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Neuropharmacology. 2016 Aug;107:339-350. doi: 10.1016/j.neuropharm.2016.03.041. Epub 2016 Apr 1.

Desogestrel enhances ventilation in ondine patients: Animal data involving serotoninergic systems.

Author information

1
Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France.
2
Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France; University Paris 13, Sorbonne Paris Cité, Laboratory "Hypoxia & Lung" EA2363, 74 rue Marcel Cachin, 93017, Bobigny, France.
3
Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France; Équipe de Statistique Appliquée, ESPCI ParisTech, PSL Research University, F-75005, Paris, France.
4
Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale (Département "R3S"), F-75013, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Branche "Adultes" du Centre de Référence du Syndrome d'Ondine, F-75013, Paris, France.
5
Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Branche "Adultes" du Centre de Référence du Syndrome d'Ondine, F-75013, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service d'Explorations Fonctionnelles de la Respiration, de l'Exercice et de la Dyspnée (Département "R3S"), Paris, France.
6
Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France. Electronic address: laurence.bodineau@upmc.fr.

Abstract

Congenital central hypoventilation syndrome (CCHS) is a neurorespiratory disease characterized by life-threatening sleep-related hypoventilation involving an alteration of CO2/H(+) chemosensitivity. Incidental findings have suggested that desogestrel may allow recovery of the ventilatory response to CO2. The effects of desogestrel on resting ventilation have not been reported. This study was designed to test the hypothesis that desogestrel strengthens baseline ventilation by analyzing the ventilation of CCHS patients. Rodent models were used in order to determine the mechanisms involved. Ventilation in CCHS patients was measured with a pneumotachometer. In mice, ventilatory neural activity was recorded from ex vivo medullary-spinal cord preparations, ventilation was measured by plethysmography and c-fos expression was studied in medullary respiratory nuclei. Desogestrel increased baseline respiratory frequency of CCHS patients leading to a decrease in their PETCO2. In medullary spinal-cord preparations or in vivo mice, the metabolite of desogestrel, etonogestrel, induced an increase in respiratory frequency that necessitated the functioning of serotoninergic systems, and modulated GABAA and NMDA ventilatory regulations. c-FOS analysis showed the involvement of medullary respiratory groups of cell including serotoninergic neurons of the raphe pallidus and raphe obscurus nuclei that seem to play a key role. Thus, desogestrel may improve resting ventilation in CCHS patients by a stimulant effect on baseline respiratory frequency. Our data open up clinical perspectives based on the combination of this progestin with serotoninergic drugs to enhance ventilation in CCHS patients.

KEYWORDS:

Central congenital hypoventilation syndrome; Etonogestrel; Ex vivo medullary-spinal cord preparations; In vivo; Mice; Progestin

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