Enhanced c-Fos expression in the rostral ventral respiratory complex and rostral parapyramidal region by inhibition of the Na+/H+ exchanger type 3

Ribas-Salgueiro, Juan Luis; Matarredona, Esperanza R.; Ribas, J.; Pásaro, Rosario

doi:10.1016/j.autneu.2006.01.022

Cited by 8 publications

(2 citation statements)

References 37 publications

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“…In addition to RTN, other medullary and supramedullary structures, including vlNTS, PP, LC, vlPAG, and PeF, displayed increased c-fos expression and thus may be involved in the increase in both c-fos expression in VLM and f R . Indeed, these structures all contain CO 2 /H + chemosensitive neurons and exert an excitatory influence on CRD (Coates et al, 1993; Ryan and Waldrop, 1995; Horn and Waldrop, 1998; Oyamada et al, 1998; Ribas-Salgueiro et al, 2006; Biancardi et al, 2008; Pagliardini et al, 2011; Li N. et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Orexin Neurons Contribute to Central Modulation of Respiratory Drive by Progestins on ex vivo Newborn Rodent Preparations

Loiseau¹,

Casciato²,

Barka³

et al. 2019

Front. Physiol.

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Dysfunction of central respiratory CO2/H+ chemosensitivity is a pivotal factor that elicits deep hypoventilation in patients suffering from central hypoventilation syndromes. No pharmacological treatment is currently available. The progestin desogestrel has been suggested to allow recovery of respiratory response to CO2/H+ in patients suffering from central hypoventilation, but except the fact that supramedullary regions may be involved, mechanisms are still unknown. Here, we tested in neonates whether orexin systems contribute to desogestrel’s central effects on respiratory function. Using isolated ex vivo central nervous system preparations from newborn rats, we show orexin and almorexant, an antagonist of orexin receptors, supressed strengthening of the increase in respiratory frequency induced by prolonged metabolic acidosis under exposure to etonogestrel, the active metabolite of desogestrel. In parallel, almorexant suppressed the increase and enhanced increase in c-fos expression in respiratory-related brainstem structures induced by etonogestrel. These results suggest orexin signalisation is a key component of acidosis reinforcement of respiratory drive by etonogestrel in neonates. Although stage of development used is different as that for progestin clinical observations, presents results provide clues about conditions under which desogestrel or etonogestrel may enhance ventilation in patients suffering from central hypoventilation syndromes.

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Section: Discussionmentioning

confidence: 99%

Orexin Neurons Contribute to Central Modulation of Respiratory Drive by Progestins on ex vivo Newborn Rodent Preparations

Loiseau¹,

Casciato²,

Barka³

et al. 2019

Front. Physiol.

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“…Inhibition of NHE3 increases the activity of CO 2 /H + -sensitive neurons upon intracellular acidification . Inhibition of NHE3 expressed in brain stem areas ,, is able to modulate the ventilation drive and therefore reduce central sleep apneas. In addition NHE3 inhibition leads to increased muscle tone of the upper airways .…”

Section: Introductionmentioning

confidence: 99%

Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na⁺/H⁺ Exchanger Type 3 (NHE3)

et al. 2016

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The design, synthesis, and structure-activity relationship of 1-phenoxy-2-aminoindanes as inhibitors of the Na/H exchanger type 3 (NHE3) are described based on a hit from high-throughput screening (HTS). The chemical optimization resulted in the discovery of potent, selective, and orally bioavailable NHE3 inhibitors with 13d as best compound, showing high in vitro permeability and lacking CYP2D6 inhibition as main optimization parameters. Aligning 1-phenoxy-2-aminoindanes onto the X-ray structure of 13d then provided 3D-QSAR models for NHE3 inhibition capturing guidelines for optimization. These models showed good correlation coefficients and allowed for activity estimation. In silico ADMET models for Caco-2 permeability and CYP2D6 inhibition were also successfully applied for this series. Moreover, docking into the CYP2D6 X-ray structure provided a reliable alignment for 3D-QSAR models. Finally 13d, renamed as SAR197, was characterized in vitro and by in vivo pharmacokinetic (PK) and pharmacological studies to unveil its potential for reduction of obstructive sleep apneas.

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The Central Respiratory Chemoreceptor: Where Is It Located?–Invited Article

Okada

Kuwana

et al. 2009

Advances in Experimental Medicine and Biology

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We review previous reports on the localization of the central chemoreceptor focusing on our studies that used various experimental techniques including lesioning (brainstem transection and removal of pia mater), analyses of neuronal responses to CO(2) by electrophysiological and optical recording, mapping of CO(2)-excitable neurons by c-fos immunohistochemistry and local acidic stimulation. Among these experimental techniques, voltage imaging with calculation of cross correlation coefficients between the respiratory output activity and each pixel, i.e., correlation coefficient imaging technique, enabled us to effectively analyze imaging data without empirical signal processing. The reviewed studies have indicated that the most superficial layer of the rostral ventral medulla, i.e., the surface portions of the nucleus retrotrapezoideus/parafacial respiratory group, nucleus parapyramidal superficialis and nucleus raphe pallidus, is important in central chemoreception. We suggest that one of the major respiratory rhythm generators, i.e., the preBötzinger complex, is not chemosensitive in itself or rather inhibited by CO(2). Based on our detailed analysis of c-fos immunohistochemistry, we propose a cell-vessel architecture model for the central respiratory chemoreceptor. Primary chemoreceptor cells are mainly located beneath large surface vessels within the marginal glial layer of the ventral medulla, and surround fine penetrating vessels that branch from a large surface vessel. Respiratory neurons in the rostral portion of the ventral respiratory group could be intrinsically chemosensitive, but their role in chemoreception might be secondary. Definitive identification of chemosensitive sites and chemoreceptor cells needs further studies.

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Enhanced c-Fos expression in the rostral ventral respiratory complex and rostral parapyramidal region by inhibition of the Na+/H+ exchanger type 3

Cited by 8 publications

References 37 publications

Orexin Neurons Contribute to Central Modulation of Respiratory Drive by Progestins on ex vivo Newborn Rodent Preparations

Orexin Neurons Contribute to Central Modulation of Respiratory Drive by Progestins on ex vivo Newborn Rodent Preparations

Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na⁺/H⁺ Exchanger Type 3 (NHE3)

The Central Respiratory Chemoreceptor: Where Is It Located?–Invited Article

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Enhanced c-Fos expression in the rostral ventral respiratory complex and rostral parapyramidal region by inhibition of the Na+/H+ exchanger type 3

Cited by 8 publications

References 37 publications

Orexin Neurons Contribute to Central Modulation of Respiratory Drive by Progestins on ex vivo Newborn Rodent Preparations

Orexin Neurons Contribute to Central Modulation of Respiratory Drive by Progestins on ex vivo Newborn Rodent Preparations

Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na+/H+ Exchanger Type 3 (NHE3)

The Central Respiratory Chemoreceptor: Where Is It Located?–Invited Article

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Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na⁺/H⁺ Exchanger Type 3 (NHE3)