Redox modulation of NMDA receptor-mediated toxicity in mammalian central neurons.
Acute neurological injury from hypoxia-ischemia, hypoglycemia, and trauma is thought to be predominantly mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the brain and the subsequent influx of calcium ions through receptor-operated channels. Several chronic degenerative diseases, such as Huntington's disease and the amyotrophic lateral sclerosis-Parkinsonism-dementia complex found on Guam, may share a similar pathogenesis due to a glutamate-like toxin. This laboratory recently reported that exposure to a reducing agent, such as dithiothreitol (DTT), selectively increases ionic current flow through NMDA-activated channels in several types of central neurons; conversely, oxidizing agents reverse this effect. To investigate the novel influence of redox modulation on NMDA neurotoxicity, in the present in vitro study we monitored survival of an identified central neuron, the retinal ganglion cell, approximately 24 h after a brief exposure to DTT. To determine the degree of killing specifically related to activation of the NMDA receptor, 2-amino-5-phosphonovalerate (APV, a selective NMDA antagonist) was added to sibling cultures. APV-preventable, glutamate-induced death was increased 70 +/- 9% with DTT treatment. This effect was totally blocked by the concomitant addition of an oxidizing agent, 5,5-dithiobis-2-nitrobenzoic acid (DTNB). These findings suggest that the enhanced killing following chemical reduction with DTT is mediated at the NMDA receptor site, and that the redox state of the NMDA receptor is crucial for the survival of neurons facing glutamate-related injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Levy
D I
DI
Department of Neurology, Children's Hospital, Boston, MA 02115.
Sucher
N J
NJ
Lipton
S A
SA
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004229:Dithiothreitol / Q000633:toxicity*; D010084:Oxidation-Reduction; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*; D012160:Retina / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D015763:2-Amino-5-phosphonovalerate; D004228:Dithionitrobenzoic Acid; D004229:Dithiothreitol