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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.

本研究发现，诱导型一氧化氮合酶（iNOS）在新生儿重度缺氧缺血性脑病模型仔猪12 h后的神经元中表达。被称为iNOS辅助因子的血液生物蝶呤水平也有所升高。NMDA受体拮抗剂MK-801可抑制其升高。而iNOS的表达不受影响。鸟苷三磷酸环水解酶（GTPCH）是生物蝶呤合成途径的限速酶。先前的报道描述了促炎细胞因子上调GTPCH的活性。提示兴奋性神经传递影响促炎细胞因子的合成。另一方面，用谷氨酸类似物kainic酸建立大鼠癫痫持续状态模型，神经元iNOS未见增加。这些结果表明，猪和啮齿动物的信号转导途径不同。人类Segawa病是由GTPCH缺陷引起的。一般来说，生物蚁素缺乏会导致高苯丙氨酸血症。而Segawa病患者血苯丙氨酸浓度在正常范围内，因为GTPCH突变为杂合性。我们比较了Segawa病患者和对照组的血液苯丙氨酸水平。结果表明：血苯丙氨酸水平在正常范围内，但显著高于对照组。