A variety of mechanisms have been proposed for NO neurotoxicity, including inhibition of mitochondrial enzymes such as cis-aconitase, inhibition of the mitochondria1 electron transport chain, inhibition of ribonucleotide reductase, DNA damage, mono-adenosine diphosphate (ADP)-ribosylation, and S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase. Excessive stimulation of N-methyl-D-aspartate (NMDA) by glutamate leads to excess production of NO, which is toxic to neurons under a variety of experimental paradigms and pathological conditions. When excessive amounts of NO are formed in response to the actions of the excitatory neurotransmitter, glutamate, acting at NMDA receptors, NO mediates components of neuronal killing NMDA toxicity acting via NO may account for neural damage associated with acquired immunodeficiency syndrome (AIDS) dementia as well as neural damage in cerebral infarction. Strategies aimed at decreasing the formation of NO or identifying targets of NO'S action may have clinical relevance for the development of agents which can prevent or reverse these degenerative disorders.
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