Neurobiological and immunogenetic aspects of narcolepsy

Implications for pharmacotherapy

Steven T. Szabo, Michael J. Thorpy, Geert Mayer, John H. Peever, Thomas S. Kilduff

Research output: Contribution to journalReview article

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)23-36
Number of pages14
JournalSleep Medicine Reviews
Volume43
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

Fingerprint

Narcolepsy
Immunogenetics
Locus Coeruleus
Cataplexy
Norepinephrine
Drug Therapy
Neurons
Catecholamines
Histamine H3 Receptors
Methylphenidate
Tricyclic Antidepressive Agents
Serotonin Uptake Inhibitors
Amphetamine
Therapeutics
Amygdala
Pharmaceutical Preparations
Antidepressive Agents
Sleep
Clinical Trials
Muscles

Keywords

  • Amygdala
  • Autoimmune
  • Cataplexy
  • Excessive daytime sleepiness
  • Hypocretin
  • Locus coeruleus
  • Mechanism of action
  • Narcolepsy
  • Norepinephrine
  • Orexin

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Neurology
  • Clinical Neurology
  • Physiology (medical)

Cite this

Neurobiological and immunogenetic aspects of narcolepsy : Implications for pharmacotherapy. / Szabo, Steven T.; Thorpy, Michael J.; Mayer, Geert; Peever, John H.; Kilduff, Thomas S.

In: Sleep Medicine Reviews, Vol. 43, 01.02.2019, p. 23-36.

Research output: Contribution to journalReview article

Szabo, Steven T. ; Thorpy, Michael J. ; Mayer, Geert ; Peever, John H. ; Kilduff, Thomas S. / Neurobiological and immunogenetic aspects of narcolepsy : Implications for pharmacotherapy. In: Sleep Medicine Reviews. 2019 ; Vol. 43. pp. 23-36.
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