidence (RR 0.76 (0.54, 1.07), p = 0.12; I2 = 64%), although a sensitivity analysis conducted adding other four studies showed a reduction in the risk of delirium (RR = 0.67 (95%CI 0.48, 0.92), p = 0.01; I2 = 67). Among the secondary outcomes, we found a trend towards a reduction in the duration of MV (MD -2.80 (-6.06, 0.47), p = 0.09; I2 = 94%) but no differences in ICU-LOS (MD -0.26 (95%CI -0.89, 0.37), p = 0.42; I2 = 75%) and mortality (RR = 0.85 (95%CI 0.63, 1.15), p = 0.30; I2 = 0%). Melatonin and ramelteon do not seem to reduce delirium incidence in ICU patients but evidence is weak. More studies are needed to confirm this finding.
Collapse
Affiliation(s)
- Giuseppe Aiello
- Department Biomedical and Biotechnological Sciences (BIOMETEC), Section of Pharmacology, University of Catania, 95123 Catania, Italy
| | - Micol Cuocina
- Department Biomedical and Biotechnological Sciences (BIOMETEC), Section of Pharmacology, University of Catania, 95123 Catania, Italy
| | - Luigi La Via
- Department of Anesthesiology and Intensive Care, AOU “Policlinico-San Marco”, 95123 Catania, Italy
| | - Simone Messina
- School of Specialization in Anesthesiology and Intensive Care, University “Magna Graecia”, 88100 Catanzaro, Italy
| | - Giuseppe A. Attaguile
- Department Biomedical and Biotechnological Sciences (BIOMETEC), Section of Pharmacology, University of Catania, 95123 Catania, Italy
| | - Giuseppina Cantarella
- Department Biomedical and Biotechnological Sciences (BIOMETEC), Section of Pharmacology, University of Catania, 95123 Catania, Italy
- Correspondence:
| | - Filippo Sanfilippo
- Department of Anesthesiology and Intensive Care, AOU “Policlinico-San Marco”, 95123 Catania, Italy
| | - Renato Bernardini
- Department Biomedical and Biotechnological Sciences (BIOMETEC), Section of Pharmacology, University of Catania, 95123 Catania, Italy
- Clinical Toxicology Unit, University Hospital of Catania, 95123 Catania, Italy
| |
Collapse
|
|
2
|
Zhang Y, Lang R, Guo S, Luo X, Li H, Liu C, Dong W, Bao C, Yu Y. Intestinal microbiota and melatonin in the treatment of secondary injury and complications after spinal cord injury. Front Neurosci 2022; 16:981772. [PMID: 36440294 PMCID: PMC9682189 DOI: 10.3389/fnins.2022.981772] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 10/24/2022] [Indexed: 09/12/2023] Open
Abstract
Spinal cord injury (SCI) is a central nervous system (CNS) disease that can cause sensory and motor impairment below the level of injury. Currently, the treatment scheme for SCI mainly focuses on secondary injury and complications. Recent studies have shown that SCI leads to an imbalance of intestinal microbiota and the imbalance is also associated with complications after SCI, possibly through the microbial-brain-gut axis. Melatonin is secreted in many parts of the body including pineal gland and gut, effectively protecting the spinal cord from secondary damage. The secretion of melatonin is affected by circadian rhythms, known as the dark light cycle, and SCI would also cause dysregulation of melatonin secretion. In addition, melatonin is closely related to the intestinal microbiota, which protects the barrier function of the gut through its antioxidant and anti-inflammatory effects, and increases the abundance of intestinal microbiota by influencing the metabolism of the intestinal microbiota. Furthermore, the intestinal microbiota can influence melatonin formation by regulating tryptophan and serotonin metabolism. This paper summarizes and reviews the knowledge on the relationship among intestinal microbiota, melatonin, and SCI in recent years, to provide new theories and ideas for clinical research related to SCI treatment.
Collapse
Affiliation(s)
- Yiwen Zhang
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Rui Lang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shunyu Guo
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoqin Luo
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Huiting Li
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Cencen Liu
- Department of Pathology, People’s Hospital of Zhongjiang County, Deyang, China
| | - Wei Dong
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Changshun Bao
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Neurological Diseases and Brain Function Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yang Yu
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| |
Collapse
|
|
3
|
Tsotinis A, Kompogennitaki R, Papanastasiou I, Garratt PJ, Bocianowska A, Sugden D. Fluorine substituted methoxyphenylalkyl amides as potent melatonin receptor agonists. MEDCHEMCOMM 2019; 10:460-464. [PMID: 31191854 PMCID: PMC6530086 DOI: 10.1039/c8md00604k] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/10/2019] [Indexed: 11/21/2022]
Abstract
A series of fluorine substituted methoxyphenylalkyl amides were prepared with different orientations of the fluorine and methoxy groups with respect to the alkylamide side chain and with alkyl sides of differing lengths (n = 1-3). β-Dimethyl and α-methyl derivatives were also synthesised. The compounds were tested as melatonin agonists and antagonists using the pigment aggregation of Xenopus melanophores as the biological assay. A number of these compounds were potent melatonin agonists, the potency depending on the length of the alkyl chain, the orientation of the methoxy and fluorine substituents, the amide chain length and, for the ethyl side-chain analogues, the presence of β-substituents.
