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Medicinas Complementárias
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1.
Proc Natl Acad Sci U S A ; 114(22): 5731-5736, 2017 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-28507129

RESUMEN

Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexin-deficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists.


Asunto(s)
Compuestos de Anilina/farmacología , Benzamidas/farmacología , Cataplejía/tratamiento farmacológico , Narcolepsia/tratamiento farmacológico , Receptores de Orexina/agonistas , Orexinas/metabolismo , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Promotores de la Vigilia/uso terapéutico , Vigilia/efectos de los fármacos , Compuestos de Anilina/química , Animales , Benzamidas/química , Modelos Animales de Enfermedad , Hipotálamo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Orexina/genética , Orexinas/genética , Técnicas de Placa-Clamp , Sueño/efectos de los fármacos
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