Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during Non-REM Sleep in Healthy Subjects

Taranto‐Montemurro, Luigi; Edwards, Bradley A.; Sands, Scott A.; Marques, Melania; Eckert, Danny J.; White, David P.; Wellman, Andrew

doi:10.1164/rccm.201511-2172oc

Cited by 75 publications

(66 citation statements)

References 37 publications

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“…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 α 2 -adrenergic blockade. subjects reportedly increased the tonic component of GG activity during non-REM sleep (22). However, a similar effect was not demonstrated during REM sleep; indeed, desipramine is known to inhibit REM sleep (23).…”

Section: Introductionmentioning

confidence: 89%

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

Song¹,

Poon²

2017

JCI Insight

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Section: Introductionmentioning

confidence: 89%

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

Song¹,

Poon²

2017

JCI Insight

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“…OSA patients also have blunted neuromuscular responses to the upper airway obstruction, which further contribute to nocturnal collapse of the upper airway 14,15 . Adrenergic and serotoninergic mechanisms stimulate hypoglossal motorneurons, but serotonin and noradrenaline reuptake inhibitors have not been effective [16][17][18] . More recently the inward rectifying potassium 2.4 channel (Kir2.4) has been identified as a novel drug target for OSA, but molecules modulating this channel have not been discovered 19,20 .…”

Section: Discussionmentioning

confidence: 99%

0008 Chemogenetic Stimulation of the Hypoglossal Neurons Improves the Upper Airway Patency

Curado

Fishbein

Pho

et al. 2017

Sleep

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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 DREADDtreated 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.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 . Nasal continuous positive airway pressure can relieve upper airway obstruction, although poor adherence limits its therapeutic effectiveness 5 . 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, however, had a therapeutic effect only in a subset OSA patients 6 . Similarly, pharmacological approaches had limited success 8 . Recent developments in chemo-and optogenetics suggest novel approaches for treating OSA. Optogenetics entails the expression of light sensitive proteins (i.e., channel rhodopsin-2 (ChR2)) in neurons 9 . Light-activated contraction of a variety of muscles has been demonstrated when ChR2 is deployed in the motor cortex, peripheral motorneurons or skeletal muscles 10 . However, this approach requires illumination of upper airway motorneurons and/or muscles, which is not practical for clinical application. An alternative approach is to deploy designer receptors exclusively activated by designer drug (DREADD) in motorneurons with subsequent activation by a unique ligand, clozapine-N-oxide (CNO) 11 . In this study we examined whether such chemogenetic stimulation of hypoglossal motorneurons can increase GG muscle tone and pharyngeal patency. ResultsSix -eight weeks after infection with rAAV5-hSyn-hM3(Gq)-mCherry, all thirteen mice expressed DREADD throughout the hypoglossal nucleus (Fig. 1). All six rAAV-hSyn-EGFP trea...

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“…This approach is necessary for this review because previous attempts at OSA pharmacotherapy have largely been ineffective (for reviews see 33–38 ) and in many ways this has been predictable based on the targets chosen, and because the trials were comprised of un-phenotyped OSA patients, only a subset of which would be expected to benefit even if the pharmacological target was rational and effectively manipulated (discussed in Section 3.2). More recent clinical studies, however, using agents targeting the significant mechanisms of state-dependent pharyngeal muscle control identified from basic science experiments 39–42 , have proved beneficial when administered to phenotyped patients 43, 44 , with other studies ongoing 45–47 .…”

Section: Strategic Directions From the Phenotype Model And Identifmentioning

confidence: 99%

“…Protein products of 26/99 genes are targets of 175 FDA approved drugs. Of those drugs trialled for the treatment of OSA, a total of nine act pharmacologically on ten of the targets (a list drugs trialled for the treatment of OSA 28, 38, 44–46 annotated with protein targets 55 is available in Database S1). Importantly, although the identified targets, or combinations thereof, may not ultimately prove effective for OSA pharmacotherapy, our analysis does reveal significant unexplored potential in terms of trialling approved drugs and developing new drugs for differentially expressed targets in the circuitry critical for OSA pathogenesis and that modulate Active V 0 .…”

Section: Mapping Potential Drug Targets In the Circuitry Controllimentioning

confidence: 99%

“…Nevertheless, the number and selectivity of drugs associated with a given target is useful information, not least because it can be taken as an indicator of the relative druggability of that target. Moreover, initial studies have shown that desipramine has beneficial effects on genioglossus muscle tone, upper airway collapsibility and OSA severity 43, 44 . Desipramine is a tricyclic anti-depressant with strong noradrenergic and some anti-muscarinic effects.…”

Section: Mapping Potential Drug Targets In the Circuitry Controllimentioning

confidence: 99%

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A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

2017

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There is currently no pharmacotherapy for OSA, but there is no principled a-priori reason why there shouldn’t be one. This review identifies a rational decision-making strategy with the necessary logical underpinnings that any reasonable approach would be expected to navigate to develop a viable pharmacotherapy for OSA. The process first involves phenotyping an individual to quantify and characterize the critical predisposing factor(s) to their OSA pathogenesis and identify, a-priori, if the patient is likely to benefit from a pharmacotherapy that targets those factors. We then identify rational strategies to manipulate those critical predisposing factor(s), and the barriers that have to be overcome for success of any OSA pharmacotherapy. A new analysis then identifies candidate drug targets to manipulate the upper airway motor circuitry for OSA pharmacotherapy. The first conclusion is that there are two general pharmacological approaches for OSA treatment that are of most potential benefit and are practically realistic, one being fairly intuitive but the second perhaps less so. The second conclusion is that after identifying the critical physiological obstacles to OSA pharmacotherapy, there are current therapeutic targets of high interest for future development. The final analysis provides a tabulated resource of “druggable” targets that are relatively restricted to the circuitry controlling the upper airway musculature, with these candidate targets being of high priority for screening and further study. We also emphasize that a pharmacotherapy may not cure OSA per se, but may still be a useful adjunct to improve the effectiveness of, and adherence to, other treatment mainstays.

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Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during Non-REM Sleep in Healthy Subjects

Cited by 75 publications

References 37 publications

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

0008 Chemogenetic Stimulation of the Hypoglossal Neurons Improves the Upper Airway Patency

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

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