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

Abstract

Background: Central alveolar hypoventilation syndromes (CHS) encompass neurorespiratory diseases resulting from congenital or acquired neurological disorders. Hypercapnia, acidosis, and hypoxemia resulting from CHS negatively affect physiological functions and can be lifethreatening. To date, the absence of pharmacological treatment implies that the patients must receive assisted ventilation throughout their lives.

Objective: To highlight the relevance of determining conditions in which using gonane synthetic progestins could be of potential clinical interest for the treatment of CHS.

Methods: The mechanisms by which gonanes modulate the respiratory drive were put into the context of those established for natural progesterone and other synthetic progestins.

Results: The clinical benefits of synthetic progestins to treat respiratory diseases are mixed with either positive outcomes or no improvement. A benefit for CHS patients has only recently been proposed. We incidentally observed restoration of CO2 chemosensitivity, the functional deficit of this disease, in two adult CHS women by desogestrel, a gonane progestin, used for contraception. This effect was not observed by another group, studying a single patient. These contradictory findings are probably due to the complex nature of the action of desogestrel on breathing and led us to carry out mechanistic studies in rodents. Our results show that desogestrel influences the respiratory command by modulating the GABAA and NMDA signaling in the respiratory network, medullary serotoninergic systems, and supramedullary areas.

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

Keywords: Central congenital hypoventilation syndrome; Ondine’s curse syndrome; desogestrel; etonogestrel; gonane; progesterone; respiratory control..

Fig. (1)

Natural progesterone, progesterone derivatives, and families of synthetic progestin and their genomic and non-genomic modes of action within the CNS. The upper part of the figure shows the chemical structures of natural progesterone, its derivatives, and synthetic progestins. The enzymes required for the biosynthesis of natural progesterone and its derivatives are indicated. The two members of the gonane family, desogestrel and etonogestrel, which are the focus of this review, are highlighted by a gray rectangle. The lower part of the figure shows the receptors targeted by neuroactive steroids and synthetic progestins. The left-hand side shows the cognate nuclear and membrane receptors of progesterone that mediate their genomic and non-genomic effects, respectively. The right-hand side shows the receptors which belong to other neurotransmitter systems that are targets of neuroactive steroids and synthetic progestins. For nuclear receptors, the canonical mature mRNA is represented with its 5’ and 3’ untranslated regions. The scheme of the canonical mature mRNA is composed of boxes containing numbers which correspond to the exon from which they were transcribed. The various protein isoforms translated from the mature mRNA are represented with their functional domains located just below the representation of the mature mRNA. For the nuclear progesterone receptor isoforms PR-S and PR-T, boxes S and T represent nucleotide sequences that are translated from intronic-exons not represented in the canonical mature mRNA. Abbreviations: steroid 17-alpha-hydroxylase/17,20 lyase precursor (P450c17), untranslated region (UTR), activation function (AF), inhibition factor (IF), DNA binding domain (DBD), nuclear location signal (h), ligand binding domain (LBD), intronic-exons (T and S), N-terminal domain (NTD), nuclear progesterone receptor (PR), nuclear glucocorticoid receptor (GR), nuclear mineralocorticoid receptor (MR), nuclear androgen receptor (AR).

Fig. (2)

Consequences of desogestrel exposure on the ventilation of a CCHS patient. (A) Ventilatory response of a CCHS patient during a CO₂ rebreathing test [50]. The left panel shows the change in ventilation (V_E) with the increase in end tidal CO₂ partial pressure assessed before desogestrel exposure. The right panel shows the same assessment after approximately 18 months of treatment with desogestrel. Reprinted from Respiratory Physiology & Neurobiology, 171(2), C Straus, H Trang, M-H Becquemin, P Touraine, T Similowski, Chemosensitivity recovery in Ondine's curse syndrome under treatment with desogestrel, 171-174, Copyright (2010), with permission from Elsevier. (B) Box plot showing the median breath-by-breath respiratory frequency and median breath-by breath end tidal CO₂ partial pressure of the CCHS patient at baseline [52]. † indicates a significant difference between before and after desogestrel treatment and during desogestrel exposure. One-way ANOVA – post hoc Bonferroni correction. ^††p < 0.01, ^†††p < 0.001. Abbreviation: desogestrel (DSG). Reprinted from Neuropharmacology, 107, F Joubert, A-S Perrin-Terrin, E Verkaeren, P Cardot, M-N Fiamma, A Frugière, I Rivals, T Similowski, C Straus, L Bodineau, Desogestrel enhances ventilation in ondine patients: Animal data involving serotoninergic systems, 339-350, Copyright (2016), with permission from Elsevier.

