Role of kynurenine metabolites in causing and preventing excitotoxic brain damage in the fetus.

一些婴儿在出生时就会出现脑损伤，最近的流行病学和临床研究强烈表明，这种损伤要么发生在怀孕期间的某个时间，要么胎儿的大脑特别容易受到分娩和分娩期间出现的压力的影响。在这个项目中，我们提出，子宫内的缺氧（低氧）条件，无论是单独的还是与母体感染释放的物质结合，都会导致神经毒性物质-喹啉酸-在胎儿大脑和循环中积累。喹啉酸产生的增加是因为某些细胞对低氧和感染条件做出反应——这些细胞包括大脑中的一种细胞——小胶质细胞。目前对发育中的大脑中的小胶质细胞知之甚少。因此，我们将研究缺氧和感染对胎羊的影响，并确定这些条件如何影响胎儿大脑中的小胶质细胞和喹啉酸的合成。大脑产生喹啉酸的能力与饮食中必需氨基酸色氨酸的摄入量密切相关，当注入合成的色氨酸类似物时，大脑产生喹啉酸的能力下降。因此，我们设计了一种治疗方案，使用这些色氨酸类似物来防止胎儿大脑中喹诺啉酸浓度的增加，我们建议一种简单的治疗方法可以减少人类怀孕期间围产期脑损伤的发生率。

Brain damage is present in some babies at birth, and recent epidemiological and clinical studies strongly suggest that this either occurs some time during the pregnancy, or the conditions are such that the fetal brain is particularly vulnerable to the stresses that are present during labor and birth. In this project we propose that hypoxic (low oxygen) conditions in the womb, either alone or in combination with substances released because of maternal infection, cause accumulation of a neurotoxic substance - QUINOLINIC ACID - in the fetal brain and circulation. The increased production of QUINOLINIC ACID occurs because certain cells react to the low oxygen and infectious conditions - these cells include MICROGLIA, a cell type in the brain. Little is currently known about MICROGLIA in the developing brain. We will therefore study the effects of hypoxia and infection in fetal sheep, and we will determine how these conditions affect MICROGLIA and the synthesis of QUINOLINIC ACID in the fetal brain. The capacity of the brain to produce QUINOLINIC ACID is closely related to the dietary intake of the essential amino acid TRYPTOPHAN, and it is decreased when synthetic analogues of tryptophan are infused. Therefore, we have devised a treatment regime using these tryptophan analogues to prevent increases of QUINOLINIC ACID concnetrations in the fetal brain, and we propose that a simple treament is at hand to reduce the incidence of perinatal brain damage in human pregnancies.