ABSTRACT
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.
Subject(s)
Aniline Compounds/pharmacology , Benzamides/pharmacology , Cataplexy/drug therapy , Narcolepsy/drug therapy , Orexin Receptors/agonists , Orexins/metabolism , Sleep Disorders, Circadian Rhythm/drug therapy , Wakefulness-Promoting Agents/therapeutic use , Wakefulness/drug effects , Aniline Compounds/chemistry , Animals , Benzamides/chemistry , Disease Models, Animal , Hypothalamus/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Orexin Receptors/genetics , Orexins/genetics , Patch-Clamp Techniques , Sleep/drug effectsABSTRACT
BACKGROUND: We previously reported that the novel selective delta opioid receptor (DOP) agonist KNT-127 did not cause convulsions in mice, whereas the prototype DOP agonist SNC80 did. Previous studies have reported that SNC80 caused electroencephalographic (EEG) disturbances in rodents. However, whether KNT-127 affects EEG responses is unknown. Therefore, the present study aimed to compare the effect of KNT-127 on EEG responses with that of SNC80 in mice. METHODS: For behavioral experiments, male C57BL6/J mice were injected intraperitoneally with either KNT-127 (30â¯mg/kg) or SNC80 (30â¯mg/kg) and monitored for convulsions and subsequent catalepsy-like behavior for 10â¯min immediately after drug treatment. For EEG recording experiments, EEG electrodes were implanted into the right hemisphere. EEG signals exceeding twice the baseline amplitude were defined as seizure spikes. RESULTS: KNT-127 did not induce convulsive or catalepsy-like behaviors in mice and did not result in seizure spikes, while significantly higher EEG power density was observed at 2â¯Hz. In contrast, SNC80 administration resulted in convulsive behaviors, seizure spikes, and significantly higher EEG power density between 2 and 10â¯Hz in mice. CONCLUSIONS: In this study, we clearly demonstrated that KNT-127 administration induces neither convulsive effects nor seizure spikes in mice. We propose that KNT-127 should be considered a candidate compound for the development of improved DOP-based psychotropic drug that lack the convulsive properties.
Subject(s)
Electroencephalography/drug effects , Morphinans/pharmacology , Receptors, Opioid, delta/agonists , Animals , Behavior, Animal/drug effects , Benzamides/pharmacology , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Piperazines/pharmacology , Seizures/drug therapy , Seizures/metabolismABSTRACT
Sepsis is a systemic inflammatory response to infection, accounting for the most common cause of death in intensive care units. Here, we report that peripheral administration of the hypothalamic neuropeptide orexin improves the survival of mice with lipopolysaccharide (LPS) induced endotoxin shock, a well-studied septic shock model. The effect is accompanied by a suppression of excessive cytokine production and an increase of catecholamines and corticosterone. We found that peripherally administered orexin penetrates the blood-brain barrier under endotoxin shock, and that central administration of orexin also suppresses the cytokine production and improves the survival, indicating orexin's direct action in the central nervous system (CNS). Orexin helps restore body temperature and potentiates cardiovascular function in LPS-injected mice. Pleiotropic modulation of inflammatory response by orexin through the CNS may constitute a novel therapeutic approach for septic shock.