0048 Orexin 2 receptor agonist activates pre-Bötzinger complex neurons, hypoglossal motoneurons and the genioglossus muscle in rodents

Abstract

Abstract Introduction Neurons in the pre-Bötzinger complex are critical for the generation of inspiratory rhythm and control the activity of the genioglossus muscle via activation of hypoglossal motoneurons. Activation of the genioglossus muscle causes anterior movement of the tongue and widens the upper airway. As obstructive sleep apnea (OSA) is associated with obstruction of the upper airway, activation of this neuronal pathway may be a novel therapeutic approach. Orexins have been shown to activate these neurons by stimulation of both orexin 1 receptor (OX1R) and/or orexin 2 receptor (OX2R). In this study, we assessed effects of OX2R-selective agonists on activity of neurons in the pre-Bötzinger complex, hypoglossal motoneurons, and the genioglossus muscle. Methods OX2R-selective agonists danavorexton (TAK-925) and OX-201 (a tool compound with longer plasma half-life than danavorexton in rodents) were used. Arousal effects were investigated by electroencephalogram/electromyogram recording in C57BL/6J mice and OX2R knockout mice. Activity of neurons in the pre-Bötzinger complex and hypoglossal motoneurons was investigated by electrophysiological recording in rat tissues. Activity of the genioglossus muscle was evaluated by electromyogram recording in anesthetized rats. Results Oral administration of OX-201 increased wakefulness time during sleep phase in C57BL6J mice but not in OX2R knockout mice. In in vitro electrophysiological analyses, danavorexton, and OX-201 increased the burst frequency of neurons in the pre-Bötzinger complex (EC50: 300 nM and 760 nM, respectively) and hypoglossal motoneurons (EC50: 610 nM and 260 nM, respectively). Intravenous administration of OX-201 at 1 mg/kg increased burst amplitude of the genioglossus muscle in anesthetized rats. Conclusion OX2R-selective agonists may enhance the respiratory function via activation of the genioglossus muscle through stimulation of neurons in the pre-Bötzinger complex and hypoglossal motoneurons. OX2R agonists may have therapeutic potential in patients with OSA if enhancement of respiratory function by OX2R agonists can be observed at non-arousal concentrations. Further preclinical and clinical studies are worth conducting in patients with OSA. Support (if any) This work was conducted by Takeda Pharmaceutical Company Limited.