Effects of dextromethorphan on glial cell function: Proliferation, maturation, and protection from cytotoxic molecules

Authors

  • Robert P. Lisak,

    1. Department of Neurology, Wayne State University School of Medicine, Detroit, Missouri
    2. Department of Immunology/Microbiology, Wayne State University School of Medicine, Detroit, Missouri
    Search for more papers by this author
  • Liljana Nedelkoska,

    1. Department of Neurology, Wayne State University School of Medicine, Detroit, Missouri
    Search for more papers by this author
  • Joyce A. Benjamins

    Corresponding author
    1. Department of Neurology, Wayne State University School of Medicine, Detroit, Missouri
    2. Department of Immunology/Microbiology, Wayne State University School of Medicine, Detroit, Missouri
    • Address correspondence to Dr. Robert P. Lisak, Department of Neurology, 8D University Health Center, 4201 St. Antoine, Wayne State University School of Medicine, Detroit MI 48201. E-mail: rlisak@med.wayne.edu

    Search for more papers by this author

Abstract

Dextromethorphan (DM), a sigma receptor agonist and NMDA receptor antagonist, protects neurons from glutamate excitotoxicity, hypoxia and ischemia, and inhibits microglial activation, but its effects on differentiation and protection of cells in the oligodendroglial lineage are unknown. It is important to protect oligodendroglia (OL) to prevent demyelination and preserve axons, and to protect oligodendroglial progenitors (OPC) to optimize myelination during development and remyelination following damage. Enriched glial cultures from newborn rat brain were used 1–2 days or 6–8 days after shakeoff for OPC or mature OL. DM had large effects on glial proliferation in less mature cultures in contrast to small variable effects in mature cultures; 1 μM DM stimulated proliferation of OPC by 4-fold, microglia (MG) by 2.5-fold and astroglia (AS) by 2-fold. In agreement with increased OPC proliferation, treatment of OPC with DM for 3 days increased the % of OPC relative to OL, with a smaller difference by 5 days, suggesting that maturation of OPC to OL was “catching up” by 5 days. DM at 2 and 20 μM protected both OL and OPC from killing by glutamate as well as NMDA, AMPA, quinolinic acid, staurosporine, and reactive oxygen species (ROS). DM did not protect against kynurenic acid, and only modestly against NO. These agents and DM were not toxic to AS or MG at the concentrations used. Thus, DM stimulates proliferation of OPC, and protects both OL and OPC against excitotoxic and inflammatory insults. GLIA 2014;62:751–762

Ancillary