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Pharmacological research on Ca^<2+> channel abnormality which induces epileptic seizures

Research Project

Project/Area Number 12470018
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionHIROSHIMA UNIVERSITY

Principal Investigator

SASA Masashi  Hiroshima University, Faculty of Medicine, Professor, 医学部, 教授 (20025654)

Co-Investigator(Kenkyū-buntansha) AMANO Taku  Hiroshima University, Faculty of Medicine, Research Associate, 医学部, 助手 (10294547)
MATSUBAYASHI Hiroaki  Hiroshima University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (60165850)
ISHIHARA Kumatoshi  Hiroshima University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (20212912)
SERIKAWA Tadao  Kyoto University, Faculty of Medicine, Professor, 医学研究科, 教授 (30025655)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥16,900,000 (Direct Cost: ¥16,900,000)
Fiscal Year 2001: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2000: ¥14,300,000 (Direct Cost: ¥14,300,000)
Keywordstremor rat / epileptic seizure / aspartoacetylase gene / N-acetyl aspartate / SER / metabotropic glutamate receptor / Ca^<2+> channel / GABA_A receptor / N-アセチルアスパルテート / パッチクランプ法 / アスパルトアセチレース / 海馬CA3ニューロン / パッチクランプ / ASP遺伝子
Research Abstract

The spontaneously epileptic rat (SER : tm/tm, zi/zi) is obtained by mating a heterozygote of the tremor rat (tm/tm) derived from the Kyoto Wistar colony with the zitter rat (zi/zi) from the SD rat clony. The SER shows both absence-like seizures and tonic convulsion after 8 weeks old. We have previously found that tm and zi genes were located on 10q24 and 3q35, respectively.
Based on our studies of 1999-2001, the following results were obtained. (1) Aspartacetylase gene (ASPA) was delated in the tm gene region, resulting in an increase of L-acetyl-aspartate (NAA) in the tremora rat and SER brain. (2) NAA induced an inward current in hippocampal CA3 neurons of normal wister rats via metabotropic glutamate receptors. (3) Application of ASPA recommbinant in adenovirlus into the lateral venticle of the tremor rat resulted in a reduction of epileptic seizures. These findings suggest that increased NAA resulting from ASPA delation is responsible for epiletic seizures in tremora rats and SER. Furthermore, (4) selectively enhanced CA^<2+> inclux was observed in the hippocampal CA3 neurons of SER with single stimulation of the mossy fibers. (5) Vigabatrin, which is an inhibitor of GABA transaminase, acted on the GABA_A receptors of hippocampal CA3 neurons of SER, but not normal wistar rats, to induce a bicucculline-reversible current. These findings confirm the previous findings that SER hippocampal CA3 neurons have abnormaly acting CA^<2+> channels. Inaddigion, changes in GABA_A receptor such as conformation are suggested to be altered in SER hippocampal CA3 neurons.

Report

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

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Amano, H. et al.: "Enhanced calcium influx in hippocampal CA3 neurons of spontaneously epileptc rats"Epilepsia. 42. 345-350 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Akbar, M. et al.: "Inhibition by L-3,4-dihydroxyphenilalanine of hippocampal CA1 neurons with facilitation of noradrenaline and γ-aminobutyric acid release"Eur. J. Pharmacol.. 414. 197-203 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsubayashi, H. et al.: "Excitation of rat striatal large neurons by dopamine and/or glutamate released from nerve terminals via presynaptic nicotinic receptor(α_4β_2Type) stimulation"Jpn. J. Pharmacol.. 86. 429-436 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Amano, H. et al.: "Enhanced Ca^<2+> influx with mossy fiber stimulation in hippocampal CA3 neurons of spontaneously epileptic rats"Brain Research. 910. 199-203 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hai-Dun, Y. et al.: "Direct action of vigabatrin, a GABA transaminase inhibitor, on GABA_A receptor of acutely dissociated hippocampal neurons in the spontaneously epileptic rat(SER)"Brain Research. (印刷中). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hanaya, R. et al.: "Effects of vigabatrin on epileptiform abnormal discharges in hippocampal CA3 neurons spontaneously epileptic rats(SER)"Epilepsy Research. (印刷中). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Taku Amano: "Enhanced calcium influx in hippocampal CA3 neurons of spontaneously epileptc rats"Epilepsia. 42. 345-350 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Muhammad Akbar: "Inhibition by L-3,4-dihydroxyphenilalanine of hippocampal CA1 neurons with facilitation of noradrenaline and γ-aminobutyric acid release"European Journal of Pharmacology. 414. 197-203 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiroaki Matsubayashi: "Excitation of rat striatal large neurons by dopamine and/or glutamate released from nerve terminals via presynaptic nicotinic receptor (α_4β_2type) stimulation"Japanese Journal of Pharmacology. 86. 429-436 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Taku Amano: "Enhanced Ca^<2+> influx with mossy fiber stimulation in hippocampal CA3 neurons of spontaneously epileptic rats"Brain Research. 910. 199-203 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hai-Dun, Yan: "Direct action of vigabatrin, a GABA transaminase inhibitor, on GABA_A receptor of acutely dissociated hippocampal neurons in the spontaneously epileptic rat (SER)"Brain Research. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ryosuke Hanaya: "Effects of vigabatrin on epileptiform abnormal discharges in hippocampal CA3 neurons spontaneously epileptic rats (SER)"Epilepsy Research. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Amano, H. et al.: "Enhanced calcium influx in hippocampal CA3 neurons of spontaneously epileptc rats"Epilepsia. 42. 345-350 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Akbar, M. et al.: "Inhibition by L-3, 4-dihydroxyphenilalanine of hippocampal CA1 neurons with facilitation of noradrenaline and γ-aminobutyric acid release"Eur.J.Pharmacol.. 414. 197-203 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Matsubayashi, H. et al.: "Excitation of rat striatal large neurons by dopamine and/or glutamate released from nerve terminals via presynaptic nicotinic receptor (α_4β_2Type) stimulation"Jpn.J.Pharmacol.. 86. 429-436 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Amano, T. et al.: "Inhibitory effects of tandospirone, 5-HT_<1A>-antagonist, on medial vestibular nucleus neurons responding to lateral roll tilt stimulation in rats"Brain Research. 910. 195-198 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ishihara, K. et al.: "Potentiation of 5-HT_3 receptor function in the hippocampal CA1 region of rats following repeated electroconvulsive shock treatments"Epilepsia. 42. 345-350 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hanaya, R. et al.: "Effects of vigabatrin on epileptiform abnormal discharges in hippocampal CA3 neuron spontaneously epileptic rats (SER)"Epilepsy Research. (印刷中). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kazuhiro Kitada: "Accumulation of N-acetyl-L-aspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system."Journal of Neurochemistry. 74・2. 2512-2519 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tomohide Akimitsu: "Epileptiuc seizures induced by N-acetyl-L-asparatate in rats : in vivo and in vitro studies."Brain Research. 861・1. 143-150 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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