Reduced extracellular zinc levels facilitate glutamate-mediated oligodendrocyte death after trauma

Joshua T. Johnstone, Paul D. Morton, Arumugam R. Jayakumar, Valerie Bracchi-Ricard, Erik Runko, Daniel J. Liebl, Michael D. Norenberg, John R. Bethea

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Spinal cord injury results in irreversible paralysis, axonal injury, widespread oligodendrocyte death, and white matter damage. Although the mechanisms underlying these phenomena are poorly understood, previous studies from our laboratory indicate that inhibiting activation of the nuclear factor-κB transcription factor in astrocytes reduces white matter damage and improves functional recovery following spinal cord injury. In the current study, we demonstrate that activation of the nuclear factor-κB transcription factor within astrocytes results in a significant increase in oligodendrocyte death following trauma by reducing extracellular zinc levels and inducing glutamate excitotoxicity. By using an ionotropic glutamate receptor antagonist (CNQX), we show that astroglial nuclear factor-κB-mediated oligodendrocyte death is dependent on glutamate signaling despite no change in extracellular glutamate concentrations. Further analysis demonstrated a reduction in levels of extracellular zinc in astrocyte cultures with functional nuclear factor-κB signaling following trauma. Cotreatment of oligodendrocytes with glutamate and zinc showed a significant increase in oligodendrocyte toxicity under low-zinc conditions, suggesting that the presence of zinc at specific concentrations can prevent glutamate excitotoxicity. These studies demonstrate a novel role for zinc in regulating oligodendrocyte excitotoxicity and identify new therapeutic targets to prevent oligodendrocyte cell death in central nervous system trauma and disease.

Original languageEnglish (US)
Pages (from-to)828-837
Number of pages10
JournalJournal of Neuroscience Research
Volume91
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Astrocytes
  • Excitotoxicity
  • Glutamate
  • Oligodendrocytes
  • Zinc

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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