Fig. (3)

Ex vivo CNS preparations in an electrophysiological recording chamber and the effect of etonogestrel on respiratory frequency under conditions of metabolic acidosis on these preparations. (A) Schematic representation of an ex vivo preparation of the CNS from a newborn rodent placed in an electrophysiological recording chamber. After the surgical procedure, ex vivo preparations were placed in a recording chamber and superfused either with artificial cerebrospinal fluid (aCSF) corresponding to normal pH (pH 7.4 aCSF: 129.0 mM NaCl, 3.35 mM KCl, 1.26 mM CaCl₂ 2H₂O, 1.15 mM MgCl₂ 6H₂O, 0.58 mM NaH₂PO₄ H₂O, 21.0 mM NaHCO₃, 30.0 mM D-glucose) or metabolic acidosis (pH 7.23 aCSF: 129.0 mM NaCl, 3.35 mM KCl, 1.26 mM CaCl₂ 2H₂O, 1.15 mM MgCl₂ 6H₂O, 0.58 mM NaH₂PO₄ H₂O, 15.0 mM NaHCO₃, 30.0 mM D-glucose), both saturated with O₂ and adjusted to pH by bubbling with 95% O₂ and 5% CO₂. Pharmacological agents can be added to aCSF according to the experimental conditions. The illustrated ex vivo preparation contains the medulla oblongata and supramedullary regions up to the diencephalon. Dotted lines show the levels of transection: the rostral extremity for diencephalon-brainstem-spinal cord (DBS) preparations (1) and medullary-spinal cord (MS) preparations (2) and the caudal extremity for both MS and DBS preparations (3). A typical electrophysiological respiratory-like activity recording at the level of ventral C4 and its integration is presented to the right. (B) Experimental protocol performed to test the effect of etonogestrel on CNS preparation from newborn rat under conditions of metabolic acidosis [51]. After a stabilization period (30 min superfused with normal pH aCSF without drug), preparations were pre-incubated 15 min either with etonogestrel (1 µM) or dimethyl sulfoxide (DMSO, 0.01%, the solvent for etonogestrel) i.e pre-metabolic acidosis period, before being superfused for 30 min with metabolic acidosis aCSF containing the same drugs i.e. metabolic acidosis period. Pre-metabolic acidosis and metabolic acidosis values were defined as the mean calculated over the last 5 min of the pre-metabolic acidosis and metabolic acidosis periods, respectively. The dot plot shows the percentage change in respiratory frequency (f_R) between respective pre-metabolic acidosis and metabolic acidosis values obtained in MS and DBS preparations exposed to DMSO (dark gray circles) or etonogestrel (light gray circles). All values are expressed as the mean ± SEM. Two-way ANOVA followed by a post hoc Bonferroni correction were performed. Differences were considered to significant for p < 0.05. # significant increase in mean f_R compared to control values; * significant difference between etonogestrel and DMSO exposures. # p < 0.05, ### p < 0.001, *** p < 0.001, n.s.: non-significant. Abbreviations: artificial cerebrospinal fluid (aCSF); integrated activity of the C4 ventral nerve root (ʃC4); electrical activity of the C4 ventral nerve root (C4); dimethyl sulfoxide (DMSO); etonogestrel (ETO); respiratory frequency (f_R), medullary-spinal cord (MS); diencephalon-brainstem-spinal cord (DBS). Adapted from [51]. Reprinted from Neuroscience Letters, 567, C Loiseau, D Osinski, F Joubert, C Straus, T Similowski, L Bodineau, The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures, 63-67, Copyright (2014), with permission from Elsevier.

