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Carrie E Mahoney, Andrew Cogswell, Igor J Koralnik, Thomas E Scammell
Narcolepsy is the most common neurological cause of chronic sleepiness. The discovery about 20 years ago that narcolepsy is caused by selective loss of the neurons producing orexins (also known as hypocretins) sparked great advances in the field. Here, we review the current understanding of how orexin neurons regulate sleep-wake behaviour and the consequences of the loss of orexin neurons. We also summarize the developing evidence that narcolepsy is an autoimmune disorder that may be caused by a T cell-mediated attack on the orexin neurons and explain how these new perspectives can inform better therapeutic approaches...
December 13, 2018: Nature Reviews. Neuroscience
Guo Luo, Aditya Ambati, Ling Lin, Mélodie Bonvalet, Markku Partinen, Xuhuai Ji, Holden Terry Maecker, Emmanuel Jean-Marie Mignot
Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide-specific CD4+ T cells tested in 35 T1N cases and 22 DQ0602 controls...
December 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Bende Zou, William S Cao, Zhiwei Guan, Kui Xiao, Conrado Pascual, Julian Xie, Jingxi Zhang, James Xie, Frank Kayser, Craig W Lindsley, C David Weaver, Jidong Fang, Xinmin Simon Xie
Study Objectives: A major challenge in treating insomnia is to find effective medicines with fewer side effects. Activation of G-protein-gated inward rectifying K+ channels (GIRKs) by GABAB agonists baclofen or γ-hydroxybutyric acid (GHB) promotes non-rapid eye movement (NREM) sleep and consolidates sleep. However, baclofen has poor brain penetration, GHB possesses abuse liability, and in rodents both drugs cause spike-wave discharges (SWDs), an absence seizure activity. We tested the hypothesis that direct GIRK activation promotes sleep without inducing SWD using ML297, a potent and selective GIRK activator...
December 11, 2018: Sleep
Elda Arrigoni, Melissa J S Chee, Patrick M Fuller
The lateral hypothalamus (LH) is a functionally and anatomically complex brain region that is involved in the regulation of many behavioral and physiological processes including feeding, arousal, energy balance, stress, reward and motivated behaviors, pain perception, body temperature regulation, digestive functions and blood pressure. Despite noteworthy experimental efforts over the past decades, the circuit, cellular and synaptic bases by which these different processes are regulated by the LH remains incompletely understood...
November 29, 2018: Neuropharmacology
Steven T Szabo, Michael J Thorpy, Geert Mayer, John H Peever, Thomas S Kilduff
Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons. Although only a few drugs have received regulatory approval for narcolepsy to date, treatment involves diverse medications that affect multiple biochemical targets and neural circuits. Clinical trials have demonstrated efficacy for the following classes of drugs as narcolepsy treatments: alerting medications (amphetamine, methylphenidate, modafinil/armodafinil, solriamfetol [JZP-110]), antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors), sodium oxybate, and the H3 -receptor inverse agonist/antagonist pitolisant...
November 8, 2018: Sleep Medicine Reviews
Shahram Zarrabian, Esmail Riahi, Sara Karimi, Yasaman Razavi, Abbas Haghparast
Despite a history of more than a century of intense research in drug addiction, with currently available medication and behavioral therapy, the rate of relapse to drug use is 40-60 percent within a year after the cessation of treatment. The discovery of the neuropeptide orexin/hypocretin in 1998 and subsequent research during the past 20 years revealed an important role for the lateral hypothalamus (LH) in driving the reward pathway. The present review includes an overview of the orexinergic system and focuses on the role of LH orexin neurons targeting different components of the brain's reward pathway in addictive behaviors...
November 23, 2018: Brain Research
Tomi Sarkanen, Anniina Alakuijala, Markku Partinen
Study objectives: To validate Ullanlinna Narcolepsy Scale (UNS) as a screening tool for narcolepsy in a clinical population and to compare it with Swiss Narcolepsy Scale (SNS) and Epworth Sleepiness Scale (ESS). Methods: UNS questionnaires of 267 subjects visiting Helsinki Sleep Clinic were analyzed. The diagnoses of the subjects were narcolepsy type 1 (NT1, n = 89), type 2 (NT2, n = 10), other hypersomnias (n = 24), sleep apnea (n = 37), restless legs or periodic limb movement disorder (n = 56), and other sleep-related disorders (n = 51)...
