Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy.

Abstract

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. Enhanced catecholamine availability and regulation of locus coeruleus (LC) norepinephrine (NE) neuron activity is likely central to the therapeutic activity of most of these compounds. LC NE neurons are integral to sleep/wake regulation and muscle tone; reduced excitatory input to the LC due to compromise of Hcrt/orexin neurons (likely due to autoimmune factors) results in LC NE dysregulation and contributes to narcolepsy/cataplexy symptoms. Agents that increase catecholamines and/or LC activity may mitigate EDS and cataplexy by elevating NE regulation of GABAergic inputs from the amygdala. Consequently, novel medications and treatment strategies aimed at preserving and/or modulating Hcrt/orexin-LC circuit integrity are warranted in narcolepsy/cataplexy.

• Authors: Steven T Szabo, Michael J Thorpy, Geert Mayer, John H Peever, Thomas S Kilduff
• Journal: Sleep medicine reviews (Sleep Med Rev) Vol. 43 Pg. 23-36 (02 2019) ISSN: 1532-2955 [Electronic] England
• PMID: 30503715 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Adjuvants, Anesthesia
• Antidepressive Agents
• Antidepressive Agents, Tricyclic
• Central Nervous System Stimulants
• Intracellular Signaling Peptides and Proteins
• Sodium Oxybate
• Modafinil

Topics

• Adjuvants, Anesthesia (administration & dosage)
• Antidepressive Agents (administration & dosage)
• Antidepressive Agents, Tricyclic (administration & dosage)
• Cataplexy (drug therapy, metabolism)
• Central Nervous System Stimulants (administration & dosage)
• Drug Therapy (methods)
• Humans
• Immunogenetics
• Intracellular Signaling Peptides and Proteins (metabolism)
• Modafinil (administration & dosage)
• Narcolepsy (drug therapy, metabolism)
• Neurobiology
• Sodium Oxybate (administration & dosage)