Addressing a Folate Imbalance in Fetal Cerebrospinal Fluid Can Decrease the Incidence of Congenital Hydrocephalus
Addressing a Folate Imbalance in Fetal Cerebrospinal Fluid Can Decrease the Incidence of Congenital Hydrocephalus
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DOI：
10.1097/nen.0b013e31819e64a7
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发表时间：
2009-04-01
影响因子：
3.2
通讯作者：
Miyan, Jaleel
中科院分区：
文献类型：
--
作者：
Cains, Sarah;Shepherd, Andrew;Miyan, Jaleel
胎儿发病性脑积水（HQ）影响1：500至1：5000活产婴儿，由脑脊液（CSF）的产生和排出不均衡引起，并与大脑皮质发育异常相关，导致严重的神经功能缺损。我们以前发现，在脑积水的得克萨斯州大鼠，受影响的胎儿CSF诱导神经祖细胞的细胞周期停滞。在这里，我们表明，叶酸代谢的变化在脑脊液中的发育大脑可能是负责这种影响。我们确定了3种叶酸酶在CSF中，并证明低水平的其中之一，10-甲酰四氢叶酸脱氢酶，与HC在脑积水的得克萨斯州大鼠。因此，我们测试了补充特定的叶酸是否会改善发育结果。在每天给予妊娠母鼠四氢叶酸和5-甲酰四氢叶酸的组合后，HC的发生率显著降低，大脑发育改善。相比之下，补充叶酸增加了该模型中先天性HC的发病率。这些结果表明，叶酸代谢在发育中的大脑的复杂性，并表明，叶酸失衡导致HC的脑积水德克萨斯州大鼠胎儿可以治疗母体叶酸补充剂使用特定的叶酸代谢物及其组合。
Fetal-onset hydrocephalus (HQ, which affects between 1:500 and 1:5000 live human births, results from unequal production and drainage of cerebrospinal fluid (CSF) and is associated with abnormal development of the cerebral cortex leading to severe neurological deficits. We previously found that in the hydrocephalic Texas rat, the CSF of affected fetuses induced a cell cycle arrest in neural progenitor cells. Here, we show that alterations in folate metabolism in the CSF of the developing cerebrum are likely responsible for this effect. We identified 3 folate enzymes in the CSF and demonstrate that low levels of one of these, 10-formyltetrahydrofolate dehydrogenase, are associated with HC in the hydrocephalic Texas rat. Therefore, we tested whether supplementation with specific folate species would improve developmental outcome. After daily administration of a combination of tetrahydrofolic and 5-formyltetrahydrofolic acids to pregnant dams, there was a significant reduction in the incidence of HC and improved brain development. By contrast, supplementation with folic acid increased the incidence of congenital HC in this model. These results indicate the complexities of folate metabolism in the developing brain and suggest that folate imbalance leading to HC in the hydrocephalic Texas rat fetuses can be treated with maternal folate supplementation using specific folate metabolites and combinations thereof.