Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism

J Neuropathol Exp Neurol. 2004 Sep;63(9):964-77. doi: 10.1093/jnen/63.9.964.


Recent studies suggest that motor neuron (MN) death may be non-cell autonomous, with cell injury mediated by interactions involving non-neuronal cells, such as microglia and astrocytes. To help define these interactions, we used primary MN cultures to investigate the effects of microglia activated by lipopolysaccharide or IgG immune complexes from patients with amyotrophic lateral sclerosis. Following activation, microglia induced MN injury, which was prevented by a microglial iNOS inhibitor as well as by catalase or glutathione. Glutamate was also required since inhibition of the MN AMPA/kainate receptor by CNQX prevented the toxic effects of activated microglia. Peroxynitrite and glutamate were synergistic in producing MN injury. Their toxic effects were also blocked by CNQX and prevented by calcium removal from the media. The addition of astrocytes to cocultures of MN and activated microglia prevented MN injury by removing glutamate from the media. The protective effects could be reversed by inhibiting astrocytic glutamate transport with dihydrokainic acid or pretreating astrocytes with H2O2. Astrocytic glutamate uptake was also decreased by activated microglia or by added peroxynitrite. These data suggest that free radicals released from activated microglia may initiate MN injury by increasing the susceptibility of the MN AMPA/kainate receptor to the toxic effects of glutamate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System X-AG / antagonists & inhibitors
  • Amino Acid Transport System X-AG / metabolism
  • Amyotrophic Lateral Sclerosis / immunology
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Astrocytes / metabolism
  • Catalase / metabolism
  • Catalase / pharmacology
  • Cell Communication / physiology
  • Cell Death / physiology
  • Cells, Cultured
  • Coculture Techniques
  • Free Radicals / metabolism
  • Glutamic Acid / metabolism*
  • Glutamic Acid / toxicity
  • Glutathione / metabolism
  • Glutathione / pharmacology
  • Microglia / metabolism*
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Oxidative Stress / physiology*
  • Peroxynitrous Acid / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism
  • Spinal Cord / metabolism
  • Spinal Cord / pathology


  • Amino Acid Transport System X-AG
  • Free Radicals
  • Receptors, AMPA
  • Peroxynitrous Acid
  • Nitric Oxide
  • Glutamic Acid
  • Catalase
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Glutathione