Collapse
Affiliation(s)
- Andrew Tsotinis
- School of Health Sciences , Department of Pharmacy , Division of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimioupoli-Zografou , 157 84 Athens , Greece .
| | - Rodanthi Kompogennitaki
- School of Health Sciences , Department of Pharmacy , Division of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimioupoli-Zografou , 157 84 Athens , Greece .
| | - Ioannis Papanastasiou
- School of Health Sciences , Department of Pharmacy , Division of Pharmaceutical Chemistry , National and Kapodistrian University of Athens , Panepistimioupoli-Zografou , 157 84 Athens , Greece .
| | - Peter J Garratt
- Department of Chemistry , University College London , 20 Gordon Street , London WC1H 0AJ , UK
| | - Alina Bocianowska
- School of Biomedical and Health Sciences , Division of Reproduction and Endocrinology , King's College London , London SE1 1UL , UK
| | - David Sugden
- School of Biomedical and Health Sciences , Division of Reproduction and Endocrinology , King's College London , London SE1 1UL , UK
| |
Collapse
|
|
4
|
Neu-P11, a novel MT1/MT2 agonist, reverses diabetes by suppressing the hypothalamic-pituitary-adrenal axis in rats. Eur J Pharmacol 2017; 812:225-233. [PMID: 28687198 DOI: 10.1016/j.ejphar.2017.07.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 06/19/2017] [Accepted: 07/03/2017] [Indexed: 12/15/2022]
Abstract
Excessive glucocorticoid (GC) in type 2 diabetes mellitus (T2DM) reduces insulin sensitivity, impairs β-cell function, increases gluconeogenesis and glycogenolysis, impairs glucose uptake and metabolism, and reduces the insulinotropic effects of glucagon-like peptide 1. Melatonin, which serves as a physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis, has been suggested to have anti-diabetic effects. The objective of the present study was to investigate the effect of the MT1/MT2 melatonin agonist Neu-P11 on glucose and lipid metabolism in T2DM rats induced by a high fat diet combined with low doses of streptozotocin. T2DM rats were intragastrically administered melatonin (20mg/kg), Neu-P11 (20, 10, 5mg/kg), or a vehicle for 4 weeks. The results showed that the increased food intake, water consumption, hyperglycemia, glucose intolerance, and insulin resistance in T2DM rats were all improved by Neu-P11 treatment. Neu-P11 increased GC receptor expression and suppressed 11β-hydroxysteroid dehydrogenase 1 activity in the hippocampus by enhancing GC sensitivity and HPA feedback, thus decreasing the high GC levels. Transcript levels of the glucose metabolism-related genes peroxisome proliferator-activated receptor-γ, glucose transporter type-4, and adiponectin in adipose tissue were significantly increased after Neu-P11 treatment, while leptin mRNA was significantly decreased. Furthermore, MT1 and MT2 protein levels were enhanced by Neu-P11. These data suggest that normalization of the hyperactivated HPA axis by melatonin and Neu-P11 in T2DM regulates metabolic profiles and insulin sensitivity, which may attenuate insulin resistance and glucose homeostasis. Because Neu-P11 has superior pharmacokinetics and a longer half-life than melatonin, it might be beneficial in treating obesity and T2DM.
Collapse
|
|
5
|
Exogenous Melatonin for Delirium Prevention: a Meta-analysis of Randomized Controlled Trials. Mol Neurobiol 2015; 53:4046-4053. [DOI: 10.1007/s12035-015-9350-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 07/07/2015] [Indexed: 12/11/2022]
|
|
6
|
Ma Y, Dong M, Mita C, Sun S, Peng CK, Yang AC. Publication analysis on insomnia: how much has been done in the past two decades? Sleep Med 2015; 16:820-6. [PMID: 25979182 DOI: 10.1016/j.sleep.2014.12.028] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 12/07/2014] [Accepted: 12/29/2014] [Indexed: 12/19/2022]
Abstract
Insomnia has been a rising public concern in recent years. As one example of a multidisciplinary topic, the theme of insomnia research has gradually shifted over time; however, there is very little quantitative characterization of the research trends in insomnia. The current study aims to quantitatively analyze trends in insomnia publications for the past 20 years. We retrospectively analyzed insomnia-related publications retrieved from PubMed and Google Scholar between 1994 and from a number of different perspectives. We investigated the major areas of research focus for insomnia, journal characteristics, as well as trends in clinical management and treatment modalities. The resulting 5841 publications presented an exponential growth trend over the past two decades, with mean annual growth rates at nearly 10% for each publication type. Analysis of major research focuses indicated that depression, hypnotics and sedatives, questionnaires, and polysomnography are the most common topics at present. Furthermore, we found that while studies on drug therapy and adverse effects decreased in the most recent five years, the greatest expansion of insomnia publications were in the areas of cognitive behavioral therapy for insomnia (CBT-I) and alternative therapies. Collectively, insomnia publications present a continuous trend of increase. While sedative and hypnotic drugs dominated the treatment of insomnia, non-pharmacological therapies may have great potential for advancement in future years. Future research effort is warranted for novel tools and clinical trials, especially on insomnia treatments with inadequate evidence or not-yet-clear efficacy and side effects.
