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.
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.
Kubota
M
M
Department of Patho-functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Iida
Y
Y
Magata
Y
Y
Kitamura
Y
Y
Kawashima
H
H
Saji
H
H
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D018698:Glutamic Acid / Q000502:physiology* / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D007608:Kainic Acid / Q000633:toxicity; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013882:Thiosemicarbazones / Q000494:pharmacology*
C420686:(2,3-butanedione bis(N(4)-dimethylthiosemicarbazone))zinc(II); D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D016194:Receptors, N-Methyl-D-Aspartate; D013882:Thiosemicarbazones; D018698:Glutamic Acid; D016202:N-Methylaspartate; D007608:Kainic Acid; D002118:Calcium