Designer Receptors Exclusively Activated by Designer Drugs Approach to Treatment of Sleep-disordered Breathing.

Autor: Fleury Curado T; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Otolaryngology, University of São Paulo, São Paulo, Brazil., Pho H; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Freire C; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Otolaryngology, University of São Paulo, São Paulo, Brazil., Amorim MR; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Dental School of Ribeirao Preto, University of São Paulo, Ribeirao Preto, Brazil., Bonaventura J; Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse, and., Kim LJ; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, Maryland., Lee R; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Cabassa ME; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Streeter SR; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Branco LG; Dental School of Ribeirao Preto, University of São Paulo, Ribeirao Preto, Brazil., Sennes LU; Department of Otolaryngology, University of São Paulo, São Paulo, Brazil., Fishbein K; Departament of Psychobiology, Federal University of São Paulo, São Paulo, Brazil., Spencer RG; Departament of Psychobiology, Federal University of São Paulo, São Paulo, Brazil., Schwartz AR; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Otorhinolaryngology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and., Brennick MJ; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Michaelides M; Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse, and., Fuller DD; Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, Florida., Polotsky VY; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Jazyk: angličtina
Zdroj: American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2021 Jan 01; Vol. 203 (1), pp. 102-110.
DOI: 10.1164/rccm.202002-0321OC
Abstrakt: Rationale: Obstructive sleep apnea is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. The main goal of our study was to determine if designer receptors exclusively activated by designer drugs (DREADD) could be used to activate the genioglossus muscle as a potential novel treatment strategy for sleep apnea. We have previously shown that the prototypical DREADD ligand clozapine-N-oxide increased pharyngeal diameter in mice expressing DREADD in the hypoglossal nucleus. However, the need for direct brainstem viral injections and clozapine-N-oxide toxicity diminished translational potential of this approach, and breathing during sleep was not examined. Objectives: Here, we took advantage of our model of sleep-disordered breathing in diet-induced obese mice, retrograde properties of the adeno-associated virus serotype 9 (AAV9) viral vector, and the novel DREADD ligand J60. Methods: We administered AAV9-hSyn-hM3(Gq)-mCherry or control AAV9 into the genioglossus muscle of diet-induced obese mice and examined the effect of J60 on genioglossus activity, pharyngeal patency, and breathing during sleep. Measurements and Main Results: Compared with control, J60 increased genioglossus tonic activity by greater than sixfold and tongue uptake of 2-deoxy-2-[ 18 F]fluoro-d-glucose by 1.5-fold. J60 increased pharyngeal patency and relieved upper airway obstruction during non-REM sleep. Conclusions: We conclude that following intralingual administration of AAV9-DREADD, J60 can activate the genioglossus muscle and improve pharyngeal patency and breathing during sleep.
Databáze: MEDLINE