The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions.
Narcolepsy is characterized by excessive daytime sleepiness, cataplexy and other manifestations of dissociated rapid eye movement sleep. Narcolepsy is typically treated with amphetamine-like stimulants (sleepiness) and antidepressants (cataplexy). Newer compounds, such as modafinil (non-amphetamine wake-promoting compound for excessive daytime sleepiness) and sodium oxybate (short-acting sedative for fragmented nighttime sleep, cataplexy, excessive daytime sleepiness), are increasingly used. Recent discoveries indicate that the major pathophysiology of human narcolepsy is the loss of lateral hypothalamic neurons that produce the neuropeptide hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are hypocretin ligand deficient. This has led to the development of new diagnostic tests (cerebrospinal fluid hypocretin-1 measurements). Hypocretin receptor agonists are likely to be ideal therapeutic options for hypocretin-deficient narcolepsy but such compounds are still not available in humans.
Zeitzer
Jamie M
JM
Department of Psychiatry, Stanford University, 701-B Welch Road, Palo Alto, CA 94304, USA. jzeitzer@stanford.edu
Nishino
Seiji
S
Mignot
Emmanuel
E
D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D009290:Narcolepsy / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D009479:Neuropeptides / Q000502:physiology*; D000068797:Orexins; D012890:Sleep / Q000502:physiology
C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins