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NMDA-dependent superoxide production and neurotoxicity
M Lafon-Cazal1, S Pietri, M Culcasi
1Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Montpellier, France.
Nature
|August 5, 1993
Summary
Superoxide (O2.-) is produced when N-methyl-D-aspartate (NMDA) receptors are stimulated, contributing to neuronal death. Antioxidant spin traps are more effective than nitric oxide synthase inhibitors in preventing this NMDA-induced damage.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Neuronal injury is linked to N-methyl-D-aspartate (NMDA) glutamate receptors.
- Antioxidants suggest a role for oxygen radicals in brain damage.
- Mutations in Cu/Zn-superoxide dismutase (SOD) are associated with familial amyotrophic lateral sclerosis (ALS).
Purpose of the Study:
- To investigate the production of superoxide (O2.-) upon NMDA receptor stimulation.
- To determine the role of superoxide in NMDA-induced neuronal death.
- To compare the efficacy of spin traps and nitric oxide synthase inhibitors in neuroprotection.
Main Methods:
- Cultured cerebellar granule cells were used.
- Electron paramagnetic resonance assessed superoxide production.
- Neuronal death was measured following NMDA receptor stimulation.
Main Results:
- Superoxide (O2.-) was produced upon NMDA receptor stimulation, partly due to arachidonic acid release.
- Activation of kainic acid receptors or voltage-sensitive Ca2+ channels did not produce detectable O2.-.
- The spin trap DMPO (5,5-dimethyl pyrroline 1-oxide) was more effective than L-NG-nitro-arginine in reducing NMDA-induced neuronal death.
Conclusions:
- NMDA receptor stimulation generates superoxide (O2.-) in cerebellar granule cells.
- Superoxide contributes to NMDA-induced neuronal injury.
- Antioxidant spin traps offer a promising neuroprotective strategy against NMDA receptor-mediated excitotoxicity.