Collapse
Affiliation(s)
- Yan Ma
- Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; Sleep Center, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ming Dong
- IBM, Software Development Lab, Littleton, Massachusetts, USA
| | - Carol Mita
- Reference & Education Services, Countway Library of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Shuchen Sun
- Department of Otolaryngology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chung-Kang Peng
- Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Albert C Yang
- Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Department of Psychiatry, Taipei Veterans General Hospital, Taipei City, Taiwan.
| |
Collapse
|
|
7
|
Masters A, Pandi-Perumal SR, Seixas A, Girardin JL, McFarlane SI. Melatonin, the Hormone of Darkness: From Sleep Promotion to Ebola Treatment. ACTA ACUST UNITED AC 2015; 4. [PMID: 25705578 DOI: 10.4172/2168-975x.1000151] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Melatonin is a hormone secreted by the enigmatic pineal gland in response to darkness, hence the name hormone of darkness. It has generated a great deal of interest as a therapeutic modality for various diseases particularly sleep disorders. This pleiotropic molecule has anti-inflammatory, antioxidant and anticoagulopathic properties in addition to its endothelial protective effects. In this article we discuss melatonin secretion and mechanisms of action as well as therapeutic rationale. We also highlight the potential utility of melatonin in the deadly modern-day Ebola epidemic.
Collapse
Affiliation(s)
- Alina Masters
- Division of Endocrinology, Department of Medicine, SUNY Downstate Medical Center, 11203 Brooklyn, NY, USA
| | - Seithikurippu R Pandi-Perumal
- Center for Healthful Behavior Change, Division of Health and Behavior, Department of Population Health, New York University Langone Medical Center, New York University School of Medicine, 227 East 30th St, 10016 New York, NY, USA
| | - Azizi Seixas
- Center for Healthful Behavior Change, Division of Health and Behavior, Department of Population Health, New York University Langone Medical Center, New York University School of Medicine, 227 East 30th St, 10016 New York, NY, USA
| | - Jean-Louis Girardin
- Center for Healthful Behavior Change, Division of Health and Behavior, Department of Population Health, New York University Langone Medical Center, New York University School of Medicine, 227 East 30th St, 10016 New York, NY, USA
| | - Samy I McFarlane
- Division of Endocrinology, Department of Medicine, SUNY Downstate Medical Center, 11203 Brooklyn, NY, USA
| |
Collapse
|
|
8
|
Chen C, Fichna J, Laudon M, Storr M. Antinociceptive effects of novel melatonin receptor agonists in mouse models of abdominal pain. World J Gastroenterol 2014; 20:1298-1304. [PMID: 24574803 PMCID: PMC3921511 DOI: 10.3748/wjg.v20.i5.1298] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 09/10/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize the antinociceptive action of the novel melatonin receptor (MT) agonists, Neu-P11 and Neu-P12 in animal models of visceral pain.
METHODS: Visceral pain was induced by intracolonic (ic) application of mustard oil or capsaicin solution or by intraperitoneal (ip) administration of acetic acid. Neu-P11, Neu-P12, or melatonin were given ip or orally and their effects on pain-induced behavioral responses were evaluated. To identify the receptors involved, the non-selective MT1/MT2 receptor antagonist luzindole, the MT2 receptor antagonist 4-P-PDOT, or the μ-opioid receptor antagonist naloxone were injected ip or intracerebroventricularly (icv) prior to the induction of pain.
RESULTS: Orally and ip administered melatonin, Neu-P11, and Neu-P12 reduced pain responses in a dose-dependent manner. Neu-P12 was more effective and displayed longer duration of action compared to melatonin. The antinociceptive effects of Neu-P11 or Neu-P12 were antagonized by ip or icv. administered naloxone. Intracerebroventricularly, but not ip administration of luzindole or 4-P-PDOT blocked the antinociceptive actions of Neu-P11 or Neu-P12.
CONCLUSION: Neu-P12 produced the most potent and long-lasting antinociceptive effect. Further development of Neu-P12 for future treatment of abdominal pain seems promising.
