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

2009 Fiscal Year Final Research Report

• Project/Area Number: 20790771
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Embryonic/Neonatal medicine
• Research Institution: Osaka City University
• Principal Investigator: FUJIOKA Hiroki Osaka City University, 大学院・医学研究科, 登録医 (70382083)
• Project Period (FY): 2008 – 2009
• Keywords: 低酸素虚血 / ビオプテリン / inducible NOS (iNOS) / GTPCH I / NMDA受容体拮抗剤

Research Abstract

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.

Research Products

• [Journal Article] Plasma Phenylalanine Level in Dopa-Responsive Dystonia (2009)
  • Author(s): H Fujioka, et, al.
  • Journal Title: Movement Disorders 24(15) Pages: 2289-2290
  • Peer Reviewed
• [Presentation] Japan PND study group NATION-WIDE (2010)
  • Author(s): Haruo Shintaku, Masaya Segawa, Hiroki Fujioka
  • Organizer: EPIDEMIOLOGIC STUDY OF PEDIATRIC NEUROLOGIC DISEASE IN JAPAN (THE 1ST REPORT) International Symposium on Epilepsy in Neurometabolic Diseases (ISENMD) & The 13th Annual Meeting of the Infantile Seizure Society (ISS)
  • Place of Presentation: Taipei
  • Year and Date: 20100326-20100328
• [Presentation] T Yamano Usefulness of the plasma neopterin concentration in screening for dopa-responsive dystonia (2009)
  • Author(s): H Fujioka, H Shintaku, S Kudo, T Sakaguchi
  • Organizer: 11th international congress of inborn errors of metabolism
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 20090829-20090902
• [Presentation] Tsunekazu Yamano Lower plasma neopterin concentration in dopa-responsive dystonia patients (2009)
  • Author(s): Hiroki Fujioka, Haruo Shintaku, Masaya Segawa, Satoshi Kudo
  • Organizer: Pteridines and Folates
  • Place of Presentation: Jeju - Korea
  • Year and Date: 20090607-20090612
• [Presentation] 一過性高フェニルアラニン血症を認めた瀬川病の一例 (2009)
  • Author(s): 藤岡弘季、新宅治夫、平林真一、山野恒一
  • Organizer: 第112回日本小児科学会学術集会
  • Place of Presentation: 奈良
  • Year and Date: 20090417-20090419
• [Presentation] NMDA受容体阻害剤が新生児の低酸素虚血に与える生化学的影響-新生仔ブタモデルを用いた検討- (2009)
  • Author(s): 藤岡弘季, 他
  • Organizer: 第54回日本未熟児新生児学会学術集会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2009-12-01
• [Presentation] Plasma and CSF pteridines in Dopa responsive dystonia (2008)
  • Author(s): 藤岡弘季, 他
  • Organizer: 日本小児神経学会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-30