Potassium Attenuates Zinc-Induced Death of Cultured Cortical Astrocytes

Christian T. Sheline, Toshihiro Takata, Howard Ying, Lorella M.T. Canzoniero, Aizhen Yang, Shan Ping Yu, Dennis W. Choi

Research output: Contribution to journalArticle

Abstract

Transient global ischemia induces CA1 hippocampal neuronal death without astrocyte death, perhaps mediated in part by the toxic translocation of zinc from presynaptic terminals to postsynaptic neurons. We tested the hypothesis that cellular depolarization, which occurs in the ischemic brain due to increased extracellular potassium and energy failure, might contribute to astrocyte resistance to zinc-induced death. We previously reported that neurons in mixed cortical neuronal-astrocyte cultures were more vulnerable to a 5-15-min exposure to Zn2+ than astrocytes in the same cultures. In the present report, we show that (1) neurons in isolation or in conjunction with astrocytes were 2-3-fold more sensitive to a 15-min nondepolarizing Zn 2+ exposure than are glia; (2) KCl-induced depolarization attenuated glial vulnerability to zinc toxicity but potentiated neuronal vulnerability to zinc toxicity; (3) Zn2+-induced glial death was attenuated by T-type Ca2+ channel blockade, as well as compounds that increase NAD + levels; and (4) both astrocytic 65Zn2+ accumulation and the increase in astrocytic [Zn2+]i induced by Zn2+ exposure were also attenuated by depolarization or T-type Ca2+ channel blockers. Zn2+-induced cell death in astrocytes was at least in part apoptotic, as caspase-3 was activated, and the caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone partially attenuated Zn 2+-induced death. The levels of peak [Zn2+]i achieved in astrocytes during this toxic nondepolarizing Zn2+ exposure (250 nM) were substantially greater than those achieved in neurons (40 nM). In glia, exposure to 400 μM Zn2+ induced a 13-mV depolarization, which can activate T-type Ca2+ channels. This Zn 2+-induced astrocyte death, like neuronal death, was attenuated by the addition of pyruvate or niacinamide to the exposure medium.

Original languageEnglish (US)
Pages (from-to)18-27
Number of pages10
JournalGlia
Volume46
Issue number1
DOIs
StatePublished - Apr 1 2004

Keywords

  • Astrocytes
  • Depolarization
  • Intracellular zinc
  • Neurons
  • Zinc accumulation
  • Zinc toxicity

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Sheline, C. T., Takata, T., Ying, H., Canzoniero, L. M. T., Yang, A., Yu, S. P., & Choi, D. W. (2004). Potassium Attenuates Zinc-Induced Death of Cultured Cortical Astrocytes. Glia, 46(1), 18-27. https://doi.org/10.1002/glia.10313