NMDA-dependent superoxide production and neurotoxicity

Nature. 1993 Aug 5;364(6437):535-7. doi: 10.1038/364535a0.

Abstract

Neuronal injury resulting from acute brain insults and some neurodegenerative diseases implicates N-methyl-D-aspartate (NMDA) glutamate receptors. The fact that antioxidants reduce some types of brain damage suggests that oxygen radicals may have a role. It has been shown that mutations in Cu/Zn-superoxide dismutase (SOD), an enzyme catalysing superoxide (O2.-) detoxification in the cell, are linked to a familial form of amyotrophic lateral sclerosis (ALS). Here we report that O2.- is produced upon NMDA receptor stimulation in cultured cerebellar granule cells. Electron paramagnetic resonance was used to assess O2.- production that was due in part to the release of arachidonic acid. Activation of kainic acid receptors, or voltage-sensitive Ca2+ channels, did not produce detectable O2.-. We also find that the nitrone DMPO (5,5-dimethyl pyrroline 1-oxide), used as a spin trap, is more efficient than the nitric oxide synthase inhibitor, L-NG-nitro-arginine, in reducing NMDA-induced neuronal death in these cultures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / antagonists & inhibitors
  • Amino Acid Oxidoreductases / metabolism
  • Animals
  • Arachidonic Acid / metabolism
  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Calcium Channels / metabolism
  • Cell Death / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism*
  • Computer Simulation
  • Cyclic N-Oxides / pharmacology
  • Electron Spin Resonance Spectroscopy
  • Mice
  • Nitric Oxide Synthase
  • Nitroarginine
  • Quinacrine / pharmacology
  • Receptors, Glutamate / metabolism
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxides / metabolism*
  • Xanthine
  • Xanthine Oxidase / pharmacology
  • Xanthines / pharmacology

Substances

  • Calcium Channels
  • Cyclic N-Oxides
  • Receptors, Glutamate
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Xanthines
  • Superoxides
  • Xanthine
  • Nitroarginine
  • Arachidonic Acid
  • 5,5-dimethyl-1-pyrroline-1-oxide
  • Arginine
  • Nitric Oxide Synthase
  • Superoxide Dismutase
  • Xanthine Oxidase
  • Amino Acid Oxidoreductases
  • Quinacrine