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Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193301 Year: Pages: 219 DOI: 10.3389/978-2-88919-330-1 Language: English
Publisher: Frontiers Media SA
Subject: Psychiatry --- Therapeutics --- Neurology --- Medicine (General) --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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Abstract

Orexin/hypocretin neuropeptides, produced by a few thousand neurons in the lateral hypothalamus, are of critical importance for the control of vigilance and arousal of vertebrates, from fish to amphibians, birds and mammals. Two orexin peptides, called orexin-A and orexin-B, exist in mammals. They bind with different affinities to two distinct, widely distributed, excitatory G-protein- coupled receptors, orexin receptor type 1 and type 2 (OXR-1/2). The discovery of an OXR mutation causing canine narcolepsy, the narcolepsy-like phenotype of orexin peptide knockout mice, and the orexin neuron loss associated with human narcoleptic patients laid the foundation for the discovery of small molecule OXR antagonists as novel treatments for sleep disorders. Proof of concept studies from Glaxo Smith Kline, Actelion Pharmaceuticals Ltd. and Merck have now consistently demonstrated the efficacy of dual OXR antagonists (DORAs) in promoting sleep in rodents, dogs, non-human primates and humans. Some of these antagonists have completed late stage clinical testing in primary insomnia. Orexin drug discovery programs have also been initiated by other large pharmaceutical companies including Hoffmann La Roche, Novartis, Eli Lilly and Johnson & Johnson. Orexins are increasingly recognized for orchestrating the activity of the organism’s arousal system with appetite, reward and stress processing pathways. Therefore, in addition to models of insomnia, pharmacological effects of DORAs have begun to be investigated in rodent models of addiction, depression and anxiety. The first clinical trials in diabetic neuropathy, migraine and depression have been initiated with Merck’s MK-6096 (www.clinicaltrials.gov). Whereas the pharmacology of DORAs is established for their effects on wakefulness, pharmacological effects of selective OXR-1 or OXR-2 antagonists (SORAs) have remained less clear. From an evolutionary point of view, the OXR-2 was expressed first in most vertebrate lineages, whereas the OXR-1 is believed to result from a gene duplication event, when mammals emerged. Yet, both receptors do not have redundant function. Their brain expression pattern, their intracellular signaling, as well as their affinity for orexin-A and orexin-B differs. During the past decade most preclinical research on selective OXR-1 antagonism was performed with SB-334867. Only in recent years, other selective OXR-1 and OXR-2 antagonists with optimized selectivity profiles and pharmacokinetic properties have been discovered, and phenotypes of OXR-1 and OXR-2 knockout mice were described. The present Research Topic (referred to in the Editorial as “special topics issue”) comprises submissions of original research manuscripts as well as reviews, directed towards the neuropharmacology of OXR antagonists. The submissions are preclinical papers dealing with dual and/or selective OXR antagonists that shed light on the differential contribution of endogenous orexin signaling through both OXRs for cellular, physiological and behavioral processes. Some manuscripts also report on convergence or divergence of DORA vs. SORA effects with phenotypes expressed by OXR-1 or OXR-2 knockout animals. Ultimately these findings may help further define the potential of DORAs and SORAs in particular therapeutic areas in insomnia and beyond insomnia.

Sleep and cognition in the elderly

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192953 Year: Pages: 78 DOI: 10.3389/978-2-88919-295-3 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Medicine (General)
Added to DOAB on : 2015-12-10 11:59:07
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Understanding the role of sleep and the mechanisms at play in ageing are among the most exciting challenges in neuroscience. Although our understanding of the mechanisms governing sleep stages and their role in cognitive processes including memory functions is gradually increasing. most of the currently available data have been gathered in young adults. Still, substantial physiological changes in sleep are observed with increasing age, that may markedly impacts on daily functioning. This is why this Research Topic focuses on our current understanding of the impact of age-related changes in sleep architecture on various domains of cognition. The three editors Julie Carrier (Montréal, Canada), Philippe Peigneux (Brussels, Belgium) and Géraldine Rauchs (Caen, France) are specialized in various fields of sleep research. Here, they bring together an outstanding group of neuroscientist and clinical investigators engaged in the study of sleep, encompassing state-of-the-art studies of sleep disorders such as sleep apnoea or REM sleep behaviour disorder, studies assessing new treatments to improve sleep quality, together with experts in various domains of cognition such as vigilance, memory and dreams, in a perspective aimed at offering the interested reader a comprehensive view of the impact of age-related changes in sleep architecture on cognition.

Updates in Pediatric Sleep and Child Psychiatry

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ISBN: 9783038979388 / 9783038979395 Year: Pages: 160 DOI: 10.3390/books978-3-03897-939-5 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Medicine (General) --- Pediatrics
Added to DOAB on : 2019-06-26 08:44:06
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Sleep-related symptoms are common in the majority of psychiatric diagnostic categories. The overlap of sleep and psychiatric disorders have been demonstrated in numerous studies. The understanding of sleep and child psychiatry has progressively evolved in the last decade and newer insights have developed regarding the complex interaction between sleep and psychopathology. This collection of articles represents updates on sleep and psychiatric disorders with medical and neurological co-morbidities in children and adolescents.

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