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.

Desogestrel down-regulates PHOX2B and its target genes in progesterone responsive neuroblastoma cells

“…Unlike what has been observed in neuroblastoma cell lines in which PHOX2B overexpression plays a pathogenic role, the respiratory and autonomic symptoms of CCHS patients, and their predisposition to Hirschsprung's disease and intestinal developmental and functional defects, are due to PHOX2B haploinsufficiency [12,33]. In this perspective, the positive effects of desogestrel on ventilation and chemosensitivity observed in two CCHS patients [14,15] are somewhat unexpected because, at molecular level, 3-KDG decreases PHOX2B expression.…”

“…One putative structure is the nucleus of the solitary tract (NTS), which expresses Phox2b in adult rats, is not affected by Phox2b poly-alanine mutations, and contains neurons that are inhibited by hypoxia but whose activity is restored by progesterone administration [34,[44][45][46]. Consistently, neurons in the commissural part of the NTS are activated by 3-KDG [15,20]. C1 neurons may also be involved in the recovery of the two CCHS patients as PHOX2B has been identified in selected populations of TH-expressing neurons in adult rats, including the C1 neurons [44] that regulate the breathing network at multiple levels [47,48].…”

“…C1 neurons may also be involved in the recovery of the two CCHS patients as PHOX2B has been identified in selected populations of TH-expressing neurons in adult rats, including the C1 neurons [44] that regulate the breathing network at multiple levels [47,48]. It has also been shown that 3-KDG activates catecholaminergic neurons in the ventrolateral medullary reticular nucleus [15].…”

“…Recent findings [14] have shown that two CCHS female patients (respectively with +5 and +6 alanine expansions) using the progestin contraceptive desogestrel for contraceptive purposes experienced a partial recovery of chemosensitivity and increased ventilation, thus opening up new prospects for a pharmacological intervention that could at least improve respiratory symptoms. Desogestrel has much greater affinity for progesterone receptors than progesterone itself [14,15].…”

“…Progesterone exerts its biological effects by binding nuclear or membrane progesterone receptors, and recent data provide evidence that nuclear receptors are important modulators of respiratory control during sleep and chemoreflex sensitivity: adult female mice from which the nuclear receptor has been deleted show more frequent sighs and post-sigh apnea during non-REM sleep, and reduced responses to hypercapnia after chronic progesterone treatment [19]. Although the exact molecular mechanism of the pharmacological effect of desogestrel is unknown, recent evidence indicates that multiple pathways, involving both medullary and supramedullary neurons, may play a role in the ventilatory effects of desogestrel [15,20]. It is also worth noting that a number of rodent brain structures (including some expressing Phox2b in adulthood) are activated by desogestrel and the same structures may be involved in the recovery observed in the two CCHS patients; however, the contribution of PHOX2B and its mutations to respiratory improvement has not yet been investigated.…”