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https://www.readbyqxmd.com/read/28631980/orexin-research-patent-news-from-2016
#1
Christoph Boss, Catherine Roch
The orexin (hypocretin) system consists of two G-protein-coupled receptors, orexin 1 (Ox1) and orexin 2 (Ox2) and two endogenous peptidic ligands, orexin A (OxA) and orexin B (OxB). It is evolutionarily highly conserved. In the brain, it is involved in the promotion of wakefulness under motivational circumstances as well as in anxiety and addictive disorders. In addition, its activation via the Ox1 receptor triggers apoptosis in several cancer cell lines. Dual orexin receptor antagonists (DORAs) such as suvorexant are successfully used to treat primary insomnia...
June 20, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28630298/hypocretin-orexin-is-critical-in-sustaining-theta-gamma-rich-waking-behaviors-that-drive-sleep-need
#2
Anne Vassalli, Paul Franken
Hcrt gene inactivation in mice leads to behavioral state instability, abnormal transitions to paradoxical sleep, and cataplexy, hallmarks of narcolepsy. Sleep homeostasis is, however, considered unimpaired in patients and narcoleptic mice. We find that whereas Hcrt(ko/ko) mice respond to 6-h sleep deprivation (SD) with a slow-wave sleep (SWS) EEG δ (1.0 to 4.0 Hz) power rebound like WT littermates, spontaneous waking fails to induce a δ power reflecting prior waking duration. This correlates with impaired θ (6...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28620314/orexin-system-the-key-for-a-healthy-life
#3
REVIEW
Sergio Chieffi, Marco Carotenuto, Vincenzo Monda, Anna Valenzano, Ines Villano, Francesco Precenzano, Domenico Tafuri, Monica Salerno, Nicola Filippi, Francesco Nuccio, Maria Ruberto, Vincenzo De Luca, Luigi Cipolloni, Giuseppe Cibelli, Maria P Mollica, Diego Iacono, Ersilia Nigro, Marcellino Monda, Giovanni Messina, Antonietta Messina
The orexin-A/hypocretin-1 and orexin-B/hypocretin-2 are neuropeptides synthesized by a cluster of neurons in the lateral hypothalamus and perifornical area. Orexin neurons receive a variety of signals related to environmental, physiological and emotional stimuli, and project broadly to the entire CNS. Orexin neurons are "multi-tasking" neurons regulating a set of vital body functions, including sleep/wake states, feeding behavior, energy homeostasis, reward systems, cognition and mood. Furthermore, a dysfunction of orexinergic system may underlie different pathological conditions...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28608460/anatomical-and-electrophysiological-development-of-the-hypothalamic-orexin-neurons-from-embryos-to-neonates
#4
Yukino Ogawa, Takeshi Kanda, Kaspar Vogt, Masashi Yanagisawa
The amount, quality and diurnal pattern of sleep change greatly during development. Developmental changes of sleep/wake architecture are in a close relationship to brain development. The fragmentation of wake episodes is one of the salient features in the neonatal period, which is also observed in mature animals and human individuals lacking neuropeptide orexin/hypocretin signaling. This raises the possibility that developmental changes of lateral hypothalamic orexin neurons are relevant to the development of sleep/wake architecture...
June 12, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28601291/absence-of-autoreactive-cd4-t-cells-targeting-hla-dqa1-01-02-dqb1-06-02-restricted-hypocretin-orexin-epitopes-in-narcolepsy-type-1-when-detected-by-elispot
#5
Birgitte Rahbek Kornum, Kristoffer Sølvsten Burgdorf, Anja Holm, Henrik Ullum, Poul Jennum, Stine Knudsen
Narcolepsy type 1, a neurological sleep disorder strongly associated with Human Leukocyte Antigen (HLA-)DQB1*06:02, is caused by the loss of hypothalamic neurons producing the wake-promoting neuropeptide hypocretin (hcrt, also known as orexin). This loss is believed to be caused by an autoimmune reaction. To test whether hcrt itself could be a possible target in the autoimmune attack, CD4(+) T-cell reactivity towards six different 15-mer peptides from prepro-hypocretin with high predicted affinity to the DQA1*01:02/DQB1*06:02 MHC class II dimer was tested using EliSpot in a cohort of 22 narcolepsy patients with low CSF hcrt levels, and 23 DQB1*06:02 positive healthy controls...
August 15, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28575023/orexin-receptor-agonist-yan-7874-is-a-weak-agonist-of-orexin-hypocretin-receptors-and-shows-orexin-receptor-independent-cytotoxicity
#6
Ainoleena Turku, Maiju K Rinne, Gustav Boije Af Gennäs, Henri Xhaard, Dan Lindholm, Jyrki P Kukkonen
Two promising lead structures of small molecular orexin receptor agonist have been reported, but without detailed analyses of the pharmacological properties. One of them, 1-(3,4-dichlorophenyl)-2-[2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl]ethan-1-ol (Yan 7874), is commercially available, and we set out to analyze its properties. As test system we utilized human OX1 and OX2 orexin receptor-expressing Chinese hamster ovary (CHO) K1 cells as well as control CHO-K1 and neuro-2a neuroblastoma cells...
2017: PloS One
https://www.readbyqxmd.com/read/28570646/diurnal-fluctuation-in-the-number-of-hypocretin-orexin-and-histamine-producing-implication-for-understanding-and-treating-neuronal-loss
#7
Ronald McGregor, Ling Shan, Ming-Fung Wu, Jerome M Siegel
The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine...
2017: PloS One
https://www.readbyqxmd.com/read/28559480/in-vitro-and-in-silico-characterization-of-lemborexant-e2006-a-novel-dual-orexin-receptor-antagonist
#8
Carsten Theodor Beuckmann, Michiyuki Suzuki, Takashi Ueno, Kazuya Nagaoka, Tohru Arai, Hiroyuki Higashiyama
Orexin (hypocretin) neuropeptides have, among others, been implicated in arousal/sleep control, and antagonizing the orexin signaling pathway has been previously demonstrated to promote sleep in animals and humans. This mechanism opens up a new therapeutic approach to curb excessive wakefulness in insomnia disorder, rather than to promote sleep-related signaling. Here we describe the preclinical pharmacological in vitro and in silico characterization of lemborexant (E2006: (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide)), a dual orexin receptor antagonist (DORA), as a novel experimental therapeutic for the symptomatic treatment of insomnia disorder, and compare its properties to two other DORAs, almorexant and suvorexant...
May 30, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28552056/the-orexinergic-hypocretin-system-and-nociception-an-update-to-supraspinal-mechanisms
#9
Ali Roohbakhsh, Mohaddeseh Sadat Alavi, Hassan Azhdari Zarmehri
Chronic pain is a multifaceted and complex condition that is divided into somatic, visceral, and neuropathic pain. Although opioids and nonsteroidal anti-inflammatory drugs cause analgesia and are effective in the treatment of chronic pain, their utility is hampered by side effects, abuse potential, and development of tolerance to their pain-relieving effects. So, finding alternative analgesics with good efficacy and low side effects is of great interest and the orexinergic system is a potential candidate. Orexin-A and -B are exclusively expressed in the lateral hypothalamus and are involved in the feeding, sleep/wake cycle, cardiovascular function, hormone secretion, seizure, and pain modulation...
May 28, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28537447/hypocretin-measurement-shelf-age-of-radioimmunoassay-kit-but-not-freezer-time-influences-assay-variability
#10
Glenda Keating, Donald L Bliwise, Prabhjyot Saini, David B Rye, Lynn Marie Trotti
The hypothalamic peptide hypocretin 1 (orexin A) may be assayed in cerebrospinal fluid to diagnose narcolepsy type 1. This testing is not commercially available, and factors contributing to assay variability have not previously been comprehensively explored. In the present study, cerebrospinal fluid hypocretin concentrations were determined in duplicate in 155 patient samples, across a range of sleep disorders. Intra-assay variability of these measures was analyzed. Inter-assay correlation between samples tested at Emory and at Stanford was high (r = 0...
May 24, 2017: Scandinavian Journal of Clinical and Laboratory Investigation
https://www.readbyqxmd.com/read/28526553/hypothalamic-regulation-of-the-sleep-wake-cycle
#11
REVIEW
Daisuke Ono, Akihiro Yamanaka
Sleep is one of the most important physiological functions in mammals. It is regulated by not only homeostatic regulation but also circadian clock. Several neuropeptide-producing neurons located in the hypothalamus are implicated in the regulation of sleep/wakefulness. Among them, orexin/hypocretin-producing neurons (orexin neurons) are a crucial component for maintenance of wakefulness, because lack of orexin function results in narcolepsy, which is a sleep disorder. Recent findings have identified substances that excite or inhibit neural activity of orexin neurons...
May 17, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28522097/sleep-spindle-density-in-narcolepsy
#12
Julie Anja Engelhard Christensen, Miki Nikolic, Mathias Hvidtfelt, Birgitte Rahbek Kornum, Poul Jennum
BACKGROUND: Patients with narcolepsy type 1 (NT1) show alterations in sleep stage transitions, rapid-eye-movement (REM) and non-REM sleep due to the loss of hypocretinergic signaling. However, the sleep microstructure has not yet been evaluated in these patients. We aimed to evaluate whether the sleep spindle (SS) density is altered in patients with NT1 compared to controls and patients with narcolepsy type 2 (NT2). METHODS: All-night polysomnographic recordings from 28 NT1 patients, 19 NT2 patients, 20 controls (C) with narcolepsy-like symptoms, but with normal cerebrospinal fluid hypocretin levels and multiple sleep latency tests, and 18 healthy controls (HC) were included...
June 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28522076/sleep-wake-stability-in-narcolepsy-patients-with-normal-low-and-unmeasurable-hypocretin-levels
#13
Mathias Hvidtfelt Hansen, Birgitte Rahbek Kornum, Poul Jennum
OBJECTIVE: To compare diurnal and nocturnal electrophysiological data from narcolepsy patients with undetectable (<20 pg/mL), low (20-110 pg/mL) and normal (>110 pg/mL) cerebrospinal fluid (CSF) hypocretin-1 levels. PATIENTS/METHODS: A total of 109 narcolepsy patients and 37 controls were studied; all had available CSF hypocretin-1 measurements. The sleep laboratory studies were conducted between 2008 and 2014. The study retrospectively examined measurements of sleep stage transitions in diurnal and nocturnal continuous polysomnography...
June 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28509114/implicating-the-potential-role-of-orexin-in-hypertension
#14
REVIEW
Monika Rani, Raghuvansh Kumar, Pawan Krishan
Orexins (orexin A and orexin B), neuropeptides of hypothalamic origin also known as hypocretins, have been well documented for regulating the different physiological functions including feeding, sleep wakefulness, stress, and reward. However, from the past few years, orexins have evolved as an emerging biomarker for various endocrine disorders including diabetes mellitus and obesity which ultimately leads to various cardiovascular risk factors. Orexins exist in two isoforms orexin A and orexin B and exert their effect by acting on the G protein-coupled receptors orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R)...
May 16, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28472332/the-spectrum-of-rem-sleep-related-episodes-in-children-with-type-1-narcolepsy
#15
Elena Antelmi, Fabio Pizza, Stefano Vandi, Giulia Neccia, Raffaele Ferri, Oliviero Bruni, Marco Filardi, Gaetano Cantalupo, Rocco Liguori, Giuseppe Plazzi
Type 1 narcolepsy is a central hypersomnia due to the loss of hypocretin-producing neurons and characterized by cataplexy, excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. In children, close to the disease onset, type 1 narcolepsy has peculiar clinical features with severe cataplexy and a complex admixture of movement disorders occurring while awake. Motor dyscontrol during sleep has never been systematically investigated. Suspecting that abnormal motor control might affect also sleep, we systematically analysed motor events recorded by means of video polysomnography in 40 children with type 1 narcolepsy (20 females; mean age 11...
June 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28460015/rare-missense-mutations-in-p2ry11-in-narcolepsy-with-cataplexy
#16
Matilda Degn, Yves Dauvilliers, Karin Dreisig, Régis Lopez, Corinne Pfister, Sylvain Pradervand, Birgitte Rahbek Kornum, Mehdi Tafti
The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients...
June 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28449906/low-cerebrospinal-fluid-hypocretin-levels-during-sudden-infant-death-syndrome-sids-risk-period
#17
Marion Lancien, Clara Odilia Inocente, Yves Dauvilliers, Beatrice Kugener, Sabine Scholz, Veronique Raverot, Jian-Sheng Lin, Aurore Guyon, Marie-Paule Gustin, Patricia Franco
OBJECTIVES: The temporal association between sudden infant death syndrome (SIDS) and sleep suggests that the arousability from sleep provides a protective mechanism for survival. Recently, the hypocretin system, which promotes wakefulness, has been implicated in SIDS, since it has been reported that SIDS victims have fewer hypocretin neurons than infants who have died from other causes. To understand the role of hypocretin in SIDS, it is essential to better understand how this system matures...
May 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28443381/pharmacological-management-of-narcolepsy-with-and-without-cataplexy
#18
Ulf Kallweit, Claudio L Bassetti
Narcolepsy is an orphan neurological disease and presents with sleep-wake, motoric, neuropsychiatric and metabolic symptoms. Narcolepsy with cataplexy is most commonly caused by an immune-mediated process including genetic and environmental factors, resulting in the selective loss of hypocretin-producing neurons. Narcolepsy has a major impact on workableness and quality of life. Areas covered: This review provides an overview of the temporal available treatment options for narcolepsy (type 1 and 2) in adults, including authorization status by regulatory agencies...
June 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28427008/lateral-hypothalamic-circuits-for-sleep-wake-control
#19
REVIEW
Takayuki Yamashita, Akihiro Yamanaka
The lateral hypothalamic area (LHA) of the diencephalon is crucially involved in controlling instinctive behavior such as sleep-wake cycle and feeding behavior. LHA is a heterogeneous structure that contains spatially intermingled, genetically distinct cell populations. Among LHA neurons, orexin/hypocretin (OX) neuron is the key cell type that promotes waking, and specific loss of OX neurons results in narcolepsy. Melanin-concentrating hormone (MCH) containing neurons are known to be active during rapid eye movement (REM) sleep and stimulation of these neurons promotes REM sleep...
April 17, 2017: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/28424564/new-developments-in-the-management-of-narcolepsy
#20
REVIEW
Vivien C Abad, Christian Guilleminault
Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%-0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy's strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss...
2017: Nature and Science of Sleep
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