Collapse
|
|
9
|
Rawashdeh O, Hudson RL, Stepien I, Dubocovich ML. Circadian periods of sensitivity for ramelteon on the onset of running-wheel activity and the peak of suprachiasmatic nucleus neuronal firing rhythms in C3H/HeN mice. Chronobiol Int 2011; 28:31-8. [PMID: 21182402 DOI: 10.3109/07420528.2010.532894] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Ramelteon, an MT(1)/MT(2) melatonin receptor agonist, is used for the treatment of sleep-onset insomnia and circadian sleep disorders. Ramelteon phase shifts circadian rhythms in rodents and humans when given at the end of the subjective day; however, its efficacy at other circadian times is not known. Here, the authors determined in C3H/HeN mice the maximal circadian sensitivity for ramelteon in vivo on the onset of circadian running-wheel activity rhythms, and in vitro on the peak of circadian rhythm of neuronal firing in suprachiasmatic nucleus (SCN) brain slices. The phase response curve (PRC) for ramelteon (90 µg/mouse, subcutaneous [sc]) on circadian wheel-activity rhythms shows maximal sensitivity during the late mid to end of the subjective day, between CT8 and CT12 (phase advance), and late subjective night and early subjective day, between CT20 and CT2 (phase delay), using a 3-day-pulse treatment regimen in C3H/HeN mice. The PRC for ramelteon resembles that for melatonin in C3H/HeN mice, showing the same magnitude of maximal shifts at CT10 and CT2, except that the range of sensitivity for ramelteon (CT8-CT12) during the subjective day is broader. Furthermore, in SCN brain slices in vitro, ramelteon (10 pM) administered at CT10 phase advances (5.6 ± 0.29 h, n = 3) and at CT2 phase delays (-3.2 ± 0.12 h, n = 6) the peak of circadian rhythm of neuronal firing, with the shifts being significantly larger than those induced by melatonin (10 pM) at the same circadian times (CT10: 2.7 ± 0.15 h, n = 4, p < .05; CT2: -1.13 ± 0.08 h, n = 6, p < .001, respectively). The phase shifts induced by both melatonin and ramelteon in the SCN brain slice at either CT10 or CT2 corresponded with the period of sensitivity observed in vivo. In conclusion, melatonin and ramelteon showed identical periods of circadian sensitivity at CT10 (advance) and CT2 (delay) to shift the onset of circadian activity rhythms in vivo and the peak of SCN neuronal firing rhythms in vitro.
Collapse
Affiliation(s)
- Oliver Rawashdeh
- Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | | | | | | |
Collapse
|
|
10
|
Pandi-Perumal SR, Spence DW, Verster JC, Srinivasan V, Brown GM, Cardinali DP, Hardeland R. Pharmacotherapy of insomnia with ramelteon: safety, efficacy and clinical applications. J Cent Nerv Syst Dis 2011; 3:51-65. [PMID: 23861638 PMCID: PMC3663615 DOI: 10.4137/jcnsd.s1611] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT1 and MT2 melatonin receptors. Ramelteon is the first melatonin receptor agonist approved by the Food and Drug Administration (FDA) for the treatment of insomnia characterized by sleep onset difficulties. Ramelteon is both a chronobiotic and a hypnotic that has been shown to promote sleep initiation and maintenance in various preclinical and in clinical trials. The efficacy and safety of ramelteon in patients with chronic insomnia was initially confirmed in short-term placebo-controlled trials. These showed little evidence of next-day residual effects, withdrawal symptoms or rebound insomnia. Other studies indicated that ramelteon lacked abuse potential and had a minimal risk of producing dependence or adverse effects on cognitive or psychomotor performance. A 6-month placebo-controlled international study and a 1-year open-label study in the USA demonstrated that ramelteon was effective and well tolerated. Other potential off-label uses of ramelteon include circadian rhythm sleep disorders such as shift-work and jet lag. At the present time the drug should be cautiously prescribed for short-term treatment only.
Collapse
|
|
11
|
Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev 2010; 62:343-80. [PMID: 20605968 PMCID: PMC2964901 DOI: 10.1124/pr.110.002832] [Citation(s) in RCA: 418] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The hormone melatonin (5-methoxy-N-acetyltryptamine) is synthesized primarily in the pineal gland and retina, and in several peripheral tissues and organs. In the circulation, the concentration of melatonin follows a circadian rhythm, with high levels at night providing timing cues to target tissues endowed with melatonin receptors. Melatonin receptors receive and translate melatonin's message to influence daily and seasonal rhythms of physiology and behavior. The melatonin message is translated through activation of two G protein-coupled receptors, MT(1) and MT(2), that are potential therapeutic targets in disorders ranging from insomnia and circadian sleep disorders to depression, cardiovascular diseases, and cancer. This review summarizes the steps taken since melatonin's discovery by Aaron Lerner in 1958 to functionally characterize, clone, and localize receptors in mammalian tissues. The pharmacological and molecular properties of the receptors are described as well as current efforts to discover and develop ligands for treatment of a number of illnesses, including sleep disorders, depression, and cancer.
