Current Perspectives for the use of Gonane Progesteronergic Drugs in the Treatment of Central Hypoventilation Syndromes

Loiseau, Camille; Cayetanot, Florence; Joubert, Fanny; Perrin-Terrin, Anne-Sophie; Cardot, Philippe; Fiamma, Marie-Noëlle; Frugière, Alain; Straus, Christian; Bodineau, Laurence

doi:10.2174/1570159x15666170719104605

Cited by 10 publications

(7 citation statements)

References 252 publications

(292 reference statements)

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“…Under etonogestrel, the greater number of ROb 5-HT neurons expressing c-Fos in acidosis-responder Phox2b mutants compared to acidosis-non-responders led us to suppose that 5-HT neurons play a key role. This agrees with previous observations in CCHS-free rodents (Joubert et al, 2016b, Loiseau et al, 2018). Many ex vivo and in vivo studies support the hypothesis that 5-HT neurons within the medullary raphe act as CO 2 /H + chemoreceptors and contribute a ventilatory response appropriate to maintain homeostasis (Corcoran et al, 2009, Richerson, 2004, Bernard et al, 1996, Depuy et al, 2011, Peever et al, 2001, Holtman et al, 1986).…”

Section: Discussionsupporting

confidence: 93%

Serotonin, Etonogestrel and breathing activity in murine Congenital Central Hypoventilation Syndrome

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Bianchi

Joubert

et al. 2022

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Congenital Central Hypoventilation Syndrome, a rare disease caused by PHOX2B mutation, is associated with absent or blunted CO2/H+ chemosensitivity due to the dysfunction of PHOX2B neurons of the retrotrapezoid nucleus. No pharmacological treatment is available. Clinical observations have reported non-systematic CO2/H+ chemosensitivity recovery under desogestrel. Here, we used a preclinical model of Congenital Central Hypoventilation Syndrome, the retrotrapezoid nucleus conditional Phox2b mutant mouse, to investigate whether etonogestrel, the active metabolite of desogestrel, led to a restoration of chemosensitivity by acting on serotonin neurons known to be sensitive to etonogestrel, or retrotrapezoid nucleus PHOX2B residual cells that persist despite the mutation. The effect of etonogestrel, alone or combined with serotonin drugs, on the respiratory rhythm of medullary-spinal cord preparations from Phox2b mutants and wildtype mice was analyzed under metabolic acidosis. c-FOS, serotonin and PHOX2B were immunodetected. Serotonin metabolic pathways were characterized by ultra-high-performance liquid chromatography. We observed etonogestrel restored chemosensitivity in Phox2b mutants in a non-systematic way. Histological differences between Phox2b mutants with restored chemosensitivity and others indicated greater activation of serotonin neurons of the raphe obscurus nucleus but no effect on retrotrapezoid nucleus PHOX2B residual cells. Pharmacology of serotonin systems modulated the respiratory effect of etonogestrel differently according to serotonin metabolic pathways. Etonogestrel induced a restoration of chemosensitivity in Phox2b mutants by acting on serotonin neurons. Our work thus highlights that the state of serotonin systems was critically important for the occurrence of an etonogestrel-restoration, an element to consider in potential therapeutic intervention in Congenital Central Hypoventilation Syndrome patients.

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Section: Discussionsupporting

confidence: 93%

Serotonin, Etonogestrel and breathing activity in murine Congenital Central Hypoventilation Syndrome

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Bianchi

Joubert

et al. 2022

Preprint

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“…The lateral area of hypothalamus contains CO 2 /H + chemosensitive orexin neurons ( Wang et al, 2018 ), and it has been reported that they contribute to the hypercapnic ventilatory response ( Loiseau et al, 2019 , and references therein), in a state-dependent manner ( Rodrigues et al, 2019 ). These neurons have recently been involved in the desogestrel effect ( Loiseau et al, 2014 , 2018 , 2019 ). In particular, data from Bodineau’s group ( Loiseau et al, 2014 ; Joubert et al, 2016 ) suggest that two distinct pathways, medullary and supra-medullary, are involved in the ETO ventilatory effects, excluding the involvement of RTN in the progestin effect.…”

Section: Therapeutic Research Based On Advances In Our Understanding mentioning

confidence: 99%

“…Steroids, by binding NMDAR, potentiate the NMDA induced increase in respiratory frequency. However, whether synthetic progestin metabolites modulate GABA A receptor is still a matter of debate ( Giatti et al, 2016 ; Joubert et al, 2016 ; Loiseau et al, 2018 ).…”

Section: Therapeutic Research Based On Advances In Our Understanding mentioning

confidence: 99%

“…However, potential limitations of this work are that the study has been conducted in newborn wild type animals, whereas the two CCHS patients in Straus’ study are adult, and the neuronal structures might be immature compared to adult humans. Indeed, in CCHS patients ETO potentiates also basal ventilation ( Joubert et al, 2016 ; Loiseau et al, 2018 ) that may require the functioning of serotoninergic neurons within the medullary raphe nuclei, and modulation of GABA A – and NMDA-mediated ventilatory regulations ( Loiseau et al, 2018 ). Furthermore, the use of wild type animals has not allowed to explore whether orexin neurons stimulation still contributes to respiratory improvement in the presence of PHOX2B mutations.…”

