Zinc toxicity on cultured cortical neurons: involvement of N-methyl-D-aspartate receptors.
Neuronal injury induced by the excessive release of endogenous Zn2+ at central glutamatergic synapses may contribute to the pathogenesis of epileptic brain damage. We explored the possibility that N-methyl-D-aspartate receptors might be involved in Zn2+ neurotoxicity. Exposure of murine cortical cell cultures to 300-1000 microM concentrations of Zn2+ for 15 min resulted in widespread neuronal degeneration, accompanied by the release of lactate dehydrogenase to the bathing medium. Both non-competitive and competitive N-methyl-D-aspartate antagonists attenuated this degeneration. However, the participation of N-methyl-D-aspartate receptors in Zn2+ neurotoxicity was atypical. Removal of extracellular Ca2+ attenuated N-methyl-D-aspartate neurotoxicity but potentiated Zn2+ neurotoxicity, whereas increasing extracellular Ca2+ potentiated N-methyl-D-aspartate neurotoxicity but attenuated Zn2+ neurotoxicity. Furthermore, the nature of the antagonism of Zn2+ neurotoxicity induced by N-methyl-D-aspartate antagonists was qualitatively different from that seen with other N-methyl-D-aspartate receptor-mediated events. The block of Zn2+ neurotoxicity induced by the non-competitive N-methyl-D-aspartate antagonist MK-801 was better overcome by increasing Zn2+ concentration than the block induced by the competitive antagonists D-aminophosphonovalerate and CGS-19755. We hypothesize that N-methyl-D-aspartate receptor-gated channels contribute to Zn2+ toxicity by providing a route of Zn2+ influx into neurons. Consistent with this idea, intracellular Zn2+ visualized by the fluorescent Zn2+ chelator, N-(6-methoxy-8-quinolyl)-p-toluenesulfonamide, rose during Zn2+ exposure; this rise was increased by N-methyl-D-aspartate and reduced by either N-methyl-D-aspartate antagonists or high Ca2+.2+ in neuronal cell homeostasis.
Koh
J Y
JY
Department of Neurology, Washington University School of Medicine, St Louis, MO 63110.
Choi
D W
DW
D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D051379:Mice / Q000196:embryology; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015032:Zinc / Q000633:toxicity*
D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D015032:Zinc