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Promotion of sleep by targeting the orexin system in rats, dogs and humans

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By Brisbare-Roch C, et al. • www.ProHealth.com • March 30, 2007


[Note: Orexins are hormones produced by the hypothalamus thought to play a major role in sleep regulation.]

Journal: Nature Medicine. 2007. 13, 150-155 [E-Publication ahead of print January 28]

Authors and affiliations: Brisbare-Roch C, Dingemanse J, Koberstein R, Petra Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F. Actelion Pharmaceuticals Ltd., Allschwil, Switzerland; Centre for Human Drug Research, Leiden, The Netherlands; Institute for Biological Sciences of the Chinese Academy of Sciences, Shanghai, China. [E-mail: francois.jenck@actelion.com ]

DOI:10.1038/nm1544

Orexins are hypothalamic peptides [hormones] that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine, and human narcolepsy [characterized by overwhelming daytime sleepiness, often with fragmented night-time sleep].

Here we report that in rats, dogs, and humans, somnolence is induced by pharmacological blockade of both orexin OX1 and OX2 receptors.

When administered orally during the active period of the circadian cycle, a dual antagonist:

  • Increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABAA receptor modulators;
  • In dogs, it caused somnolence and increased surrogate markers of REM sleep;
  • And in humans, it caused subjective and objective electrophysiological signs of sleep.

No signs of cataplexy [sudden weakness and collapse at moments of strong emotions] were observed - in contrast to the rodent, dog or human narcolepsy syndromes.

These results open new perspectives for investigating the role of endogenous [originating in the body] orexins in sleep-wake regulation.





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