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Molecular Mechanisms of Neuronal Death : Effects of Excitatory Amino Acids

Research Project

Project/Area Number 01571261
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field 応用薬理学・医療系薬学
Research InstitutionThe Tokyo Metropolitan Institute of Medical Science

Principal Investigator

SHINOZAKI Haruhiko  The Tokyo Metropolitan Institute of Medical Science, Pharmacology, Researcher, 薬理, 研究員 (20109945)

Co-Investigator(Kenkyū-buntansha) ISHIDA Michiko  The Tokyo Metropolitan Institute of Medical Science, Pharmacology, Researcher, 東京都臨床医学総合研究所・薬理, 研究員 (90124437)
Project Period (FY) 1989 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1990: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1989: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsGlutamate / Metabotropic receptors / Presynaptic inhibition / Monosynaptic reflex / Conformation / Stereochemistry / Neuron damage / 興奮性アミノ酸 / アクロメリン酸 / カイニン酸 / 神経細胞死 / 脊髄 / 海馬
Research Abstract

Pharmacological properties of 2-(carboxycyclopropyl) glycine (CCG) were examined. The 2S, 3S, 4S isomer of CCG (L-CCG-I) caused a depolarization of newborn rat spinal motoneurons which was insensitive to selective NMDA antagonists and CNQX, suggesting that L-CCG-I may be a novel-type glutamate agonist. The amplitude of the depolarization induced by L-CCG-I decreased when the temperature of bathing fluid was reduced, in spite of the fact that that of known excitatory amino acids was increased or unchanged. L-CCG-I increased the inositophosphtide hydrolysis in the rat hippocampal neuron, and caused oscillatory chloride responses in Xenopus oocytes injected with rat brain mRNA. Therefore, it is concluded that L-CCG-I is a potent metabotropic glutamate agonist. The depolarization induced by L-CCG-I was more marked than that by trans-ACPD. The physiological function of metabotropic glutamate receptors have not yet well documented. L-CCG-I would be expected to be a useful tool for elucidation of the physiological function of these receptors. Our preliminary examination demonstrated that L-CCG-I preferred to reduce the monosynaptic reflex in the newborn rat spinal cord, probably because of presynaptic inhibition. Therefore, it is reasonable to presume that L-CCG-I does not cause neuron damage in the mammalian central nervous system, unlike other excitatory amino acids.
A kainate derivative, 4-methoxyphenyl-2-carboxy-3-pyrroridineacetic acid (MFPA), was synthesized and its pharmacological properties were examined. MFPA was more potent than acromelic acid in causing a depolarization of newborn rat spinal motoneurons. Systemic administration of MFPA to the rat induced characteristic behavioral change which composed of the extension of the hindlimbs and limbic seizures, and binding studies of kainate derivatives including MFPA suggested that there are two kinds of kainate receptors.

Report

(3 results)
  • 1990 Annual Research Report   Final Research Report Summary
  • 1989 Annual Research Report
  • Research Products

    (53 results)

All Other

All Publications (53 results)

