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.
Jpn J Pharmacol
; 84(3): 334-8, 2000 Nov.
Article
en En
| MEDLINE
| ID: mdl-11138735
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Compuestos Organometálicos
/
Tiosemicarbazonas
/
Receptores de N-Metil-D-Aspartato
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Fármacos Neuroprotectores
/
Ácido Glutámico
/
Hipocampo
/
Neuronas
Límite:
Animals
Idioma:
En
Revista:
Jpn J Pharmacol
Año:
2000
Tipo del documento:
Article
País de afiliación:
Japón