Inhibitory respiratory responses to progesterone and allopregnanolone in newborn rats chronically treated with caffeine
Bibliographic record
Abstract
KEY POINTS: 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. 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. Surprisingly our results show that in newborn rats treated with caffeine, administration of progesterone inhibits breathing and increases apnoea frequency. Additional experiments showed an enhanced GABAergic inhibitory drive on breathing after caffeine treatment, and that progesterone is converted to allopregnanolone (an allosteric modulator of GABAA receptors) to inhibit breathing. 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% O2, 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 GABAA receptors and caffeine may enhance GABAergic inhibition in newborns, we studied the effects of the GABAA 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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".