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

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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.