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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 orexindeficient 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. neuropeptides produced by neurons exclusively localized to the lateral hypothalamus that act on two G protein-coupled receptors termed OX1R and OX2R (1). Orexin-producing neurons send axons diffusely through the central nervous system, with especially dense innervations to several nuclei involved in sleep/wakefulness regulation (2, 3). Because orexins have been implicated in the maintenance of wakefulness, many groups are trying to develop nonpeptidic orexin receptor antagonists aiming at new medication for insomnia. Recently, suvorexant, a dual orexin receptor antagonist, was clinically approved in Japan and the United States (4, 5).A crucial role of the orexin system in the regulation of sleep/ wakefulness was initially uncovered by the discovery that OX2R-deficient dogs (6) and prepro-orexin knockout (Hcrt −/− , abbreviated as OXKO) mice (2) exhibited symptoms resembling human narcolepsy-cataplexy. According to the clinical definition by the International Classification of Sleep Disorders-Third Edition, two types of narcoleptic disorders are categorized (7). Narcolepsy type 1 is characterized by the existence of cataplexy and low levels of orexin-A in cerebrospinal fluid (CSF) (8-10). However, patients with narcolepsy type 2 show no cataplexy and normal orexin-A levels in CSF. Narcolepsy-cataplexy, or narcolepsy type 1 (11), is characterized by a marked instability of sleep/ wake state transitions, resulting in nonrapid eye movement (NREM) sleep-related symptoms (e.g., excessive daytime sleepiness, "sleep attacks," and fragmented nighttime sleep), and rapid eye movement (REM) sleep-related symptoms (e.g., cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations). In polysomnography, narcolepsy-cataplexy patients show markedly reduced daytime sleep latency, and sleep-onset REM periods (SOREMs). Currently available treatments for narcolepsyca...

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Prehypertension is associated with an increased 10-year risk of cardiovascular disease; the provocative finding that this risk may be especially elevated during the second 5-year period in the nonelderly requires confirmation in a larger cohort.