Centre de recherche de l'institut de cardiologie et de pneumologie de Québec, Département de Pédiatrie, Faculté de médicine, Université Laval, Québec, Québec, Canada.
Centre de recherche de l'institut de cardiologie et de pneumologie de Québec, Département de Pédiatrie, Faculté de médicine, Université Laval, Québec, Québec, Canada.
Respir Physiol Neurobiol. 2019 May;263:55-61. doi: 10.1016/j.resp.2019.03.004. Epub 2019 Mar 14.
The steroid hormone progesterone is well-known for its role in neuroprotection, in the pre- and postnatal brain development, and is also recognized as a potent respiratory stimulant that reduces the frequency of sleep apnea in adult female subjects. Over the past few years, we have used newborn rats or mice to provide convincing evidence that the respiratory effect of progesterone involves a balance between excitation mediated by progesterone receptors, and an inhibition due to the fast conversion of progesterone to allopregnanolone, a positive allosteric modulator of GABA receptors. This review focuses on the sex- and age- specific roles of nuclear and membrane progesterone receptors (nPR or mPR), and highlight the clinical potential of these receptors for the treatment of apnea of prematurity. We present original data showing that in newborn rats, selective nPR or mPR agonists are more efficient to reduce apnea frequency at postnatal days 12 than at postnatal day 1, and appear more efficient in males than in females. Furthermore, new results obtained by using intra-cisternal injection of specific siRNA targeting mPRα, mPRβ (two mPR with high brain expression) or nPR suggest that mPRβ regulates the stability of the breathing pattern in males, while effects of nPR appear in females. While several important questions remain to be addressed before a safe clinical use could be proposed, these results highlight the potential role of these drugs as complementary, and sex-specific tools for the treatment of apnea in preterm neonates.
甾体激素孕酮以其在神经保护、产前和产后大脑发育中的作用而闻名，也被认为是一种有效的呼吸兴奋剂，可降低成年女性睡眠呼吸暂停的频率。在过去的几年中，我们使用新生大鼠或小鼠提供了令人信服的证据，表明孕酮的呼吸作用涉及到孕酮受体介导的兴奋与孕酮快速转化为正变构调节剂 allo 孕烷醇酮（GABA 受体的正变构调节剂）之间的平衡。这篇综述重点介绍了核和膜孕酮受体（nPR 或 mPR）的性别和年龄特异性作用，并强调了这些受体在治疗早产儿呼吸暂停方面的临床潜力。我们提供了原始数据，表明在新生大鼠中，选择性 nPR 或 mPR 激动剂在出生后第 12 天比在第 1 天更有效地减少呼吸暂停的频率，并且在雄性中比在雌性中更有效。此外，使用针对 mPRα、mPRβ（两个在大脑中高表达的 mPR）或 nPR 的特异性 siRNA 进行的脑室内注射的新结果表明，mPRβ调节雄性呼吸模式的稳定性，而 nPR 的作用则出现在雌性中。在提出安全的临床应用之前，仍有几个重要的问题需要解决，但这些结果强调了这些药物作为早产儿呼吸暂停的补充治疗工具，具有潜在的性别特异性作用。