Fig. (4)

Effect of etonogestrel on baseline respiratory frequency on in vivo newborn mice and ex vivo medullary-spinal cord preparations. Implication of GABA_A receptors. (A) Effect of etonogestrel on baseline respiratory frequency (f_R) on in vivo newborn mice. Newborn mice received per os either etonogestrel (ETO; 10^-3 mg/kg; concentration equivalent to that of the human exposure) dissolved in oil or oil alone. The f_R was recorded by whole body plethysmography. Traces illustrate ventilation after oil or etonogestrel exposure. The dotplot shows the baseline f_R obtained after oil (dark gray circles) or etonogestrel (light gray circles) exposure. (B) Effect of etonogestrel on f_R of ex vivo medullary-spinal cord preparations. Preparations were exposed to etonogestrel (0.05, 0.5, 1, or 2 µM) or dimethyl sulfoxide (DMSO, 0.01%, etonogestrel solvent). The respiratory-like activity was recorded at the level of the fourth cervical ventral root (Fig. 3). The dot plot shows the percentage change of the mean f_R during DMSO (dark gray circles) or etonogestrel (light gray circles) exposure. (C) Effect of etonogestrel under conditions of GABA_A receptor blockade on ex vivo medullary-spinal cord preparations. Preparations were pre-incubated with bicuculline (GABA_A receptor antagonist) before etonogestrel exposure. The dotplot shows the percentage change of the f_R during etonogestrel exposure (0.05 μM and 2 μM) in the absence and presence of 3 μM bicuculline (a concentration previously shown to be sufficient to block the effect of GABA on GABA_A receptor -mediated regulation of respiration [206]). (D) Effect of etonogestrel on GABA_A receptor modulation of ex vivo medullary-spinal cord preparations. Preparations were first exposed to etonogestrel (0.05 μM and 2 μM) or DMSO (0.01%) and then DMSO/muscimol (0.14 μM; EC₅₀, as determined in [52]) or etonogestrel/muscimol (0.14 μM). The dotplot shows the percentage change of the f_R during DMSO/muscimol (dark gray circles) or etonogestrel /muscimol (light gray circles) exposure. All values are expressed as the mean ± SEM. The student t-test or two-way ANOVA, followed by post hoc Bonferroni correction were performed as appropriate. Differences were considered to be significant for p < 0.05. # significant increase in mean f_R relative to pre-DMSO and pre- etonogestrel values as appropriate; * significant difference between etonogestrel and DMSO or oil exposures or between the absence and presence of bicuculline. ## p < 0.01, ### p < 0.001, * p < 0.05, ** p < 0.01, *** p < 0.001, n.s.: non-significant. Abbreviations: bicuculline (BIC); dimethyl sulfoxide (DMSO); etonogestrel (ETO); respiratory frequency (f_R); muscimol (MUS). Adapted from [52]. Reprinted from Neuropharmacology, 107, F Joubert, A-S Perrin-Terrin, E Verkaeren, P Cardot, M-N Fiamma, A Frugière, I Rivals, T Similowski, C Straus, L Bodineau, Desogestrel enhances ventilation in ondine patients: Animal data involving serotoninergic systems, 339-350, Copyright (2016), with permission from Elsevier.

Fig. (5)

The effect of etonogestrel on respiration implies the medullary serotoninergic systems. (A) Effect of etonogestrel on c-fos expression in medullary respiratory structures containing serotoninergic neurons. On the left, gray photomicrographs illustrate c-FOS immunoreactivity in the caudal parts of the pallidus and obscurus raphe nuclei after dimethyl sulfoxide (DMSO) or etonogestrel exposure. Scale bar: 100 μm. On the right, photomicrographs illustrate the serotoninergic character of c-FOS-immunoreactive cells in these two structures. Scale bars: 10 µm. (B) Effect of etonogestrel under conditions of blockade of serotoninergic respiratory influence on ex vivo medullary-spinal cord preparations. Preparations were first exposed to methysergide (a 5-HT_1/2/7 receptor antagonist; 5 μM, the lowest concentration that completely antagonizes the effect of 5-HT, as determined in [52]) and then etonogestrel (0.05 μM). The scatter plot shows the percentage change of the f_R during etonogestrel exposure in the absence or presence of methysergide. All values are expressed as the mean ± SEM. The Kruskal-Wallis test was performed. Differences were considered to be significant for p < 0.05. # significant increase in mean f_R relative to pre-ETO values; * significant difference between the presence and absence of methysergide. ### p < 0.001, *** p < 0.001, n.s.: non-significant. Abbreviations: etonogestrel (ETO); inferior olives (IO); respiratory frequency (f_R); methysergide (MET). Adapted from [52]. Reprinted from Neuropharmacology, 107, F Joubert, A-S Perrin-Terrin, E Verkaeren, P Cardot, M-N Fiamma, A Frugière, I Rivals, T Similowski, C Straus, L Bodineau, Desogestrel enhances ventilation in ondine patients: Animal data involving serotoninergic systems, 339-350, Copyright (2016), with permission from Elsevier.