Neurosteroid mediated protection after birth: approaches for maximising protective steroid levels in the neonatal brain

怀孕期间的并发症、出生窒息或早产可导致新生儿神经功能受损。尽管新生儿得到了很好的护理，但这些婴儿中的许多人仍然有严重的残疾。神经类固醇是一组调节大脑活动的类固醇。这些类固醇通过抑制过度活动引起的毒性来保护脑细胞免受氧气供应不足引起的损伤。我们已经证明，这些保护性类固醇的水平在胎儿大脑中非常高，并且水平在胎儿应激时进一步升高。胎盘提供类固醇前体，帮助维持这些高神经类固醇水平。这种胎盘-胎儿大脑的相互作用包括一种内部机制，可以保护胎儿大脑免受怀孕期间不良事件的影响。然而，在出生时，在胎盘前体供应丧失后，大脑中的神经类固醇浓度急剧下降。在出生时生长受限的动物中，浓度的下降幅度更大。这表明，新生儿，特别是那些从妥协怀孕，是在增加脑损伤的风险，由于低神经类固醇水平。我们认为，某些常用的类固醇疗法也可能降低大脑中的类固醇水平，并导致出生期间或新生儿早期脑损伤的脆弱性增加。或者，我们建议在新生儿中更换神经类固醇前体可能会提高脑神经类固醇水平，并防止脑损伤。在拟议的研究中，我们将评估可以提高类固醇浓度的治疗方法，并确定减少妊娠期间，出生时和新生儿早期并发症后脑损伤的最佳策略。这项工作将确定最佳的治疗方法，以最大限度地提高神经类固醇诱导的脑保护和降低脑损伤的风险。

Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the fetal brain and levels rise further in response to fetal stress. The placenta contributes steroid precursors that help maintain these high neurosteroid levels. This placenta-fetal brain interaction comprises an internal mechanism that protects the fetal brain from adverse events during pregnancy. At birth, however, there is a dramatic decline in neurosteroid concentrations in the brain after the loss of the placental precursor supply. The fall in concentrations is even greater in animals that are born growth restricted. This suggests that newborns, particularly those from compromised pregnancies, are at increased risk of brain damage due to low neurosteroid levels. We believe that certain commonly used steroid therapies may also lower steroid levels in the brain and result in increased vulnerability to brain damage during birth or in the early neonatal period. Alternatively, we propose that replacement of neurosteroid precursors in the newborn may raise brain neurosteroid levels and protect against brain damage. In the proposed studies we will evaluate treatments that can raise the concentration of steroids and determine the best strategy for reducing brain injury following complications during pregnancy, at birth and during the early newborn period. This work will determine the best therapeutic approaches for maximising neurosteroid-induced brain protection and for reducing the risk of brain damage.