Collapse
Affiliation(s)
- Margarita L Dubocovich
- Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo State University of New York, 3435 Main Street, Buffalo, NY 14214, USA.
| | | | | | | | | | | |
Collapse
|
|
12
|
Abstract
IMPORTANCE OF THE FIELD Melatonin is a major chronobiological regulator involved in circadian phasing, sleep, and numerous other functions including cyto-/neuroprotection, immune modulation, and energy metabolism. The suitability of melatonin as a drug is limited because of its short half-life. Therefore, various indolic and non-indolic melatonergic agonists have been developed. Frequent health problems such as sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance are targeted by melatonergic agonists. AREAS COVERED IN THIS REVIEW Various synthetic melatonergic drugs are compared with regard to receptor affinities, selectivity, effects on sleep, endogenous melatonin, circadian phase and insulin-related metabolism. WHAT THE READER WILL GAIN The chemical design of melatonin receptor agonists is discussed in relation to consequences for receptor affinity, selectivity, metabolism, and spectrum of effects. TAKE HOME MESSAGE Melatonergic agonists are suitable for phase-shifting circadian rhythms, and may be used for treating disorders related to circadian dysfunction including sleep difficulties. Facilitation of sleep onset is a general property, whereas promotion of sleep maintenance is demonstrable but not always fully sufficient. Details are especially available for tasimelteon. Support of insulin sensitivity may become a new area of application for compounds such as NEU-P11. Some drugs acting additionally as serotonergic antagonists display antidepressant properties.
Collapse
Affiliation(s)
- Rüdiger Hardeland
- University of Göttingen, Johann Friedrich Blumenbach Institute of Zoology and Anthropology, Göttingen, Germany.
| |
Collapse
|
|
13
|
Fisher SP, Sugden D. Endogenous melatonin is not obligatory for the regulation of the rat sleep-wake cycle. Sleep 2010; 33:833-40. [PMID: 20550025 DOI: 10.1093/sleep/33.6.833] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
STUDY OBJECTIVES Though melatonin and melatonin receptor agonists are in clinical use and under development for treating insomnia, the role of endogenous melatonin in the regulation of the sleep-wake cycle remains uncertain. Some clinical case reports suggest that reduced nocturnal melatonin secretion is linked to sleep disruption, but pineal-gland removal in experimental animals has given variable results. DESIGN The present study examined the effects of pinealectomy on the diurnal sleep-wake cycle of rats implanted with a radiotransmitter to allow continuous measurement of cortical electroencephalogram, electromyogram, and core temperature (Tc) without restraint in their home cages. MEASUREMENTS AND RESULTS Tc was slightly (0.2 degrees C) but significantly lower after pineal removal. The total amount and diurnal distribution of locomotor activity, wake, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep were unaltered in pinealectomized rats compared to sham-operated controls. Sleep consolidation measured by determining wake, NREM sleep, and REM sleep bout length and frequency was also unchanged. The EEG power spectrum during NREM sleep was unchanged, but a significant decrease in theta power (5-8 Hz) during REM sleep episodes was found. CONCLUSIONS Our data provide no evidence that endogenous circulating melatonin plays a role in regulating the sleep-wake cycle in rats. However, because cortical theta oscillations are generated in the CA1-3 layer of the hippocampus, neurons known to express melatonin receptors, this suggests that a lack of melatonin following pineal removal influences the function of these neurons and is consistent with previous work suggesting that endogenous melatonin is an important regulator of hippocampal physiology.
Collapse
Affiliation(s)
- Simon P Fisher
- Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King's College London, London, UK
| | | |
Collapse
|
|
14
|
Abstract
Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT(1) and MT(2) melatonin receptors. Ramelteon's half-life is longer than that of melatonin, being metabolized in the body to four main metabolites, M-I, M-II, M-III, and M-IV. M-II has an affinity to MT(1) and MT(2) of about one-tenth of the parent compound, but its concentration in the circulation exceeds that of ramelteon by more than an order of magnitude. Ramelteon is effective in decreasing latency to persistent sleep and increasing total sleep time in freely moving monkeys. A number of clinical studies have been undertaken to study the efficacy of ramelteon in subjects with chronic insomnia. In almost all of these studies, ramelteon, in various doses of 4, 8, or 16 mg most commonly, significantly reduced sleep latency and increased sleep duration. Its primary action in sleep promotion is not a generalized gamma-aminobutyric (GABA)-ergic central nervous system depression, but rather it acts as a melatonergic agonist in the suprachiasmatic nucleus (and at other central nervous system sites), from where downstream processes, including GABA-ergic effects, are controlled via the hypothalamic sleep switch. Unlike other commonly prescribed hypnotic drugs, ramelteon is not associated with next morning hangover effects or reductions in alertness, nor has it been shown to cause withdrawal symptoms. The adverse symptoms reported with ramelteon are mild. All long-term investigations that have been carried out support the conclusion that ramelteon is a well tolerated and effective drug for the treatment of insomnia.
