Investigation of mechanism of developing neonatal hypoxic ischemic encephalopathy establishment of novel therapy.

新生儿缺氧缺血性脑病发病机制探讨，建立新疗法。

基本信息

批准号：
20790771
负责人：
FUJIOKA Hiroki
金额：
$ 2.66万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2009
项目状态：
已结题

项目摘要

In this study, we found the expression of inducible nitric oxide synthase (iNOS) in neurons of severe neonatal hypoxic ischemic encephalopathy model piglets after 12 hours. Level of blood biopterin, known as a co-factor of iNOS, was also increased. The increase was inhibited by MK-801, one of NMDA receptor antagonist. However, expression of iNOS was not affected. Guanosine triphosphate cyclohydrolase I (GTPCH) is the rate-limiting enzyme of biopterin synthesis pathway. Previous reports described that proinflammatory cytokines up-regulated the activity of GTPCH. It was suggested that excitatory neurotransmission affected the synthesis of proinflammatory cytokines. On the other hand, rat model of status epilepticus by using kainic acid, an analogue of glutamate, indicated no increase of iNOS in neuron. Those results suggested that the pathways of signal transductions were different between swine and rodents.Human Segawa Disease was caused by the defect of GTPCH. Generally, biopterin shortage causes hyperphenylalaninemia. However blood phenylalanine concentration of Segawa disease patients was within normal range, for the mutations of GTPCH in Segawa disease were heterozygous. We compared blood phenylalanine levels between patients of Segawa disease and controls. The result was that the blood phenylalanine level in Segawa disease was within normal range however the values were significantly higher than those of controls.

在这项研究中，我们在12小时后发现了严重的新生儿缺血性缺血性脑病模型小猪的神经元中诱导型一氧化氮合酶（INOS）的表达。血液生物蛋白的水平也被称为iNOS的共同因素。 NMDA受体拮抗剂之一MK-801抑制了增加。但是，iNOS的表达不受影响。三磷酸鸟苷环氢酶I（GTPCH）是生物蛋白质合成途径的速率限制酶。先前的报告描述了促炎性细胞因子上调了GTPCH的活性。有人提出兴奋性神经传递影响促炎细胞因子的合成。另一方面，通过使用谷氨酸的类似物的Kainic Acid使用Kainic Acud，表明神经元中的iNOS没有增加。这些结果表明，猪和啮齿动物之间的信号转导途径不同。人类segawa疾病是由GTPCH的缺陷引起的。通常，生物蛋白短缺会引起高苯基丙氨酸血症。然而，塞加瓦病患者的血液苯丙氨酸浓度在正常范围内，塞加瓦疾病中GTPCH的突变是杂合的。我们比较了塞加瓦疾病患者和对照组之间的血液苯丙氨酸水平。结果是，塞加瓦疾病中的血苯丙氨酸水平在正常范围内，但是该值明显高于对照组。