Mechanisms of [2,3-Butanedione Bis(N^4-Dimethylthiosemicarbazone)] zinc(Zn-ATSM_2)-Induced Protection of Cultured Hippocampal Neurons Against N-Methyl-_D-Aspartate Receptor-Mediated Glutamate Cytotoxicity

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Author(s)

    • KITAMURA Youji
    • Department of Patho-functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University
    • KAWASHIMA Hideaki
    • Department of Patho-functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University
    • SAJI Hideo
    • Department of Patho-functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University

Abstract

Hyperexcitation of glutamatergic neurons may play a key role in ischemia-related neurodegeneration. Recent studies have suggested that the zinc ion (Zn<SUP>2+</SUP>), which is present in the central nervous system, has a modulatory role in glutamatergic neuron activity. Zinc ions block glutamate-induced depolarizing currents and neuronal damage by binding with zinc sites on the NMDA subtypes. Therefore, we examined the usefulness of zinc as a therapeutic agent for the prevention of ischemic neuronal damage in the brain. In our previous study, 2, 3-butanedione bis(N<SUP>4</SUP>-dimethylthiosemicarbazonato) zinc complex (Zn-ATSM<SUB>2</SUB>), with high brain uptake, showed significant neuroprotective effects against cerebral ischemia in rats when administered systemically. In this study, to elucidate the mechanism of the neuroprotective effect of Zn-ATSM<SUB>2</SUB>, we first examined its in vitro protective effects against glutamate-, NMDA- and kainite-induced neurotoxicity in primary cultures of hippocampal neurons. Zn-ATSM<SUB>2</SUB> elicited protective effects against this glutamate- and NMDA-induced neurotoxicity, but did not affect kainite-induced cytotoxicity. In addition, we studied the effects of Zn-ATSM<SUB>2</SUB> on influx of Ca<SUP>2+</SUP>, which undergoes modification subsequent to NMDA activation. Zn-ATSM<SUB>2</SUB> significantly decreased glutamate-induced <SUP>45</SUP>Ca<SUP>2+</SUP> uptake. Thus, Zn-ATSM<SUB>2</SUB> protected against glutamate-induced neurotoxicity and its protective effect was, at least in part, due to the blockage of NMDA receptor-mediated Ca<SUP>2+</SUP> influx.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 84(3), 334-338, 2000-11-01

    The Japanese Pharmacological Society

References:  30

Cited by:  1

Codes

  • NII Article ID (NAID)
    10008186319
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    00215198
  • NDL Article ID
    5586994
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  CJPref  NDL  J-STAGE 
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