Collapse
|
|
15
|
Abstract
Insomnia, which is severe enough to warrant treatment, occurs in approximately 10% of the general population. It is associated with a range of adverse consequences for human health, economic productivity and quality of life. In animal and human studies, administration of melatonin has been reported to promote sleep, although there has been controversy regarding its effectiveness. The present study used a chronically implanted radiotelemetry transmitter to record electroencephalogram (EEG) and electromyogram (EMG) to enable discrimination of wake (W), nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in un-restrained rats. The acute action of melatonin and ramelteon, a melatonin agonist recently approved for long-term treatment of insomnia in the USA, was examined. Radioligand binding assays on recombinant human MT(1)/MT(2) receptors showed that both the melatonin and ramelteon were both high affinity, nonsubtype selective ligands. Both compounds acted as potent full agonists on a cellular model of melatonin action, the pigment aggregation response in Xenopus laevis melanophores. Both melatonin and ramelteon (10 mg/kg, i/p), administered close to the mid-point of the dark phase of the L:D cycle, significantly reduced NREM sleep latency (time from injection to the appearance of NREM sleep). Both the drugs also produced a short-lasting increase in NREM sleep duration, but the NREM power spectrum was unaltered. Neither drug altered REM latency, REM sleep duration nor power spectrum during REM sleep. In conclusion, ramelteon administration, like melatonin, exerted an acute, short-lasting sleep-promoting effect in the rat, the model most commonly used to evaluate the activity of novel hypnotic drugs.
Collapse
Affiliation(s)
- Simon P Fisher
- Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King's College London, London, UK
| | | | | | | |
Collapse
|
|
16
|
Pandi-Perumal SR, Srinivasan V, Spence DW, Cardinali DP. Role of the melatonin system in the control of sleep: therapeutic implications. CNS Drugs 2008; 21:995-1018. [PMID: 18020480 DOI: 10.2165/00023210-200721120-00004] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The circadian rhythm of pineal melatonin secretion, which is controlled by the suprachiasmatic nucleus (SCN), is reflective of mechanisms that are involved in the control of the sleep/wake cycle. Melatonin can influence sleep-promoting and sleep/wake rhythm-regulating actions through the specific activation of MT(1) (melatonin 1a) and MT(2) (melatonin 1b) receptors, the two major melatonin receptor subtypes found in mammals. Both receptors are highly concentrated in the SCN. In diurnal animals, exogenous melatonin induces sleep over a wide range of doses. In healthy humans, melatonin also induces sleep, although its maximum hypnotic effectiveness, as shown by studies of the timing of dose administration, is influenced by the circadian phase. In both young and elderly individuals with primary insomnia, nocturnal plasma melatonin levels tend to be lower than those in healthy controls. There are data indicating that, in affected individuals, melatonin therapy may be beneficial for ameliorating insomnia symptoms. Melatonin has been successfully used to treat insomnia in children with attention-deficit hyperactivity disorder or autism, as well as in other neurodevelopmental disorders in which sleep disturbance is commonly reported. In circadian rhythm sleep disorders, such as delayed sleep-phase syndrome, melatonin can significantly advance the phase of the sleep/wake rhythm. Similarly, among shift workers or individuals experiencing jet lag, melatonin is beneficial for promoting adjustment to work schedules and improving sleep quality. The hypnotic and rhythm-regulating properties of melatonin and its agonists (ramelteon, agomelatine) make them an important addition to the armamentarium of drugs for treating primary and secondary insomnia and circadian rhythm sleep disorders.
Collapse
Affiliation(s)
- Seithikurippu R Pandi-Perumal
- Comprehensive Center for Sleep Medicine, Department of Pulmonary, Critical Care, and Sleep Medicine, Mt Sinai School of Medicine, New York, New York 10029, USA.
| | | | | | | |
Collapse
|
|
17
|
Cardinali DP, Pandi-Perumal SR, Srinivasan V, Spence DW, Trakht I. Therapeutic potential of melatonin agonists. Expert Rev Endocrinol Metab 2008; 3:269-279. [PMID: 30764095 DOI: 10.1586/17446651.3.2.269] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Melatonin, a hormone secreted by the pineal gland, has been successfully employed to improve sleep in both normal patients and insomniacs, and for the treatment of circadian rhythm sleep disorders. Melatonergic MT1 and MT2 receptors exist in high concentrations in the suprachiasmatic nucleus of the hypothalamus and have been shown to be instrumental for the sleep-promoting and circadian rhythm-regulating effects of melatonin. A lack of consistency among reports on the therapeutic efficacy of melatonin has been attributed to differences in melatonin's bioavailability and the short half-life of the hormone. In view of the need for longer acting melatonergic agonists that improve sleep efficiency without causing drug abuse or dependency, ramelteon (Rozerem™, Takeda) was developed. Ramelteon, which acts via MT1/MT2 melatonergic agonism, has been found clinically effective for improving total sleep time and sleep efficiency in insomniacs. Agomelatine (Valdoxan™, Servier) is another MT1/MT2 melatonergic agonist that also displays antagonist activity at 5-HT2C serotonin receptors. Agomelatine has been found effective in treating depression and sleep disorders in patients with major depressive disorder. A slow-release preparation of melatonin (Circadin™, Neurim) has been shown to be effective in treating sleep disorders in the elderly population.
