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The study on non-cholinergic toxicity of Nerve agents

Research Project

Project/Area Number 11670408
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Legal medicine
Research InstitutionNagoya City University

Principal Investigator

NAGAO Nasataka  Nagoya City University Medical School, Professor, 医学部, 教授 (80227991)

Co-Investigator(Kenkyū-buntansha) KOYAMA Hiroyoshi  Nagoya City University Medical School, Research Associate, 医学部, 助手 (10170408)
MAENO Yoshitata  Nagoya City University Medical School, Assistant Professor, 医学部, 講師 (00145749)
IWASA Mineo  Nagoya City University Medical School, Associate Professor, 医学部, 助教授 (00021452)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsSarin / Soman / organophosphorous agent / rat / brain / PLCγ / MAPK / JNK / paraoxonase / Soman / organophosphorus agent / astrocyte / MEK / organophosphonous agent / 神経剤 / 非コリン性毒性 / サリン / ソマン / PLCβ / tyrosine kinase
Research Abstract

We report that there is a time-related change in the phospholipase C (PLC) activities of rat brain cytosol and membrane fractions after iv injection of a soman-like or a sarin-like organophosphorous agent (BIMP, bis (isopropyl methyl) phosphonate ; and BPMP, bis (pinacolyl methyl) phosphonate). PLCγ was activated in the brain cytosol fraction from BPMP- injected rats. The phosphorylating activity of rat brain membrane fractions were enhanced by BPMP treatment. The brain membrane fractions from BPMP-treated rats phosphorylated several proteins, including supposedly PLCγ in the brain cytosol fraction from control rats in vitro. These results suggest that soman and sarin may stimulate a membrane tyrosine kinase, including growth factor receptors, directly or indirectly.
BIMP and BPMP were injected intravenously (iv) in rats. An increase in the tyrosine phosphorylation of several proteins in the cytosol fraction of the brain was observed. Activation of c-Jun N-terminal kinase (JNK) and slight activation of mitogen activated protein kinase (MAPK) in the cytosol were also observed. The activation of these enzymes may be related to the high toxicity of these nerve agents.
We reported the polymorphism of the high density lipoprotein-associated enzyme paraoxonase (PON1), in the 10 sarin poisoning victims in the Tokyo subway terrorist attack. Arg_192 PON1, which has tow sarin hydrolysing activity, was found to be more common in the Japanese population than in people of other races. However, from our analyses seven of the victims expressed the phenotype with high sarin hydrolysing activity and three with low sarin hydrolysing activity. These results indicate that the main factor contributing to the tragedy of the Tokyo subway terrorist attack was high toxicity of sarin rather than the race-dependent genetic difference in the Arg_l92 PON1 polymorphism.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] Niijima H, et al.: "Sarin-like and soman-like organophosphoeous angents activate PLCγ in rat brains"Toxical Appl Pharmacol. 156. 64-69 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Niijima H, et al.: "The effect of sarin-like and soman-like organophosphorous agents on MAPK and JNK in rat brains"Forensic Sci Int. 112. 171-178 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamada Y, et al.: "Expression of paraoxonase isform did not confer protection from acute sarin poisoning in Tokyo subway Terrorist attack"Int J Legal Med. 115. 82-84 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Niijima H., Nagao M., Nakajima M. Takatori T., Matsuda Y., et al.: "Sarin-like and soman-like organophosphorous agents activate PLCγ in rat brains"Toxicol Appl Pharmacol. 156(1). 64-69 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Niijima H., Nagao M., Nakajima M., Takatori T. et al.: "The effects of sarin-like and soman-like organophosphorous agents on MAPK and JNK in rat brains"Forensic Sci. Int.. 112(2/3). 171-178 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamada Y., Takatori T., Nagao M. et al.: "Expression of paraoxonase isoform did not confer protection from acute sarin poisoning in the Tokyo subway terrorist attack"Int J Legal Med.. 115(2). 82-84 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Niijima et al.: "The effects of sarin like and soman-like organo phoshporus agents on MAPK and JNK in rat brains."Forensic Sci.Int.. 112(2/3). 171-178 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Niijima,H.,Nagao,M.,Nakajima,M.et al.: "Sarin-like and Soman-like organophosphorus Agents Activate PLCγin Rat Brains"Toxicology and Applied Pharmacology. 156・1. 64-69 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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