Neuroactive steroids in the developing brain: potential for preventing perinatal brain damage

怀孕期间的并发症、出生窒息或早产可导致新生儿严重的神经功能障碍。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。神经活性类固醇是一组神经调质，来源于激素孕酮。这些类固醇分为两类，一类似乎可以保护脑细胞免受氧气供应不足造成的损伤，另一类可能会增加细胞死亡。我们已经表明，保护性神经活性类固醇是目前在非常大量的胎儿大脑。由胎盘产生的类固醇通过大脑中的酶转化为这些神经活性产物，导致在胎儿生命期间看到的高水平。怀孕期间的某些不利条件以及早产可能会导致类固醇平衡的显着变化，这可能会增加对脑损伤的敏感性。我们发现，最常发生损伤的大脑区域通常含有最高量的保护性类固醇，但仅在怀孕后期。这表明，这些区域类固醇产生减少的干扰可能导致细胞死亡，特别是在怀孕中期和早产后。在拟议的研究中，我们将检查类固醇的毒性平衡是否在妊娠不良事件后发展，以及大脑中最明显的区域。我们将研究可能导致保护性类固醇在大脑中积累的酶表达的变化。然后，我们将研究可以提高类固醇浓度的治疗方法，并确定哪种类固醇组合最能减少怀孕期间并发症后的细胞死亡和脑损伤。这项工作的结果将表明最好的治疗方法，可以采取改变某些类固醇的浓度，以减少胎儿和新生儿脑损伤的风险。

Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown that protective neuroactive steroids are present in very large amounts in the fetal brain. Steroids produced by the placenta are converted to these neuroactive products by enzymes in the brain leading to the high levels that are seen during fetal life. Certain adverse conditions during pregnancy as well as preterm birth may cause marked changes in the balance of steroids that could increase susceptibility to brain injury. We have found that areas of the brain, where damage most often occurs, normally contain the highest amount of protective steroids, but only in late pregnancy. This suggests that disturbances that lower steroid production in these areas could contribute to the death of cells, particularly in mid-pregnancy and after premature birth. In the proposed studies, we will examine whether a toxic balance of steroids develops following adverse events in pregnancy as well as the areas of the brain where this is most pronounced. We will examine the changes in the expression of enzymes that can potentially cause the accumulation of protective steroids in the brain. We will then examine treatments that can raise the concentration of steroids and determine which combination of steroids best reduces cell death and brain injury following complications during pregnancy. The findings of this work will indicate the best therapeutic approach that may be adopted to modify the concentration of certain steroids so as to reduce the risk of brain damage in the fetus and neonate.