Dataset Information

?₂-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea.

ABSTRACT: Decreased noradrenergic excitation of hypoglossal motoneurons during sleep causing hypotonia of pharyngeal dilator muscles is a major contributor to the pathogenesis of obstructive sleep apnea (OSA), a widespread disease for which treatment options are limited. Previous OSA drug candidates targeting various excitatory/inhibitory receptors on hypoglossal motoneurons have proved unviable in reactivating these neurons, particularly during rapid-eye-movement (REM) sleep. To identify a viable drug target, we show that the repurposed ?₂-adrenergic antagonist yohimbine potently reversed the depressant effect of REM sleep on baseline hypoglossal motoneuron activity (a first-line motor defense against OSA) in rats. Remarkably, yohimbine also restored the obstructive apnea-induced long-term facilitation of hypoglossal motoneuron activity (hLTF), a much-neglected form of noradrenergic-dependent neuroplasticity that could provide a second-line motor defense against OSA but was also depressed during REM sleep. Corroborating immunohistologic, optogenetic, and pharmacologic evidence confirmed that yohimbine's beneficial effects on baseline hypoglossal motoneuron activity and hLTF were mediated mainly through activation of pontine A7 and A5 noradrenergic neurons. Our results suggest a 2-tier (impaired first- and second-line motor defense) mechanism of noradrenergic-dependent pathogenesis of OSA and a promising pharmacotherapy for rescuing both these intrinsic defenses against OSA through disinhibition of A7 and A5 neurons by ?₂-adrenergic blockade.

SUBMITTER: Song G

PROVIDER: S-EPMC5313063 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

<b>α</b><sub>2</sub>-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea.

Song Gang G Poon Chi-Sang CS

JCI insight 20170223 4

Decreased noradrenergic excitation of hypoglossal motoneurons during sleep causing hypotonia of pharyngeal dilator muscles is a major contributor to the pathogenesis of obstructive sleep apnea (OSA), a widespread disease for which treatment options are limited. Previous OSA drug candidates targeting various excitatory/inhibitory receptors on hypoglossal motoneurons have proved unviable in reactivating these neurons, particularly during rapid-eye-movement (REM) sleep. To identify a viable drug ta ...[more]

PMID: 28239660

Similar Datasets

Project description:ImportanceHypoglossal nerve stimulation is a treatment option for patients with obstructive sleep apnea unable to tolerate continuous positive airway pressure. This study evaluates demographic factors that may be associated with greater improvements in postoperative outcomes of interest.ObjectiveTo examine the association of hypoglossal nerve stimulation with obstructive sleep apnea severity, daytime sleepiness, and sleep-related quality of life.Design, setting, and participantsPatient-level data were pooled from 3 prospective cohorts and 1 retrospective observational cohort comprising 584 adults with moderate to severe obstructive sleep apnea unable to tolerate or benefit from continuous positive airway pressure. The data were gathered from the Stimulation Therapy for Apnea Reduction Trial; a postmarket approval study conducted in Germany; the multicenter, international Adherence and Outcome of Upper Airway Stimulation for OSA Registry; and a retrospective cohort study from 2 sites in the United States.ExposureHypoglossal nerve stimulation.Main outcomes and measuresSeverity of obstructive sleep apnea was the primary outcome. The apnea-hypopnea index (AHI) (<5, normal; 5-15, mild; 15-30, moderate, and >30, severe) and Epworth Sleepiness Scale (range, 0-24; score >10 indicates pathologic sleepiness) outcomes were available at 2 to 6 months from 2 cohorts (n = 398), at 12 months from 1 cohort (n = 126), and at both times from 1 cohort (n = 60). Sleep-related quality of life and oxygen saturation nadir data were collected where available. Linear mixed-effects models were constructed to examine associations between clinical variables and reported postoperative outcomes at 6 and 12 months with study included as a random effect.ResultsOf the 584 patients included in the study, 472 were men (80.8%); mean (SD) age was 58.5 (11.0) years. Greater improvement in the postoperative AHI was associated with a higher preoperative AHI (-0.74 events/h; 95% CI, -0.82 to -0.67), older patient age (-0.10 events/h; 95% CI, -0.20 to -0.00), and lower body mass index (0.52; 95% CI, 0.22-0.83). After adjusting for these variables and considering all patients in the analysis, the AHI was statistically higher at 12 months than at 6 months (3.24 events/h; 95% CI, 1.67-4.82 events/h).Conclusions and relevanceHypoglossal nerve stimulation demonstrated clinically significant improvements in obstructive sleep apnea severity, daytime sleepiness, and sleep-related quality of life in this pooled cohort of patient-level results. Age, body mass index, and preoperative AHI appeared to be associated with treatment outcomes, and these variables may explain some of the difference between 2- to 6-month and 12-month outcomes.

Dataset Information

?₂-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea.

Publications

<b>α</b><sub>2</sub>-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

?2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea.

Publications

<b>α</b><sub>2</sub>-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

?₂-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea.