{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:26:45Z","timestamp":1790666805691,"version":"4.1.0"},"reference-count":94,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T00:00:00Z","timestamp":1651017600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Women and Children\u2019s Health Research Institute","award":["55869"],"award-info":[{"award-number":["55869"]}]},{"name":"Innovation grant program","award":["55869"],"award-info":[{"award-number":["55869"]}]},{"name":"Canadian Lung Association, Grant In Aid program (SP)","award":["55869"],"award-info":[{"award-number":["55869"]}]},{"name":"Italian Society of Pharmacology","award":["55869"],"award-info":[{"award-number":["55869"]}]},{"name":"Canadian Lung Association","award":["55869"],"award-info":[{"award-number":["55869"]}]},{"name":"Investigator-Initiated Study Program","award":["55869"],"award-info":[{"award-number":["55869"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heterozygous mutations of the transcription factor PHOX2B are responsible for Congenital Central Hypoventilation Syndrome, a neurological disorder characterized by inadequate respiratory response to hypercapnia and life-threatening hypoventilation during sleep. Although no cure is currently available, it was suggested that a potent progestin drug provides partial recovery of chemoreflex response. Previous in vitro data show a direct molecular link between progestins and PHOX2B expression. However, the mechanism through which these drugs ameliorate breathing in vivo remains unknown. Here, we investigated the effects of chronic administration of the potent progestin drug Etonogestrel (ETO) on respiratory function and transcriptional activity in adult female rats. We assessed respiratory function with whole-body plethysmography and measured genomic changes in brain regions important for respiratory control. Our results show that ETO reduced metabolic activity, leading to an enhanced chemoreflex response and concurrent increased breathing cycle variability at rest. Furthermore, ETO-treated brains showed reduced mRNA and protein expression of PHOX2B and its target genes selectively in the dorsal vagal complex, while other areas were unaffected. Histological analysis suggests that changes occurred in the solitary tract nucleus (NTS). Thus, we propose that the NTS, rich in both progesterone receptors and PHOX2B, is a good candidate for ETO-induced respiratory modulation.<\/jats:p>","DOI":"10.3390\/ijms23094816","type":"journal-article","created":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T13:40:57Z","timestamp":1651066857000},"page":"4816","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Etonogestrel Administration Reduces the Expression of PHOX2B and Its Target Genes in the Solitary Tract Nucleus"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9758-2649","authenticated-orcid":false,"given":"Silvia","family":"Cardani","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2E1, Canada"},{"name":"Department of Medical Biotechnology and Translational Medicine, Universit\u00e0 degli Studi di Milano, Via Vanvitelli 32, 20129 Milan, Italy"},{"name":"Women and Children\u2019s Health Research Institute, University of Alberta, Edmonton, AB T6G2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara A.","family":"Janes","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2E1, Canada"},{"name":"Women and Children\u2019s Health Research Institute, University of Alberta, Edmonton, AB T6G2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmeen K.","family":"Saini","sequence":"additional","affiliation":[{"name":"Women and Children\u2019s Health Research Institute, University of Alberta, Edmonton, AB T6G2E1, Canada"},{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5971-1515","authenticated-orcid":false,"given":"Simona","family":"Di Lascio","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, Universit\u00e0 degli Studi di Milano, Via Vanvitelli 32, 20129 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5396-5429","authenticated-orcid":false,"given":"Roberta","family":"Benfante","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, Universit\u00e0 degli Studi di Milano, Via Vanvitelli 32, 20129 Milan, Italy"},{"name":"CNR-Institute of Neuroscience, Via Raoul Follereau 3, 20854 Vedano al Lambro, Italy"},{"name":"NeuroMi-Milan Centre for Neuroscience, University of Milano Bicocca, 20129 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Fornasari","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, Universit\u00e0 degli Studi di Milano, Via Vanvitelli 32, 20129 Milan, Italy"},{"name":"CNR-Institute of Neuroscience, Via Raoul Follereau 3, 20854 Vedano al Lambro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1482-9173","authenticated-orcid":false,"given":"Silvia","family":"Pagliardini","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2E1, Canada"},{"name":"Women and Children\u2019s Health Research Institute, University of Alberta, Edmonton, AB T6G2E1, Canada"},{"name":"Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB T6G2E1, Canada"},{"name":"3-020F Katz Group Centre for Pharmacy and Health Research, Department of Physiology, University of Alberta, 11315 87 Ave NW, Edmonton, AB T6G2E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/ng1130","article-title":"Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome","volume":"33","author":"Amiel","year":"2003","journal-title":"Nat. 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