Reduced Extracellular Zinc Levels Facilitate Glutamate-Mediated Oligodendrocyte Death after Trauma

摘要

Spinal cord injury results in irreversible paralysis, axonal injury, widespread oligodendrocyte death and white matter damage. While the mechanisms underlying this phenomenon are poorly understood, previous studies from our laboratory indicate 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. Using an ionotropic glutamate receptor antagonist (CNQX), we show astroglial nuclear factor-κB-mediated oligodendrocyte death is dependent upon 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. Co-treatment of oligodendrocytes with glutamate and zinc showed a significant increase in oligodendrocyte toxicity in low zinc conditions, suggesting 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.