Jpn. J. Pharmacol. 84 (3), 334-338 (2000)

Mechanisms of [2,3-Butanedione Bis(N4-Dimethylthiosemicarbazone)]zinc (Zn-ATSM2)-Induced Protection of Cultured Hippocampal Neurons Against N-Methyl-D-Aspartate Receptor-Mediated Glutamate Cytotoxicity

Megumi Kubota1, Yasuhiko Iida2, Yasuhiro Magata1, Youji Kitamura1, Hideaki Kawashima1 and Hideo Saji1,*

1Department of Patho-functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
2Department of Radioisotope Laboratory, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
*Corresponding author.╩╩FAX: +81-75-753-4568

Abstract: Hyperexcitation of glutamatergic neurons may play a key role in ischemia-related neurodegeneration. Recent studies have suggested that the zinc ion (Zn2+), 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(N4-dimethylthiosemicarbazonato) zinc complex (Zn-ATSM2), 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-ATSM2, we first examined its in vitro protective effects against glutamate-, NMDA- and kainite-induced neurotoxicity in primary cultures of hippocampal neurons. Zn-ATSM2 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-ATSM2 on influx of Ca2+, which undergoes modification subsequent to NMDA activation. Zn-ATSM2 significantly decreased glutamate-induced 45Ca2+ uptake. Thus, Zn-ATSM2 protected against glutamate-induced neurotoxicity and its protective effect was, at least in part, due to the blockage of NMDA receptor-mediated Ca2+ influx.

Keywords: Zinc, N-Methyl-D-aspartate receptor, Neuroprotection, Hippocampal cell culture, Glutamate

Copyrightę The Japanese Pharmacological Society 2000

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