Etude des mécanismes centraux par lesquels l'étonogestrel, un progestatif de la famille des gonanes, renforce la réponse respiratoire à l'hypercapnie. Investigations réalisées dans le cadre des hypoventilations centrales

Abstract : Ondine’s curse is a disease characterized by a dysfunction of the CO2/H+ chemosensitivity. Clinical observation suggest that desogestrel, a progestin of the gonane family, have induced a recovery of CO2/H+ chemosensitivity (Straus et al., 2010).This work aimed to have a better understanding of the central mechanisms by which etonogestrel (ETO, the metabolite of desogestrel) may have induced a recovery of CO2/H+ chemosensitivity. Pharmacological exposures and c-fos expression analysis were performed in parallel on ex vivo preparations of central nervous system from newborn rats.Our results indicated that ETO strengthens the respiratory response to metabolic acidosis in a range of concentration close to the clinical exposure, by a diencephalic-dependent mechanism. More precisely our results suggested that this effect relied on the activation of diencephalic orexinergic neurons. Besides, the analysis of the c-fos expression revealed that ETO over-activated and activated several respiratory-related brainstem structures. For most of them their activation or overactivation seems to depend on the orexinergic signalisation since the increase in c-fos expression observed in response to ETO is no longer present when orexinergic receptors are antagonized. We assume that our results highlighted, at least in part, the neuronal pathway used by ETO to induce a recovery of the CO2/H+ chemosensitivity in Ondine patients.Our data open up pieces of reflexion about conditions about the mechanisms, underlined the recovery of CO2/H+ chemosensitivity in Ondine patients.
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Camille Loiseau. Etude des mécanismes centraux par lesquels l'étonogestrel, un progestatif de la famille des gonanes, renforce la réponse respiratoire à l'hypercapnie. Investigations réalisées dans le cadre des hypoventilations centrales. Physiologie [q-bio.TO]. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066174⟩. ⟨tel-02164308⟩

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