November 26, 2018: Sleep
Vanlata Patel, Emmanouil Karteris, Jing Chen, Ioannis Kyrou, Harman S Mattu, Georgios K Dimitriadis, Glenn Rodrigo, Charalambos Antoniades, Alexios Antonopoulos, Bee K Tan, Edward W Hillhouse, Andre Ng, Harpal Randeva
Orexins/hypocretins exert cardiovascular effects which are centrally mediated. In this study we tested whether orexins and their receptors may also act in an autocrine/paracrine manner in the heart exerting direct effects. Quantitative RT-PCR, immunohistochemical and Western blot analyses revealed that the rat heart expresses orexins and orexin receptors. In isolated rat cardiomyocytes, only orexin-B (OR-B) caused an increase in contractile shortening, independent of diastolic or systolic calcium levels. A specific orexin receptor-2 (OX2R) agonist ([Ala11 , D-Leu15 ]-Orexin B) exerted similar effects as OR-B, whereas a specific OX1R antagonist (SB-408124) did not alter the responsiveness of OR-B...
November 22, 2018: Clinical Science (1979-)
M Elizabeth Deerhake, William E Barclay, Mari L Shinohara
Researchers have previously hypothesized autoimmune origins for narcolepsy on the basis of its strong genetic association with an MHC class II allele. In a recent issue of Nature, Latorre et al. (2018) discovered that narcolepsy patients had autoreactive T cells specific to the neuronal antigen hypocretin, providing more evidence of the potential immune origin of the disease.
November 20, 2018: Immunity
Hans-Peter Landolt, Sebastian C Holst, Amandine Valomon
Sleep and wakefulness are highly complex processes that are elegantly orchestrated by fine-tuned neurochemical changes among neuronal and non-neuronal ensembles, nuclei, and networks of the brain. Important neurotransmitters and neuromodulators regulating the circadian and homeostatic facets of sleep-wake physiology include melatonin, γ-aminobutyric acid, hypocretin, histamine, norepinephrine, serotonin, dopamine, and adenosine. Dysregulation of these neurochemical systems may cause sleep-wake disorders, which are commonly classified into insomnia disorder, parasomnias, circadian rhythm sleep-wake disorders, central disorders of hypersomnolence, sleep-related movement disorders, and sleep-related breathing disorders...
November 16, 2018: Handbook of Experimental Pharmacology
Eugenie Nepovimova, Jana Janockova, Jan Misik, Stepan Kubik, Ales Stuchlik, Karel Vales, Jan Korabecny, Eva Mezeiova, Rafael Dolezal, Ondrej Soukup, Tereza Kobrlova, Ngoc Lam Pham, Thuy Duong Nguyen, Jan Konecny, Kamil Kuca
Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years. Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA-ergic neuronal systems. Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc)...
November 14, 2018: Medicinal Research Reviews
Jana Janockova, Rafael Dolezal, Eugenie Nepovimova, Tereza Kobrlova, Marketa Benkova, Kamil Kuca, Jan Konecny, Eva Mezeiova, Michaela Melikova, Vendula Hepnarova, Avi Ring, Ondrej Soukup, Jan Korabecny
The neuropeptides, orexin A and orexin B (also known as hypocretins), are produced in hypothalamic neurons and belong to ligands for orphan G protein-coupled receptors. Generally, the primary role of orexins is to act as excitatory neurotransmitters and regulate the sleep process. Lack of orexins may lead to sleep disorder narcolepsy in mice, dogs, and humans. Narcolepsy is a neurological disorder of alertness characterized by a decrease of ability to manage sleep-wake cycles, excessive daytime sleepiness, and other symptoms, such as cataplexy, vivid hallucinations, and paralysis...
November 9, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Elisabeth Ruppert, Hélène Zagala, Juliette Chambe, Henri Comtet, Ulker Kilic-Huck, François Lefebvre, Marc Bataillard, Carmen Schroder, Laurent Calvel, Patrice Bourgin
Narcolepsy type 1 is a rare disabling sleep disorder mainly characterized by excessive daytime sleepiness and cataplexy, an emotion-triggered sudden loss of muscle tone. Patients have a selective degeneration of hypocretin-producing neurons in the dorsolateral posterior hypothalamus with growing evidence supporting the hypothesis of an autoimmune mechanism. Few case studies that reported intravenous immunoglobulin therapy (IVIg) suggest the efficacy of IVIg when administered early after disease onset, but the results are controversial...
