The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures

Loiseau, Camille; Osinski, Diane; Joubert, Fanny; Straus, Christian; Similowski, Thomas; Bodineau, Laurence

doi:10.1016/j.neulet.2014.03.040

Cited by 15 publications

(31 citation statements)

References 34 publications

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“…To conclude, DSG has been associated with chemosensitivity recovery in CCHS patients (Straus et al, 2010). Its metabolite, ETO, has been shown to enhance chemosensitivity in newborn rats via supramedullary mechanisms (Loiseau et al, 2014). Combined with the present data, these observations suggest that two distinct pathways are involved in the ventilatory effects of these gonane progestins.…”

Section: Resultssupporting

confidence: 69%

“…A better understanding of the mechanisms of action of DSG and ETO on breathing command and regulation is fundamental to evaluate the conditions under which these progestins could be used to treat patients with central hypoventilation. In this context, we recently showed, in rodents, that ETO enhances the ventilatory response to metabolic acidosis by a mechanism involving supramedullary structures (Loiseau et al, 2014). Whether or not DSG and ETO interfere with generation of the respiratory rhythm (namely resting ventilation) is currently unknown.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Resultssupporting

confidence: 69%

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

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

et al. 2016

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“…While the effects of progesterone on peripheral chemoreceptors would suggest that it increases hypoxic ventilatory response, in adult female rats treated with estradiol + progesterone minute ventilation increases [32], [34], but the effects on hypoxic ventilatory response were small [32]. In adult male rats, progesterone + estradiol treatment increases minute ventilation and hypercapnic ventilatory response [35], and etenogestrel (a potent progesterone receptor agonist) enhances response to metabolic acidosis on in-vitro preparation of the central nervous system in newborn rats [36]. Accordingly, the available findings indicate that in adults progesterone mainly increases ventilation under hypercapnic condition, our data indicate that this effects is mediated by the nuclear progesterone receptor.…”

Section: Discussionmentioning

confidence: 99%

The Nuclear Progesterone Receptor Reduces Post-Sigh Apneas during Sleep and Increases the Ventilatory Response to Hypercapnia in Adult Female Mice

et al. 2014

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We tested the hypothesis that the nuclear progesterone receptor (nPR) is involved in respiratory control and mediates the respiratory stimulant effect of progesterone. Adult female mice carrying a mutation in the nPR gene (PRKO mice) and wild-type controls (WT) were implanted with an osmotic pump delivering vehicle or progesterone (4 mg/kg/day). The mice were instrumented with EEG and neck EMG electrodes connected to a telemetry transmitter. The animals were placed in a whole body plethysmograph 7 days after surgery to record ventilation, metabolic rate, EEG and neck EMGs for 4 consecutive hours. The animals were exposed to hypercapnia (5% CO2), hypoxia (12% O2) and hypoxic-hypercapnia (5% CO2+12% O2–5 min each) to assess chemoreflex responses. EEG and EMG signals were used to characterize vigilance states (e.g., wake, non-REM, and REM sleep). PRKO mice exhibited similar levels of minute ventilation during non-REM and REM sleep, and higher frequencies of sighs and post-sigh apneas during non-REM sleep compared to WT. Progesterone treatment increased minute ventilation and metabolic rate in WT and PRKO mice during non-REM sleep. In WT mice, but not in PRKO mice, the ventilation under hypercapnia and hypoxic hypercapnia was enhanced after progesterone treatment. We conclude that the nPR reduces apnea frequency during non-REM sleep and enhances chemoreflex responses to hypercapnia after progesterone treatment. These results also suggest that mechanisms other than nPR activation increase metabolic rate in response to progesterone treatment in adult female mice.

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“…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].…”

Section: -Kdg Modulates Phox2b Gene Expression Via Progesterone Nucmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Cardani

Lascio

Belperio

et al. 2018

Experimental Cell Research

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The paired-like homeobox 2B gene (PHOX2B) encodes a key transcription factor that plays a role in the development of the autonomic nervous system and the neural structures involved in controlling breathing. In humans, PHOX2B over-expression plays a role in the pathogenesis of tumours arising from the sympathetic nervous system such as neuroblastomas, and heterozygous PHOX2B mutations cause Congenital Central Hypoventilation Syndrome (CCHS), a life-threatening neurocristopathy characterised by the defective autonomic control of breathing and involving altered CO/H chemosensitivity. The recovery of CO/H chemosensitivity and increased ventilation have been observed in two CCHS patients using the potent contraceptive progestin desogestrel. Given the central role of PHOX2B in the pathogenesis of CCHS, and the progesterone-mediated effects observed in the disease, we generated progesterone-responsive neuroblastoma cells, and evaluated the effects of 3-Ketodesogestrel (3-KDG), the biologically active metabolite of desogestrel, on the expression of PHOX2B and its target genes. Our findings demonstrate that, through progesterone nuclear receptor PR-B, 3-KDG down-regulates PHOX2B gene expression, by a post-transcriptional mechanism, and its target genes and open up the possibility that this mechanism may contribute to the positive effects observed in some CCHS patients.

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The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures

Cited by 15 publications

References 34 publications

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

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

The Nuclear Progesterone Receptor Reduces Post-Sigh Apneas during Sleep and Increases the Ventilatory Response to Hypercapnia in Adult Female Mice

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

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