| Project/Area Number |
05557113
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
医薬分子機能学
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| Research Institution | The Tokyo Metropolitan Institute of Medical Science |
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Principal Investigator |
SHINOZAKI Haruhiko The Tokyo Metropolitan Institute of Medical Science, Department of Pharmacology, Department Director, 薬理研究部門, 研究員 (20109945)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIDA Michiko The Tokyo Metropolitan Institute of Medical Science, Department of Pharmacology,, 薬理研究部門, 研究員 (90124437)
KWAK Sin Tokyo University, Department of Neurology, Lecturer, 医学部・神経内科, 講師 (40160981)
OHFUNE Yasufumi Suntory Research Institute for Bioorganic Chemistry, Chief, 生物有機科学研究所, 研究員 (20142078)
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| Project Period (FY) |
1993 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥11,200,000 (Direct Cost: ¥11,200,000)
Fiscal Year 1994: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 1993: ¥6,000,000 (Direct Cost: ¥6,000,000)
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| Keywords | Metabotropic glutamate receptors / Neuron damage / Limbic motor seizures / Neuroprotective action / CNS depressant / 海馬 / 辺緑系けいれん |
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| Research Abstract |
Potent agonist for metabotropic glutamate receptors, such as L-CCG-I,DCG-IV,cis-MCG-I and trans-MCG-I were found in the present study. All of them are derivatives of 2- (carboxycyclopropyl) glycine (CCG), which provided useful information about relationship between activation of glutamate receptors and conformation of agonists. Their conformation of glutamate skeleton is an extended form, and they reduced monosynaptic excitation in the isolated newborn rat spinal cord, by inhibiting transmitter release from nerve terminal. These four agonists for metabotropic glutamate receptors inhibited forskolin-stimulated cyclic AMP content in a dose dependent manner, and they demonstrated potent CNS depressant actions in the rat. Among them DCG-IV was the most potent. Pharmacological actions of our newly developed agonists for metabotropic glutamate receptors were clarified with special reference to kainate excitotoxicity. Intraventricular DCG-I・V caused selective neuron damage at relatively high doses in the cingulate cortex and the hippocampal subiculum in the rat, but other agonists did not cause neuron damage in the rat.DCG-IV considerably alleviated the kainate-induced limbic seizures. At relatively low doses, DCG-IV protected some kinds of neurons in the hippocampal CA3 and the amygdala against kainate neurotoxicity, when intraventricularly injected to the rat. These new agonists would provide useful probe for elucidating the mechanism underlying neuron damage induced by excitatory amino acids.
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