α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea
Gang Song, Chi-Sang Poon
Gang Song, Chi-Sang Poon
Published February 23, 2017
Citation Information: JCI Insight. 2017;2(4):e91456. https://doi.org/10.1172/jci.insight.91456.
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Research Article Neuroscience Pulmonology

α2-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 α2-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 α2-adrenergic blockade.

Authors

Gang Song, Chi-Sang Poon

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Figure 2

Obstructive apnea–induced hLTF was depressed during REM sleep.

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Obstructive apnea–induced hLTF was depressed during REM sleep. (A) Obstr...
(A) Obstructive apnea (lasting 10–15 seconds) in a urethane-anesthetized, paralyzed, and mechanically ventilated rat elicited time-dependent (reflexive) facilitation of the amplitude of integrated hypoglossal nerve activity (∫Hypoglossal, which comprised predominantly the inspiratory-phasic component) during each apnea episode (denoted by dots above the ∫Hypoglossal recording). Such obstructive apnea when applied repeatedly for 10–12 episodes induced sustained facilitation of ∫Hypoglossal amplitude with a long-term memory afterward, evidencing hypoglossal long-term facilitation (hLTF). (B) After microinjection of the cholinergic agonist carbachol at dorsomedial pons to induce a REM-like sleep state (indicated by increased hippocampal activity and decreased baseline ∫Hypoglossal amplitude) in one rat, baseline ∫Hypoglossal amplitude was markedly depressed, and obstructive apnea elicited relatively weak time-dependent facilitation of ∫Hypoglossal amplitude compared with the control state, seen in A. Also, episodic obstructive apnea no longer induced sustained hLTF. (C) Similar effects were seen during spontaneously occurring REM sleep (under urethane anesthesia, ref. 29) in another rat. (D) Bar graphs (overlaid with individual data points) showing the depressant effects (P < 0.05, 2-way ANOVA with repeated measures) of cholinergic-induced REM-like sleep (n = 6) and spontaneous REM sleep (n = 5) vs. no REM sleep (n = 12) on baseline ∫Hypoglossal amplitude before episodic obstructive apnea (left panel), as well as the facilitation of ∫Hypoglossal amplitude during the first and last apnea episodes (middle panel) and at 5 and 20 minutes after the last apnea episode (right panel). Values are normalized to control baseline at 100% (dashed line) and shown as means ± SEM. *P < 0.05 between values as indicated, Tukey post-hoc test.