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Hypocretin

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https://www.readbyqxmd.com/read/28729827/lateral-hypothalamic-control-of-the-ventral-tegmental-area-reward-evaluation-and-the-driving-of-motivated-behavior
#1
REVIEW
Susan M Tyree, Luis de Lecea
The lateral hypothalamus (LH) plays an important role in many motivated behaviors, sleep-wake states, food intake, drug-seeking, energy balance, etc. It is also home to a heterogeneous population of neurons that express and co-express multiple neuropeptides including hypocretin (Hcrt), melanin-concentrating hormone (MCH), cocaine- and amphetamine-regulated transcript (CART) and neurotensin (NT). These neurons project widely throughout the brain to areas such as the locus coeruleus, the bed nucleus of the stria terminalis, the amygdala and the ventral tegmental area (VTA)...
2017: Frontiers in Systems Neuroscience
https://www.readbyqxmd.com/read/28726523/investigational-therapies-for-the-treatment-of-narcolepsy
#2
Stefano de Biase, Annacarmen Nilo, Gian Luigi Gigli, Mariarosaria Valente
Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. While non-pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy...
July 20, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28717967/orexin-a-hypocretin-modulates-leptin-receptor-mediated-signaling-by-allosteric-modulations-mediated-by-the-ghrelin-ghs-r1a-receptor-in-hypothalamic-neurons
#3
Mireia Medrano, David Aguinaga, Irene Reyes-Resina, Enric I Canela, Josefa Mallol, Gemma Navarro, Rafael Franco
The hypothalamus is a key integrator of nutrient-seeking signals in the form of hormones and metabolites originated in both the central nervous system and the periphery. The main autocrine and paracrine target of orexinergic-related hormones such as leptin, orexin/hypocretin, and ghrelin are neuropeptide Y neurons located in the arcuate nucleus of the hypothalamus. The aim of this study was to investigate the expression and the molecular and functional relationships between leptin, orexin/hypocretin and ghrelin receptors...
July 17, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28707143/clinical-sleep-wake-disorders-ii-focus-on-insomnia-and-circadian-rhythm-sleep-disorders
#4
Kai Spiegelhalder, Christoph Nissen, Dieter Riemann
Insomnia and circadian rhythm sleep disorders affect large proportions of the population and have pronounced effects on quality of life and daytime performance. While the neurobiology of insomnia is not yet fully understood, circadian rhythm sleep disorders are assumed to be caused by a mismatch between the individual circadian phase position and the desired sleep-wake schedule. Benzodiazepines and non-benzodiazepine positive allosteric GABAA receptor modulators improve sleep onset and maintenance in the short-term treatment of insomnia...
July 14, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28680929/orexins-and-the-cardiovascular-events-of-awakening
#5
REVIEW
Alessandro Silvani
This brief review aims to provide an updated account of the cardiovascular events of awakening, proposing a testable conceptual framework that links these events with the neural control of sleep and the autonomic nervous system, with focus on the hypothalamic orexin (hypocretin) neurons. Awakening from non-rapid-eye-movement sleep entails coordinated changes in brain and cardiovascular activity: the neural "flip-flop" switch that governs state transitions becomes biased toward the ascending arousal systems, arterial blood pressure and heart rate rise toward waking values, and distal skin temperature falls...
2017: Temperature: Multidisciplinary Biomedical Journal
https://www.readbyqxmd.com/read/28675258/narcolepsy-cataplexy-and-psychosis-a-case-study
#6
F Canellas-Dols, C Delgado, C Arango-Lopez, R Peraita-Adrados
AIMS: To report a challenging patient a girl who developed narcolepsyy with cataplexy (NT1) and a psychosis during adolescence. To discuss diagnostic and therapeutic challenges of the comorbid cases. CASE REPORT: A 14-year-old girl was referred to Sleep and Epilepsy Unit for excessive daytime sleepiness, impaired nocturnal sleep, binge eating and weight gain, over the last year. After being diagnosed with a NT1 the patient was treated with modafinil and sodium oxybate...
July 16, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/28669028/the-excitatory-inhibitory-input-to-orexin-hypocretin-neuron-soma-undergoes-day-night-reorganization
#7
Claudia Laperchia, Roberta Imperatore, Idris A Azeez, Federico Del Gallo, Giuseppe Bertini, Gigliola Grassi-Zucconi, Luigia Cristino, Marina Bentivoglio
Orexin (OX)/hypocretin-containing neurons are main regulators of wakefulness stability, arousal, and energy homeostasis. Their activity varies in relation to the animal's behavioral state. We here tested whether such variation is subserved by synaptic plasticity phenomena in basal conditions. Mice were sacrificed during day or night, at times when sleep or wake, respectively, predominates, as assessed by electroencephalography in matched mice. Triple immunofluorescence was used to visualize OX-A perikarya and varicosities containing the vesicular glutamate transporter (VGluT)2 or the vesicular GABA transporter (VGAT) combined with synaptophysin (Syn) as a presynaptic marker...
July 1, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28667509/hypocretin-receptor-1-blockade-produces-bimodal-modulation-of-cocaine-associated-mesolimbic-dopamine-signaling
#8
K A Levy, Z D Brodnik, J K Shaw, D A Perrey, Y Zhang, R A España
RATIONALE: Cocaine addiction is a chronic psychiatric disorder characterized by pathological motivation to obtain cocaine and behavioral and neurochemical hypersensitivity to cocaine-associated cues. These features of cocaine addiction are thought to be driven by aberrant phasic dopamine signaling. We previously demonstrated that blockade of the hypocretin receptor 1 (HCRTr1) attenuates cocaine self-administration and reduces cocaine-induced enhancement of dopamine signaling. Despite this evidence, the effects of HCRTr1 blockade on endogenous phasic dopamine release are unknown...
June 30, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28631980/orexin-research-patent-news-from-2016
#9
Christoph Boss, Catherine Roch
The orexin system consists of two G-protein-coupled receptors, orexin 1 and orexin 2 and two endogenous ligands, orexin A and orexin B . It is evolutionarily highly conserved. It is involved in the promotion of wakefulness 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 are successfully used to treat primary insomnia. The major open questions are now related to the clinical validation of Ox1 selective antagonists...
June 28, 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
#10
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...
July 3, 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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28522097/sleep-spindle-density-in-narcolepsy
#20
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
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