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

Abstract

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.

Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS)

“…In conclusion, Loiseau et al (2019) suggested that ETO induces the CO 2 /H + chemosensitivity improvement in some CCHS patients by stimulating, or potentiating still functioning CO 2 /H + chemosensitive central structures. However, potential limitations of this work are that the study has been conducted in newborn wild type animals, whereas the two CCHS patients in Straus’ study are adult, and the neuronal structures might be immature compared to adult humans.…”

“…Moreover, VLPO controls the wake-sleep cycle regulation ( Saper et al, 2005 ), whereas chemical stimulation of DMH has been associated to increased phrenic nerve stimulation ( Tanaka and McAllen, 2008 ). The lateral area of hypothalamus contains CO 2 /H + chemosensitive orexin neurons ( Wang et al, 2018 ), and it has been reported that they contribute to the hypercapnic ventilatory response ( Loiseau et al, 2019 , and references therein), in a state-dependent manner ( Rodrigues et al, 2019 ). These neurons have recently been involved in the desogestrel effect ( Loiseau et al, 2014 , 2018 , 2019 ).…”

“…The lateral area of hypothalamus contains CO 2 /H + chemosensitive orexin neurons ( Wang et al, 2018 ), and it has been reported that they contribute to the hypercapnic ventilatory response ( Loiseau et al, 2019 , and references therein), in a state-dependent manner ( Rodrigues et al, 2019 ). These neurons have recently been involved in the desogestrel effect ( Loiseau et al, 2014 , 2018 , 2019 ). In particular, data from Bodineau’s group ( Loiseau et al, 2014 ; Joubert et al, 2016 ) suggest that two distinct pathways, medullary and supra-medullary, are involved in the ETO ventilatory effects, excluding the involvement of RTN in the progestin effect.…”

“…By working on ex vivo mouse medullary-spinal cord preparations or in vivo newborn mice from both genders exposed to ETO, Loiseau et al (2019) identified in orexin neurons the target of ETO-induced facilitation on respiratory frequency increase, following metabolic acidosis, and suggested that this was due to a non-genomic effect of desogestrel ( Singh et al, 2013 ). The presence of PR receptors (nuclear and/or membrane) in orexin neurons is still unknown; however, the role of membrane progesterone receptor (mPR) could be excluded because progestins have little if any binding affinity for this membrane receptor ( Giatti et al, 2016 ).…”

Progesterone decreases apnoea and reduces oxidative stress induced by chronic intermittent hypoxia in ovariectomized female rats

“…Likewise, Prog or Prog's metabolite have also been identified as allosteric modulators of brain nicotinic (Bullock et al., 1997), 5‐HT (Wetzel et al., 1998), or glycine (Yevenes & Zeilhofer, 2011) receptors. Prog might also modulate the central respiratory output by altering neurochemical regulation in brainstem or hypothalamic nuclei that are involved in respiratory control, including orexinergic neurons (Loiseau, Casciato, Barka, Cayetanot, & Bodineau, 2019), or other brainstem nuclei that are activated in a sex‐specific pattern following exposure to CIH (Baum et al., 2018).…”