Zinc toxicity on cultured cortical neurons: involvement of N-methyl-D-aspartate receptors

Neuroscience. 1994 Jun;60(4):1049-57. doi: 10.1016/0306-4522(94)90282-8.


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.

MeSH terms

  • Animals
  • Cell Death
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects*
  • Dose-Response Relationship, Drug
  • Mice / embryology
  • Mice, Inbred Strains
  • N-Methylaspartate / antagonists & inhibitors
  • N-Methylaspartate / pharmacology
  • Nerve Degeneration
  • Neurons / drug effects*
  • Neurons / physiology
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Zinc / toxicity*


  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Zinc