Effect of progesterone on respiratory response to moderate hypoxia and apnea frequency in developing rats

Bairam, Aïda; Lumbroso, Delphine; Joseph, Vincent

doi:10.1016/j.resp.2012.11.001

Cited by 15 publications

(41 citation statements)

References 48 publications

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“…Thus, our plethysmographic data should be taken with caution. Indeed, the plethysmography was used primarily to simply assure the presence of a biphasic respiratory response in one day old mice, as classically described in other newborns (Simakajornboon et al, 2004; Bairam et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Key Brainstem Structures Activated during Hypoxic Exposure in One-day-old Mice Highlight Characteristics for Modeling Breathing Network in Premature Infants

et al. 2016

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We mapped and characterized changes in the activity of brainstem cell groups under hypoxia in one-day-old newborn mice, an animal model in which the central nervous system at birth is particularly immature. The classical biphasic respiratory response characterized by transient hyperventilation, followed by severe ventilation decline, was associated with increased c-FOS immunoreactivity in brainstem cell groups: the nucleus of the solitary tract, ventral reticular nucleus of the medulla, retrotrapezoid/parafacial region, parapyramidal group, raphe magnus nucleus, lateral, and medial parabrachial nucleus, and dorsal subcoeruleus nucleus. In contrast, the hypoglossal nucleus displayed decreased c-FOS immunoreactivity. There were fewer or no activated catecholaminergic cells activated in the medulla oblongata, whereas ~45% of the c-FOS-positive cells in the dorsal subcoeruleus were co-labeled. Approximately 30% of the c-FOS-positive cells in the parapyramidal group were serotoninergic, whereas only a small portion were labeled for serotonin in the raphe magnus nucleus. None of the c-FOS-positive cells in the retrotrapezoid/parafacial region were co-labeled for PHOX2B. Thus, the hypoxia-activated brainstem neuronal network of one-day-old mice is characterized by (i) the activation of catecholaminergic cells of the dorsal subcoeruleus nucleus, a structure implicated in the strong depressive pontine influence previously reported in the fetus but not in newborns, (ii) the weak activation of catecholaminergic cells of the ventral reticular nucleus of the medulla, an area involved in hypoxic hyperventilation, and (iii) the absence of PHOX2B-positive cells activated in the retrotrapezoid/parafacial region. Based on these results, one-day-old mice could highlight characteristics for modeling the breathing network of premature infants.

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Section: Discussionmentioning

confidence: 99%

Key Brainstem Structures Activated during Hypoxic Exposure in One-day-old Mice Highlight Characteristics for Modeling Breathing Network in Premature Infants

et al. 2016

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“…; Bairam et al . ). However, in P10 rats continuous exposure to progesterone through the lactating mother increases the HVR and reduces apnoea frequency (Lefter et al .…”

Section: Introductionmentioning

confidence: 97%

Reduced hypoxic ventilatory response in newborn mice knocked‐out for the progesterone receptor

Potvin

Rossignol

Uppari

et al. 2014

Experimental Physiology

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New Findings r What is the central question of this study?Progesterone has been proposed as an alternative to xanthine therapy for the treatment of idiopathic apnoeas in preterm neonates, but our knowledge of the respiratory function of progesterone in neonates is limited. We therefore asked whether endogenous progesterone is an efficient respiratory stimulant in newborn mice. r What is the main finding and its importance?The present study shows that expression of the nuclear progesterone receptor is a key contributor to the hypoxic ventilatory response in newborn mice. This study will encourage further research on the role of other progesterone receptors in respiratory control in newborn mammals.Recent studies showed that progesterone stimulates the hypoxic ventilatory response and may reduce apnoea frequency in newborn rats, but so far we still do not know by what mechanisms and whether endogenous progesterone might contribute to respiratory control in neonates. We therefore determined the role of the nuclear progesterone receptor (PR; member of the steroid receptor superfamily) by using wild-type (WT) and PR knock-out (PRKO) mice at postnatal days (P) 1, 4 and 10. We measured the hypoxic ventilatory response (14 and 12% O 2 , 20 min each) and apnoea frequency in both male and female mice by using whole-body plethysmography. In response to hypoxia, WT male mice had a marked hypoxic ventilatory response at P1 and P10, but not at P4. At P1 and P10, PRKO male mice had a lower hypoxic ventilatory response than WT males. Wild-type female mice had a marked hypoxic ventilatory response at P10, but not at P1 and P4. At P1 and P10, PRKO female mice had a lower hypoxic ventilatory response than WT females. In basal conditions, apnoea frequency was similar in WT and PRKO mice at P1, P4 and P10. During hypoxia, apnoea frequency was higher in WT male mice compared with PRKO male mice and WT female mice at P1. We conclude that PR is a key contributor to the hypoxic ventilatory response in newborn mice, but PR deletion does not increase the frequency of apnoea during normoxia or hypoxia.