  • [Publications] 篠崎 温彦: "新しいグルタミン酸アゴニスト" 神経精神薬理. 11. 199-213 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.,Shimamoto,K.and Ohfune,Y.: "A conformationally restricted analogue of Lーglutamate,the(2S,3R,4S)isomer of Lーαー(carboxycyclopropyl)glycine,activates the NMDAーtype receptor more markedly than NMDA in the isolated rat Spinal cord." Brain Research. 480. 255-359 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.and Gotoh,Y.:"Depression of decerebrate rigidity in the rat by antagonists of excitatory amino acids." Neuropharmacol.28. 593-598 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yanagida,M.,Hashimoto,K.,Ishida,M.,Shinozaki,H.and Shirahama,H.: "Syntheses of acyclic analogues of kainoids and neuroexcitatory activity." Tetrahedron Lett.30. 3799-3802 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 篠崎 温彦: "新しいグルタミン酸アゴニスト:神経細胞破壊の機序を探るツ-ル" 実験医学. 7(16). 99-103 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.,Gotoh,Y.and Kwak,S.: "Specific lesions of rat spinal interneurons induced by systemic administration of acromelic acid,a new potent kainate analogue." Brain Research. 503. 330-333 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.,Shimamoto,K.and Ohfune,Y.: "Potent NMDAーlike actions and marked potentiation of glutamate responses of conformational variants of a glutamate analogue in the rat spinal cord." Brit.J.Pharmacol.98. 1213-1224 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 篠崎 温彦: "GABA、グリシン、グルタミン酸レセプタ-" Clinical Neurosci.8. 30-31 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.,and Gotoh: "Selective NーmetylーDーaspartate(NMDA)antagonists increase gastric motility in the rat." Neuroscience Lett.113. 56-61 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Nakagawa,Y.,saitoh,K.,Ishihara,T.,Ishida,M.and Shinozaki,H.: "(2S,3S,4S)ーαー(Carboxycyclopropyl)glycine is a novel agonist of metabotropic glutamate receptors." Europ.J.Pharmacol.184. 205-206 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 篠崎 温彦: "興奮性アミノ酸と神経細胞死" Brain Med.2. 26-69 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 篠崎 温彦: "グルタミン酸と農薬" 日本農薬学会誌. 15. 605-611 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 篠崎 温彦: "グルタミン酸レセプタ-のサブタイプ" Clin.Neurosci.9. 108-108 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 篠崎 温彦: "興奮性アミノ酸研究の最近の動向" 神経精神薬理. 13. 31-34 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Gotoh,Y.,Ishida,M.and shinozaki,H.: "Amino Acids:Chemistry,Biology and Medicine" ESCOM, 1195 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.,Gotoh,Y.and Kwak,S.: "Amino Acids:chemistry,Biology and Medicine" ESCOM, 1195 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Ishida,M.,Shinozaki,H.: "Amino Acids:Chemistry,Biology and Medicine" ESCOM, 1195 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kwak,S.,Aizawa,H.,Ishida,M.,Gotoh,Y.and Shinozaki,H.: "Amino Acids:Chemistry,Biology and Medicine" ESCOM, 1195 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 篠崎 温彦: "脳のレセプタ-と運動" 平凡社, (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 篠崎 温彦: "続医薬品の開発、第32巻「海洋資源と医薬品」" 広川書店,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.,Gotoh,Y.and Kwak,S.: "Maturation Phenomenon in Cerebral Ischemia" SpringerーVerlag,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.and Kudo,Y.: "NMDA Related agent" NPP Books,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 篠崎 温彦、石田 美知子: "生物薬科学実験講座全38巻「臓器および細胞機能測定法」" 広川書店,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.,Kwak,S.and Nakajima,T.: "Methods in Neuroscience" Academic Press,New York,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki, H., Ishida, M., Shimamoto, K. and Ohfune, Y.: "A conformationally restricted analogue of L-glutamate, the (2S, 3R, 4S) isomer of L-alpha- (carboxycyclopropyl) glycine, activates the NMDA-type receptor more markedly than NMDA in the isolated rat spinal cord." Brain Research. 480. 255-359 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki, H., Ishida, M. and Gotoh, Y.: "Depression of decerebrate rigidity in the rat by antagonists of excitatory amino acids." Neuropharmacol.28. 593-598 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yanagida, M., Hashimoto, K., Ishida, M., Shinozaki, H. and Shirahama, H.: "Syntheses of acyclic analogues of kainoids and neuroexcitatory activity." Tetrahedron Lett.30. 3799-3802 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki, H., Ishida, M., Gotoh, Y. and Kwak, S.: "Specific lesions of rat spinal interneurons induced by systemic administration of acromelic acid, a new potent kainate analogue." Brain Research. 503. 330-333 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki, H., Ishida, M., Shimamoto, K. and Ohfune, Y.: "Potent NMDA-like actions and marked potentiation of glutamate responses of conformational variants of a glutamate analogue in the rat spinal cord." Brit. J. Pharmacol.98. 1213-1224 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki, H., Ishida, M., and Gotoh, Y.: "Selective N-metyl-D-aspartate (NMDA) antagonists increase gastric motility in the rat." Neuroscience Lett.113. 56-61 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Nakagawa, Y., saitoh, K., Ishihara, T., Ishida, M. and Shinozaki, H.: "(2S, 3S, 4S) -alpha- (Carboxycyclopropyl) glycine is a novel agonist of metabotropic glutamate receptors." Europ. J. Pharmacol.184. 205-206 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shinozaki,H.,Ishida,M.,and Gotoh: "Selective NーmetylーDーaspartate (NMDA) antagonists increase gastric motility in the rat." Neuroscience Lett.113. 56-61 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nakagawa,Y.,saitoh,K.,Ishihara,T.,Ishida,M.and Shinozaki,H.: "(2S,3S,4S)ーαー(Carboxycyclopropyl)glycine is a novel agonist of metabotropic glutamate receptors." Europ.J.Pharmacol.184. 205-206 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 篠崎 温彦: "興奮性アミノ酸と神経細胞死" Brain Med.2. 26-69 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 篠崎 温彦: "グルタミン酸と農薬" 日本農薬学会誌. 15. 605-611 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 篠崎 温彦: "グルタミン酸レセプタ-のサブタイプ" Clin.Neurosci.9. 108-108 (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 篠崎 温彦: "興奮性アミノ酸研究の最近の動向" 神経精神薬理. 13. 31-34 (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] Gotoh,Y.,Ishida,M.and shinozaki,H.: "Amino Acids:Chemistry,Biology and Medicine" ESCOM, 1195 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Shinozaki,H.,Ishida,M.,Gotoh,Y.and Kwak,S.: "Amino Acids:Chemistry,Biology and Medicine" ESCOM, 1195 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Ishida,M.,Shinozaki,H.: "Amino Acids:Chemistry,Biology and Medicine" ESCOM, 1195 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Kwak,S.,Aizawa,H.,Ishida,M.,Gotoh,Y.and Shinozaki,H.: "Amino Acids:Chemistry,Biology and Medicine" ESCOM, 1195 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 篠崎 温彦: "脳のレセプタ-と運動" 平凡社, (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 篠崎 温彦: "続医薬品の開発、第32巻「海洋資源と医薬品」" 広川書店,

