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

NEUROPHARMACOLOGY

卷:107

Article

Joubert, Fanny¹  Perrin-Terrin, Anne-Sophie^1,2  Verkaeren, Emilienne¹  Cardot, Philippe¹  Fiamma, Marie-Noelle¹  Frugiere, Alain¹  Rivals, Isabelle^1,3  Similowski, Thomas^1,4,5  Straus, Christian^1,5,6  Bodineau, Laurence¹ 

[1] Univ Paris 06, Sorbonne Univ, Neurophysiol Resp Expt & Clin, INSERM,UMR S1158, F-75013 Paris, France

[2] Univ Paris 13, Sorbonne Paris Cite, Lab Hypoxia & Lung, EA2363, 74 Rue Marcel Cachin, F-93017 Bobigny, France

[3] PSL Res Univ, ESPCI ParisTech, Equipe Stat Appl, F-75005 Paris, France

[4] Grp Hosp Pitie Salpetriere Charles Foix, Serv Pneumol & Reanimat Med, AP HP, Dept R3S, F-75013 Paris, France

[5] Grp Hosp Pitie Salpetriere Charles Foix, AP HP, Branche Adultes, Ctr Reference Syndrome Ondine, F-75013 Paris, France

[6] Grp Hosp Pitie Salpetriere Charles Foix, AP HP, Serv Explorat Fonct Resp Exercice & Dyspnee, Dept R3S, F-75013 Paris, France

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

DOI  :  10.1016/j.neuropharm.2016.03.041

来源: Elsevier

【 摘 要 】

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 GABA(A) 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. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

Free