title: Desogestrel enhances ventilation in ondine patients: Animal data involving serotoninergic systems.
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.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Joubert
authors.affiliation: 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.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Perrin-Terrin
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France.
authors.forename: Emilienne
authors.initials: E
authors.lastname: Verkaeren
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cardot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France.
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Fiamma
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Frugière
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rivals
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Similowski
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Straus
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie respiratoire expérimentale et clinique, F-75013, Paris, France. Electronic address: laurence.bodineau@upmc.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Bodineau
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D017135:Desogestrel / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D006801:Humans; D007040:Hypoventilation / Q000151:congenital* / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009924:Organ Culture Techniques; D012123:Pulmonary Ventilation / Q000187:drug effects* / Q000502:physiology; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000502:physiology; D020182:Sleep Apnea, Central / Q000188:drug therapy* / Q000503:physiopathology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D058785:GABA-A Receptor Agonists; C044815:etonogestrel; D017135:Desogestrel
keywords: Central congenital hypoventilation syndrome; Etonogestrel; Ex vivo medullary-spinal cord preparations; In vivo; Mice; Progestin