Abstract
Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6–8 weeks genioglossus EMG and dynamic MRI of the upper airway were performed before and after administration of the DREADD ligand clozapine-N-oxide (CNO) or vehicle (saline). In DREADD-treated mice, CNO activated the genioglossus muscle and markedly dilated the pharynx, whereas saline had no effect. Control virus treated mice showed no effect of CNO. Our results suggest that chemogenetic approach can be considered as a treatment option for OSA and other motorneuron disorders.
Highlights
Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep
In this study we examined whether such chemogenetic stimulation of hypoglossal motorneurons can increase GG muscle tone and pharyngeal patency
We report that designer receptors exclusively activated by designer drug (DREADD)-mediated excitation of hypoglossal motorneurons (1) dramatically increased both tonic and peak phasic GG muscle activity and (2) markedly improved upper airway patency throughout the respiratory cycle
Summary
Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. Obstructive sleep apnea (OSA) is a common disorder affecting 25–30% of the adult population in the Western world[1] with the prevalence exceeding 50% in obese individuals[2] It is caused by a loss of lingual motor tone, leading to recurrent upper airway obstruction during sleep, intermittent hypoxia and sleep fragmentation[3] and substantial cardiovascular morbidity and mortality[4]. Implantable hypoglossal nerve stimulators have been developed to maintain pharyngeal patency during sleep[6] by activating lingual muscles including the genioglossus (GG), a major pharyngeal dilator[7] This device, had a therapeutic effect only in a subset OSA patients[6]. In this study we examined whether such chemogenetic stimulation of hypoglossal motorneurons can increase GG muscle tone and pharyngeal patency
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