Collapse
Affiliation(s)
- Daniel P Cardinali
- a Departamento de Fisiología, Facultad de Medicina, UBA Paraguay 2155, 1121 Buenos Aires, Argentina.
| | - Seithikurippu R Pandi-Perumal
- b Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 West 168th Street - Rm BB813, NY 10032, USA.
| | - Venkataramanujan Srinivasan
- c Department of Physiology, School of Medical Sciences, University Sains Malaysia, 16150, Kubang kerian, Kelantan, Malaysia.
| | - D Warren Spence
- d Sleep and Alertness Clinic, University Health Network, 750 Dundas Street West, Toronto, Ontario M6J-3S3, Canada.
| | - Ilya Trakht
- e Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 West 168th Street - Rm BB813, NY 10032, USA.
| |
Collapse
|
|
18
|
Abstract
Ramelteon is a novel melatonergic receptor agonist that represents a new and effective approach to sleep promotion in insomnia. By acting specifically on the melatonin MT1 and MT2 receptors, ramelteon decreases latency to persistent sleep and increases total sleep time without causing sedation. Ramelteon has a good profile, with no next-day residual effects, no rebound insomnia or withdrawal, minimal clinically meaningful disruption of sleep architecture, no memory impairment, no evidence of abuse potential and no acute effects on psychomotor function.
Collapse
Affiliation(s)
- Irshaad Ebrahim
- The London Sleep Centre, 137 Harley Street, London, W1G 6BF, UK
| |
Collapse
|
|
19
|
Tsotinis A, Afroudakis PA, Davidson K, Prashar A, Sugden D. Design, Synthesis, and Melatoninergic Activity of New Azido- and Isothiocyanato-Substituted Indoles. J Med Chem 2007; 50:6436-40. [DOI: 10.1021/jm7010723] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Andrew Tsotinis
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece, and Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King’s College London, Guy’s Campus, London Bridge, London SE1 1UL, U.K
| | - Pandelis A. Afroudakis
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece, and Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King’s College London, Guy’s Campus, London Bridge, London SE1 1UL, U.K
| | - Kathryn Davidson
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece, and Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King’s College London, Guy’s Campus, London Bridge, London SE1 1UL, U.K
| | - Anjali Prashar
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece, and Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King’s College London, Guy’s Campus, London Bridge, London SE1 1UL, U.K
| | - David Sugden
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece, and Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King’s College London, Guy’s Campus, London Bridge, London SE1 1UL, U.K
| |
Collapse
|
|
20
|
Cuellar NG, Rogers AE, Hisghman V, Volpe SL. Assessment and Treatment of Sleep Disorders in the Older Adult. Geriatr Nurs 2007; 28:254-64. [PMID: 17711790 DOI: 10.1016/j.gerinurse.2007.01.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2006] [Revised: 01/22/2007] [Accepted: 01/27/2007] [Indexed: 11/20/2022]
Affiliation(s)
- Norma G Cuellar
- University of Pennsylvania, School of Nursing, Philadelphia, PA, USA
| | | | | | | |
Collapse
|
|
21
|
Tsotinis A, Panoussopoulou M, Eleutheriades A, Davidson K, Sugden D. Design, synthesis and melatoninergic activity of new unsubstituted and β,β′-difunctionalised 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides. Eur J Med Chem 2007; 42:1004-13. [PMID: 17346859 DOI: 10.1016/j.ejmech.2007.01.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2006] [Revised: 01/03/2007] [Accepted: 01/05/2007] [Indexed: 11/26/2022]
Abstract
A series of new 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides, with and without alkyl and cycloalkyl moieties in the beta-position of the alkanamido side chain, have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT(1) and MT(2) melatonin receptor subtypes expressed in NIH 3T3 cells. An increase of the spacer's length in the side chain by a methylene unit (from 17d to 21d) leads to a six-fold decrease in antagonistic activity. On the other hand, the introduction of two methyl groups in the beta-position of the side chain of 17a induces agonist potency (compound 24), implying thus that the two beta-methyl groups are not only tolerated by the receptor, but constitute functional probes in its dynamic agonist-antagonist conformational equilibrium. The presence of more bulky beta-substituents, regardless of the size of the R group, compounds 24a,b, seems to lead to antagonism and to a noteworthy MT(2) subtype selectivity. Last, the new N1-C7 annulated derivatives presented herein are substantially more potent than their respective N1-C2 annulated counterparts, previously reported.
