Chapter 31 Reactions of nitric oxide, superoxide and peroxynitrite with superoxide dismutase in neurodegeneration

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To be successful in any attempt to regenerate the nervous system, the processes responsible for the underlying neurodegeneration must be understood and controlled. This chapter discusses three points. First, nitric oxide is far less reactive and toxic at physiologically relevant concentrations than commonly thought. Many investigators have been mislead by using millimolar solutions of nitric oxide or various relatively uncharacterized nitric oxide donors to study chemical reactivity and then equating the results with the reactivity of nitric oxide per se. The chapter describes how low concentrations of nitric oxide do not react rapidly with oxygen to form nitrogen dioxide. Instead, nitric oxide is more likely to diffuse into red blood cells and be consumed by reaction with hemoglobin. Second, the reactivity and toxicity of nitric oxide is enormously increased by its near diffusion-limited reaction with superoxide to form peroxynitrite anion. From 1 to 5% of all oxygen consumed is partially reduced to produce the oxygen radical, superoxide. Third, paradoxically, peroxynitrite reacts with superoxide dismutase (SOD) to form a powerful nitrating agent with the reactivity of nitronium ion and modifies tyrosine residues on proteins to form nitrotyrosine. Nitrotyrosine cannot be phosphorylated by tyrosine kinases and thus SOD-mediated injury may affect critical signal transduction pathways. The chapter proposes that this mechanism may account for the pathological action of SOD mutations in amyotrophic lateral sclerosis.

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