TY - JOUR
T1 - An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy
T2 - Studies in orexin-/- mice and patients
AU - Lin, Jian Sheng
AU - Dauvilliers, Yves
AU - Arnulf, Isabelle
AU - Bastuji, Hélène
AU - Anaclet, Christelle
AU - Parmentier, Régis
AU - Kocher, Laurence
AU - Yanagisawa, Masashi
AU - Lehert, Philippe
AU - Ligneau, Xavier
AU - Perrin, David
AU - Robert, Philippe
AU - Roux, Michel
AU - Lecomte, Jeanne Marie
AU - Schwartz, Jean Charles
N1 - Funding Information:
The authors wish to thank M.C. Dalin, G. Guidon, C. Buda, J.P. Sastre, M.D. Milcent, S. Dixon, S. Krief, C. Limoge for their experimental or technical assistance. This work was supported by Bioprojet and Institut National de la Santé et de la Recherche Médicale (Unit 628).
PY - 2008/4
Y1 - 2008/4
N2 - 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.
AB - 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.
KW - H-receptor inverse agonist
KW - Histamine
KW - Narcolepsy
KW - Orexin
KW - Sleep disorders
KW - Somnolence
KW - Wakefulness
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U2 - 10.1016/j.nbd.2007.12.003
DO - 10.1016/j.nbd.2007.12.003
M3 - Article
C2 - 18295497
AN - SCOPUS:40849137722
SN - 0969-9961
VL - 30
SP - 74
EP - 83
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1
ER -