2018: Behavioural Neurology
Ruth Janke van Holst, Lieneke K Janssen, Petra van Mierlo, Gert Jan Lammers, Roshan Cools, Sebastiaan Overeem, Esther Aarts
Narcolepsy type 1 is a chronic sleep disorder caused by a deficiency of the orexin (hypocretin) neuropeptides. In addition to sleep regulation, orexin is important for motivated control processes. Weight gain and obesity are common in narcolepsy. However, the neurocognitive processes associated with food-related control and overeating in narcolepsy are unknown. We explored the neural correlates of general and food-related attentional control in narcolepsy-type-1 patients (n = 23) and healthy BMI-matched controls (n = 20)...
November 6, 2018: Scientific Reports
Eva Wiberg Torstensen, Louise Schouborg Brinth, Jesper Mehlsen, Birgitte Rahbek Kornum, Poul Jørgensen Jennum
INTRODUCTION: Human papilloma virus (HPV) vaccine uptake in girls and women is dropping markedly in some countries. Concern about the presumed side effects is the commonest reason why. Reports about side effects include specific sleep complaints such as excessive daytime sleepiness, altered dream activity and periods of muscle weakness. These symptoms are commonly seen in individuals with narcolepsy type 1. We aimed to evaluate whether HPV vaccination was associated with the development of hypocretin-deficient narcolepsy...
November 2018: Danish Medical Journal
Shuancheng Ren, Yaling Wang, Faguo Yue, Xiaofang Cheng, Ruozhi Dang, Qicheng Qiao, Xueqi Sun, Xin Li, Qian Jiang, Jiwei Yao, Han Qin, Guanzhong Wang, Xiang Liao, Dong Gao, Jianxia Xia, Jun Zhang, Bo Hu, Junan Yan, Yanjiang Wang, Min Xu, Yunyun Han, Xiangdong Tang, Xiaowei Chen, Chao He, Zhian Hu
Clinical observations indicate that the paramedian region of the thalamus is a critical node for controlling wakefulness. However, the specific nucleus and neural circuitry for this function remain unknown. Using in vivo fiber photometry or multichannel electrophysiological recordings in mice, we found that glutamatergic neurons of the paraventricular thalamus (PVT) exhibited high activities during wakefulness. Suppression of PVT neuronal activity caused a reduction in wakefulness, whereas activation of PVT neurons induced a transition from sleep to wakefulness and an acceleration of emergence from general anesthesia...
October 26, 2018: Science
Paul Reading
Remarkably and almost invariably, the clinical phenomenon of cataplexy results from the loss of around 40 000 hypocretin-containing neurones in the lateral hypothalamus in the context of narcolepsy type 1. Cataplexy reflects the dysregulation of rapid-eye-movement (REM) sleep, such that REM-sleep atonia intrudes inappropriately into wakefulness as brief episodes of either focal or total paralysis of voluntary muscle. The semiology of cataplexy differs between adults and children. A defining and enigmatic aspect is that certain emotional stimuli usually trigger the episodes...
October 24, 2018: Practical Neurology
Wei Zhou, Kevin Cheung, Steven Kyu, Lynn Wang, Zhonghui Guan, Philip A Kurien, Philip E Bickler, Lily Y Jan
Orexin (also known as hypocretin) neurons in the hypothalamus play an essential role in sleep-wake control, feeding, reward, and energy homeostasis. The likelihood of anesthesia and sleep sharing common pathways notwithstanding, it is important to understand the processes underlying emergence from anesthesia. In this study, we investigated the role of the orexin system in anesthesia emergence, by specifically activating orexin neurons utilizing the designer receptors exclusively activated by designer drugs (DREADD) chemogenetic approach...
November 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
Denis Burdakov
Homeostasis is the maintenance of a healthy physiological equilibrium in a changing world. Reactive (feedback, counter-regulatory) and predictive (feedforward, anticipatory) homeostatic control strategies are both important for survival. For example, in energy homeostasis, the pancreas reacts to ingested glucose by releasing insulin, whereas the brain prepares the body for ingestion through anticipatory salivation based on food-associated cues. Reactive control is largely innate, whereas predictive control is often acquired or modified through associative learning, though some important predictive control strategies are innate, e...
October 19, 2018: Neuropharmacology
Blerina Latifi, Antoine Adamantidis, Claudio Bassetti, Markus H Schmidt
The hypocretin (Hcrt) system has been implicated in a wide range of physiological functions from sleep-wake regulation to cardiovascular, behavioral, metabolic, and thermoregulagtory control. These wide-ranging physiological effects have challenged the identification of a parsimonious function for Hcrt. A compelling hypothesis suggests that Hcrt plays a role in the integration of sleep-wake neurophysiology with energy metabolism. For example, Hcrt neurons promote waking and feeding, but are also sensors of energy balance...
2018: Frontiers in Neurology
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