NMDA-DEPENDENT SUPEROXIDE PRODUCTION AND NEUROTOXICITY

NEURONAL injury resulting from acute brain insults and some neurodegen erative diseases implicates N-methyl-D-aspartate (NMDA) glutamate rece ptors1-4. The fact that antioxidants reduce some types of brain damage suggests that oxygen radicals may have a roles5-7. It has been shown that mutations in Cu/Zn-superoxide dismutase (SOD), an enzyme catalysi ng superoxide (O2.-) detoxification in the cell, are linked to a famil ial form of amyotrophic lateral sclerosis (ALS)4. 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+ channel s, 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 effici ent than the nitric oxide synthase inhibitor, L-N(G)-nitroarginine, in reducing NMDA-induced neuronal death in these cultures.