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

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-[18F]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.

Silencing of Hypoglossal Motoneurons Leads to Sleep Disordered Breathing in Lean Mice.

Obstructive Sleep Apnea (OSA) is a prevalent condition and a major cause of morbidity and mortality in Western Society. The loss of motor input to the tongue and specifically to the genioglossus muscle during sleep is associated with pharyngeal collapsibility and the development of OSA. We applied a novel chemogenetic method to develop a mouse model of sleep disordered breathing Our goal was to reversibly silence neuromotor input to the genioglossal muscle using an adeno-associated viral vector carrying inhibitory designer receptors exclusively activated by designer drugs AAV5-hM4Di-mCherry (DREADD), which was delivered bilaterally to the hypoglossal nucleus in fifteen C57BL/6J mice. In the in vivo experiment, 4 weeks after the viral administration mice were injected with a DREADD ligand clozapine-N-oxide (CNO, i.p., 1mg/kg) or saline followed by a sleep study; a week later treatments were alternated and a second sleep study was performed. Inspiratory flow limitation was recognized by the presence of a plateau in mid-respiratory flow; oxyhemoglobin desaturations were defined as desaturations >4% from baseline. In the in vitro electrophysiology experiment, four males and three females of 5 days of age were used. Sixteen-nineteen days after DREADD injection brain slices of medulla were prepared and individual hypoglossal motoneurons were recorded before and after CNO application. Positive mCherry staining was detected in the hypoglossal nucleus in all mice confirming successful targeting. In sleep studies, CNO markedly increased the frequency of flow limitation n NREM sleep (from 1.9 ± 1.3% after vehicle injection to 14.2 ± 3.4% after CNO, p < 0.05) and REM sleep (from 22.3% ± 4.1% to 30.9 ± 4.6%, respectively, p < 0.05) compared to saline treatment, but there was no significant oxyhemoglobin desaturation or sleep fragmentation. Electrophysiology recording in brain slices showed that CNO inhibited firing frequency of DREADD-containing hypoglossal motoneurons. We conclude that chemogenetic approach allows to silence hypoglossal motoneurons in mice, which leads to sleep disordered breathing manifested by inspiratory flow limitation during NREM and REM sleep without oxyhemoglobin desaturation or sleep fragmentation. Other co-morbid factors, such as compromised upper airway anatomy, may be needed to achieve recurrent pharyngeal obstruction observed in OSA.

Anestesia em paciente portador de deficiência de glicose de fosfato desidrogenase: relato de caso / Anesthesia in glucose phosphate dehydrogenase deficient patient: case report

Justificativa e objetivos - A Deficiência de Glicoseð6ðFosfatoðDesidrogenase (G6PD) é uma enzimopatia relativamente comum, mas as publicações relacionando essa condição com a anestesia são escassas. O objetivo deste relato é apresentar um caso de paciente portador de Deficiência de G6PD, submetido à tenotomia para alongamento de tendão de Aquiles, sob anestesia venosa associada à bloqueio subaracnóideo. Relato de caso - Paciente masculino, 9 anos, 48 kg, portador de deficiência de G6PD e polineuropatia periférica, submetido à tenotomia de tendão de Aquiles, sob anestesia geral venosa com midazolam, propofol e fentanil, associada à bloqueio subaracnóideo com bupivacaína hiperbárica a 0,5 por cento. Ao final da cirurgia o paciente despertou tranqüilo, sem dor ou outras queixas, evoluiu bem, recebendo alta hospitalar sem intercorrências. Conclusões - Pela evolução do caso relatado, a anestesia subaracnóidea com bupivacaína associada à anestesia venosa total com propofol, mostrou ser uma técnica segura em pacientes portador de deficiência de G6PD

[Anesthesia in glucose 6-phosphate dehydrogenase-deficient patient: case report.]. / Anestesia em paciente portador de deficiência de glicose-6-fosfato-desidrogenase: relato de caso.

BACKGROUND AND OBJECTIVES: Glucose 6-phosphate dehydrogenase (G6PD) deficiency is a relatively common enzymopathy, but there are few publications relating such condition to anesthesia. This report aimed at presenting a case of a G6PD-deficient patient, submitted to Achilles tendon tenotomy under intravenous anesthesia associated to spinal block. CASE REPORT: Male patient, 9 years old, 48 kg, with G6PD deficiency and peripheral polineuropathy, submitted to Achilles tendon tenotomy under general intravenous anesthesia with midazolam, propofol and fentanyl, associated to spinal block with 0.5% hyperbaric bupivacaine. At surgery completion patient awakened relaxed, without pain or other complaints, had a good evolution and was discharged without intercurrences. CONCLUSIONS: According to the evolution of this case, spinal anesthesia with bupivacaine associated to total intravenous anesthesia with propofol has shown to be a safe technique for G6PD-deficient patients.