    • Related Report
      1990 Annual Research Report
  • [Publications] Shinozaki,H.,Ishida,M.,Gotoh,Y.and Kwak,S.: "Maturation Phenomenon in Cerebral Ischemia" SpringerーVerlag,

    • Related Report
      1990 Annual Research Report
  • [Publications] Shinozaki,H.,Ishida,M.and Kudo,Y.: "NMDA Related agent" NPP Books,

    • Related Report
      1990 Annual Research Report
  • [Publications] 篠崎 温彦、石田 美知子: "生物薬科学実験講座全38巻「臓器および細胞機能測定法」" 広川書店,

    • Related Report
      1990 Annual Research Report
  • [Publications] Shinozaki,H.,Ishida,M.,Kwak,S.and Nakajima,T.: "Methods in Neuroscience" Academic Press,New York,

    • Related Report
      1990 Annual Research Report
  • [Publications] Shinozaki,H: "A conformationally restricted analogue of Lーglutamate,the(2S,3R,4S)isomer of Lーαー(carboxycyclopropyl)glycine,activates the NMDA type receptor more markedly than NMDA in the isolated rat spinal cord." Brain Research. 480. 355-359 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Shinozaki,H: "Depression of decerebrate rigidity in the rat by antagonists of excitatory amino acids." Neuropharmacology. 28. 593-598 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Shinozaki,H: "Specific lesions of rat spinal interneurons induced by systemic administration of acromelic acid,a new potent kainate analogue." Brain Research. 503. 330-333 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Shinozaki,H: "Potent NMDAーlike actions and marked potentiation of glutamte responses of conformational variants of a glutamate analogue in the rat spinal cord." British Journal of Pharmacology. 98. 1213-1224 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 篠崎温彦: "新しいグルタミン酸アゴニスト:神経細胞破壊の機序を探るツ-ル" 実験医学. 7. 99-103 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Shinozaki,H: "Amino Acids:Chemistry,Biology and Medicine" ESCOM, 700 (1990)

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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