Collapse
Affiliation(s)
- Andrew Tsotinis
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece.
| | | | | | | | | |
Collapse
|
|
22
|
Pandi-Perumal SR, Srinivasan V, Poeggeler B, Hardeland R, Cardinali DP. Drug Insight: the use of melatonergic agonists for the treatment of insomnia-focus on ramelteon. ACTA ACUST UNITED AC 2007; 3:221-8. [PMID: 17410109 DOI: 10.1038/ncpneuro0467] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2006] [Accepted: 01/30/2007] [Indexed: 12/27/2022]
Abstract
Melatonin, a chronobiotic that participates in the control of the circadian system, is known for its sleep-promoting effects, which include shortening of sleep latency and lengthening of sleep duration. As a result of its short half-life, melatonin does not exhibit undesirable side effects, and its broad applicability for a variety of sleep problems has been the focus of numerous scientific studies. Melatonin has not, however, received regulatory approval from the US FDA as a drug, because it can be sold freely as a food supplement. Consequently, there has been an active search for patentable melatonin receptor ligands in recent years. Ramelteon, an agonist that acts solely on melatonin MT(1) and MT(2) receptors, is of particular interest, and preliminary research indicates that it holds considerable promise for clinical applications. Ramelteon has been shown to induce sleep initiation and maintenance in various animal models and in clinical trials. In chronic insomnia, ramelteon decreases sleep latency and increases total sleep time and sleep efficiency, without causing hangover, addiction or withdrawal effects. Ramelteon is thought to promote sleep by influencing homeostatic sleep signaling mediated by the suprachiasmatic nucleus. Although ramelteon's metabolism and pharmacokinetics differ from those of melatonin, its safety seems to be sufficient for short-term application. Its long-term effects remain to be determined.
Collapse
Affiliation(s)
- Seithikurippu R Pandi-Perumal
- Comprehensive Center for Sleep Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
| | | | | | | | | |
Collapse
|
|
23
|
Di Giacomo B, Bedini A, Spadoni G, Tarzia G, Fraschini F, Pannacci M, Lucini V. Synthesis and biological activity of new melatonin dimeric derivatives. Bioorg Med Chem 2007; 15:4643-50. [PMID: 17481904 DOI: 10.1016/j.bmc.2007.03.080] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2007] [Revised: 03/21/2007] [Accepted: 03/27/2007] [Indexed: 11/29/2022]
Abstract
A new series of melatonin (MLT) dimers were obtained by linking together two melatonin units with a linear alkyl chain through the MLT acetamido group or through a C-2 carboxyalkyl function. The binding properties of these ligands were evaluated in in vivo experiments on cloned human MT(1) and MT(2) receptors expressed in NIH3T3 rat fibroblast cells. The class of 2-carboxyalkyl dimers was the most interesting one with compounds having good MT(1)/MT(2) nanomolar affinity. The data obtained suggest that the spacer length is crucial for optimal interaction at both receptor subtypes as well as to determine functional activity of the resulting dimers.
Collapse
Affiliation(s)
- Barbara Di Giacomo
- Istituto di Chimica Farmaceutica, Università degli Studi di Urbino Carlo Bo, 61029 Urbino, Italy.
| | | | | | | | | | | | | |
Collapse
|
|
24
|
Wu YH, Swaab DF. Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer's disease. Sleep Med 2007; 8:623-36. [PMID: 17383938 DOI: 10.1016/j.sleep.2006.11.010] [Citation(s) in RCA: 182] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2006] [Revised: 11/09/2006] [Accepted: 11/11/2006] [Indexed: 12/15/2022]
Abstract
Circadian rhythm disturbances, such as sleep disorders, are frequently seen in aging and are even more pronounced in Alzheimer's disease (AD). Alterations in the biological clock, the suprachiasmatic nucleus (SCN), and the pineal gland during aging and AD are considered to be the biological basis for these circadian rhythm disturbances. Recently, our group found that pineal melatonin secretion and pineal clock gene oscillation were disrupted in AD patients, and surprisingly even in non-demented controls with the earliest signs of AD neuropathology (neuropathological Braak stages I-II), in contrast to non-demented controls without AD neuropathology. Furthermore, a functional disruption of the SCN was observed from the earliest AD stages onwards, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. The observed functional disconnection between the SCN and the pineal from the earliest AD stage onwards seems to account for the pineal clock gene and melatonin changes and underlies circadian rhythm disturbances in AD. This paper further discusses potential therapeutic strategies for reactivation of the circadian timing system, including melatonin and bright light therapy. As the presence of melatonin MT1 receptor in the SCN is extremely decreased in late AD patients, supplementary melatonin in the late AD stages may not lead to clear effects on circadian rhythm disorders.
Collapse
Affiliation(s)
- Ying-Hui Wu
- Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands
| | | |
Collapse
|