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Etonogestrel Administration Reduces the Expression of PHOX2B and Its Target Genes in the Solitary Tract Nucleus
Silvia Cardani1,2,3, Tara A Janes1,3, Jasmeen K Saini3,4
1Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2E1, Canada.
Abstract:
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.
Insights
A progestin drug, Etonogestrel, improved respiratory control in rats with Congenital Central Hypoventilation Syndrome by modulating PHOX2B expression in the brainstem. This offers a potential therapeutic avenue for this neurological disorder.
Area of Science:
- Neuroscience
- Respiratory Physiology
- Pharmacology
Background:
- Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurological disorder caused by PHOX2B gene mutations, leading to impaired breathing.
- Progestin drugs have shown potential in improving chemoreflex response in CCHS, but the underlying mechanism is unclear.
- In vitro studies suggest a molecular link between progestins and PHOX2B expression.
Purpose of the Study:
- To investigate the in vivo effects of Etonogestrel (ETO), a potent progestin, on respiratory function and PHOX2B expression in a rat model.
- To identify the specific brain regions involved in ETO's therapeutic effects on respiratory control.
Main Methods:
- Chronic administration of Etonogestrel (ETO) to adult female rats.
- Assessment of respiratory function using whole-body plethysmography.
- Measurement of PHOX2B mRNA and protein expression in key brain regions, including the dorsal vagal complex and solitary tract nucleus (NTS).
Main Results:
- ETO treatment enhanced chemoreflex response and increased breathing cycle variability at rest.
- ETO selectively reduced PHOX2B mRNA and protein expression in the dorsal vagal complex, particularly within the NTS.
- Histological analysis indicated that the NTS is a primary site of ETO's action.
Conclusions:
- The potent progestin Etonogestrel modulates respiratory control in vivo, potentially by targeting the NTS.
- Reduced PHOX2B expression in the NTS is implicated in ETO's amelioration of respiratory dysfunction.
- The NTS is a key candidate region for ETO-induced respiratory modulation in CCHS.
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