An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin-/- mice and patients

Jian Sheng Lin, Yves Dauvilliers, Isabelle Arnulf, Hélène Bastuji, Christelle Anaclet, Régis Parmentier, Laurence Kocher, Masashi Yanagisawa, Philippe Lehert, Xavier Ligneau, David Perrin, Philippe Robert, Michel Roux, Jeanne Marie Lecomte, Jean Charles Schwartz

Research output: Contribution to journalArticlepeer-review

209 Scopus citations


Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, direct onsets of rapid eye movement (REM) sleep from wakefulness (DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H3-receptor agonist. In narcoleptic orexin-/- mice, tiprolisant enhanced HA and noradrenaline neuronal activity, promoted wakefulness and decreased abnormal DREMs, all effects being amplified by co-administration of modafinil, a currently-prescribed wake-promoting drug. In a pilot single-blind trial on 22 patients receiving a placebo followed by tiprolisant, both for 1 week, the Epworth Sleepiness Scale (ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo (p > 0.05) and 5.9 with tiprolisant (p < 0.001). Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant dosing. H3-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.

Original languageEnglish (US)
Pages (from-to)74-83
Number of pages10
JournalNeurobiology of Disease
Issue number1
StatePublished - Apr 2008


  • H-receptor inverse agonist
  • Histamine
  • Narcolepsy
  • Orexin
  • Sleep disorders
  • Somnolence
  • Wakefulness

ASJC Scopus subject areas

  • Neurology


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