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“…In P4 and P12 control rats, progesterone did not affect apnoea frequency, which coincides with previous observations showing that a similar dose of progesterone decreases the frequency of apnoea in P1 rats but not in older animals (Bairam et al . a ). Our results in caffeine‐treated rats also support the well‐known effects of acute and chronic caffeine administration to reduce apnoea frequency in human newborns (Martin & Wilson, ; Porciuncula et al .…”

Section: Discussionmentioning

confidence: 99%

“…Two types of apnoeas were assessed: (1) spontaneous apnoeas, which are defined as an absence of flow for at least two normal respiratory cycles, and (2) post‐sigh apnoeas preceded by a sigh, which are defined as a breath with an amplitude of at least twice the resting tidal volume (Bairam et al . a ). Apnoea duration was reported in seconds.…”

Section: Methodsmentioning

confidence: 99%

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Inhibitory respiratory responses to progesterone and allopregnanolone in newborn rats chronically treated with caffeine

Uppari

Joseph

Bairam

2015

The Journal of Physiology

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Key pointsr In premature newborns, recurrent apnoea is systematically treated with caffeine to prevent long-term neurocognitive disorders, but a substantial percentage of apnoea persists particularly in neonates born before 28 weeks of gestation.r Progesterone has been proposed as a respiratory stimulant potentially suitable for the treatment of newborn apnoea persistent to caffeine. Accordingly we asked whether acute progesterone administration reduces apnoea frequency in newborn rats treated with caffeine.r Surprisingly our results show that in newborn rats treated with caffeine, administration of progesterone inhibits breathing and increases apnoea frequency.r Additional experiments showed an enhanced GABAergic inhibitory drive on breathing after caffeine treatment, and that progesterone is converted to allopregnanolone (an allosteric modulator of GABA A receptors) to inhibit breathing.r We conclude that combining progesterone and chronic caffeine is not an option in preterm neonates, unless the effects of allopregnanolone can be counteracted.Abstract Caffeine is the main treatment for apnoea in preterm neonates, but its interactions with other respiratory stimulants like progesterone are unknown. We tested the hypothesis that the addition of progesterone to caffeine treatments further stimulates ventilation. Newborn rats were treated with water (control) or caffeine (15 mg kg −1 ) by daily gavage between postnatal day (P)3 and P12. At P4 and P12, we measured apnoea frequency, ventilatory responses and metabolic parameters under both normoxia and hypoxia (12% O 2 , 20 min) following an acute administration of either saline or progesterone (4 mg kg −1 ; I.P.). Progesterone injection increased the serum levels of both progesterone and its neuroactive metabolite allopregnanolone. Progesterone had no effect on ventilation in control rats under normoxia. Progesterone depressed ventilation in P12 caffeine-treated rats under normoxia and hypoxia and increased apnoea frequency in both P4 and P12 rats. Because allopregnanolone is an allosteric modulator of GABA A receptors and caffeine may enhance GABAergic inhibition in newborns, we studied the effects of the GABA A receptor antagonist bicuculline at 0, 1, 2 and 3 mg kg −1 doses and allopregnanolone (10 mg kg −1 dose) in P12 rats. In caffeine-treated rats, bicuculline enhanced ventilation, while allopregnanolone decreased ventilation and increased total apnoea time. Progesterone had no effect on ventilation and apnoea frequency in caffeine-treated rats injected with finasteride, which blocks the conversion of progesterone to allopregnanolone. We conclude that combining progesterone and chronic caffeine therapy is not an option for the treatment of persistent apnoea in preterm neonates, unless the effects of allopregnanolone can be counteracted.

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Effect of progesterone on respiratory response to moderate hypoxia and apnea frequency in developing rats

Cited by 15 publications

References 48 publications

Key Brainstem Structures Activated during Hypoxic Exposure in One-day-old Mice Highlight Characteristics for Modeling Breathing Network in Premature Infants

Key Brainstem Structures Activated during Hypoxic Exposure in One-day-old Mice Highlight Characteristics for Modeling Breathing Network in Premature Infants

Reduced hypoxic ventilatory response in newborn mice knocked‐out for the progesterone receptor

Inhibitory respiratory responses to progesterone and allopregnanolone in newborn rats chronically treated with caffeine

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