Section: Therapeutic Research Based On Advances In Our Understanding mentioning

confidence: 99%

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Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS)

et al. 2021

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Congenital central hypoventilation syndrome (CCHS) is a genetic disorder of neurodevelopment, with an autosomal dominant transmission, caused by heterozygous mutations in the PHOX2B gene. CCHS is a rare disorder characterized by hypoventilation due to the failure of autonomic control of breathing. Until now no curative treatment has been found. PHOX2B is a transcription factor that plays a crucial role in the development (and maintenance) of the autonomic nervous system, and in particular the neuronal structures involved in respiratory reflexes. The underlying pathogenetic mechanism is still unclear, although studies in vivo and in CCHS patients indicate that some neuronal structures may be damaged. Moreover, in vitro experimental data suggest that transcriptional dysregulation and protein misfolding may be key pathogenic mechanisms. This review summarizes latest researches that improved the comprehension of the molecular pathogenetic mechanisms responsible for CCHS and discusses the search for therapeutic intervention in light of the current knowledge about PHOX2B function.

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“…On the basis of data from animal models, the actual consensus is that lack of CO 2 /H + sensitivity is due to a dysfunction or loss of the CO2/H + PHOX2B-positive neurons of the RTN with a priori no disturbance at the level of medullary raphe 5-HT and non-5HT neurons ( Amiel et al, 2003 ; Dubreuil et al, 2008 ; Ramanantsoa et al, 2011 ). Incidental clinical observations suggested a restoration of CO 2 /H + sensitivity in some CCHS patients who took progestin for contraceptive purposes and data from animal models free from CCHS suggest that progestin stimulates the respiratory drive through an action involving medullary raphe neurons, some of which are 5-HT neurons ( Straus et al, 2010 ; Joubert et al, 2016 ; Loiseau et al, 2018 ). Since the present study showed that the modulation of Epo leads to an increase in the sensitivity of 5-HT and non-5-HT neurons of the raphe medullary nuclei leading to stimulation of f R for moderate level of CO 2 , it could be interesting to explore if Epo pharmacological manipulation is able to restore a CO 2 /H + respiratory response in preclinical CCHS models.…”

Section: Discussionmentioning

confidence: 99%

In Transgenic Erythropoietin Deficient Mice, an Increase in Respiratory Response to Hypercapnia Parallels Abnormal Distribution of CO2/H+-Activated Cells in the Medulla Oblongata

et al. 2022

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Erythropoietin (Epo) and its receptor are expressed in central respiratory areas. We hypothesized that chronic Epo deficiency alters functioning of central respiratory areas and thus the respiratory adaptation to hypercapnia. The hypercapnic ventilatory response (HcVR) was evaluated by whole body plethysmography in wild type (WT) and Epo deficient (Epo-TAgh) adult male mice under 4%CO2. Epo-TAgh mice showed a larger HcVR than WT mice because of an increase in both respiratory frequency and tidal volume, whereas WT mice only increased their tidal volume. A functional histological approach revealed changes in CO2/H+-activated cells between Epo-TAgh and WT mice. First, Epo-TAgh mice showed a smaller increase under hypercapnia in c-FOS-positive number of cells in the retrotrapezoid nucleus/parafacial respiratory group than WT, and this, independently of changes in the number of PHOX2B-expressing cells. Second, we did not observe in Epo-TAgh mice the hypercapnic increase in c-FOS-positive number of cells in the nucleus of the solitary tract present in WT mice. Finally, whereas hypercapnia did not induce an increase in the c-FOS-positive number of cells in medullary raphe nuclei in WT mice, chronic Epo deficiency leads to raphe pallidus and magnus nuclei activation by hyperacpnia, with a significant part of c-FOS positive cells displaying an immunoreactivity for serotonin in the raphe pallidus nucleus. All of these results suggest that chronic Epo-deficiency affects both the pattern of ventilatory response to hypercapnia and associated medullary respiratory network at adult stage with an increase in the sensitivity of 5-HT and non-5-HT neurons of the raphe medullary nuclei leading to stimulation of fR for moderate level of CO2.

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Current Perspectives for the use of Gonane Progesteronergic Drugs in the Treatment of Central Hypoventilation Syndromes

Abstract: Gonanes show promise for improving ventilation of CHS patients, although the conditions of their use need to be better understood.

Cited by 10 publications

References 252 publications

Serotonin, Etonogestrel and breathing activity in murine Congenital Central Hypoventilation Syndrome

Serotonin, Etonogestrel and breathing activity in murine Congenital Central Hypoventilation Syndrome

Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS)

In Transgenic Erythropoietin Deficient Mice, an Increase in Respiratory Response to Hypercapnia Parallels Abnormal Distribution of CO2/H+-Activated Cells in the Medulla Oblongata

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