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.