Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures.

The physiological activity of many proteins can be regulated by S-nitrosylation or reaction of nitric oxide (NO)-related species with cysteine residues to produce S-nitrosoproteins (S-nitrosothiols). However, S-nitrosothiols, such as S-nitrosocysteine (SNOC) and S-nitrosohomocysteine (SNHC), can also be neurotoxic by generating NO which reacts with endogenous O2- to form peroxynitrite. Additionally, thiols such as cysteine and homocysteine can be neurotoxic by acting as N-methyl-D-aspartate (NMDA) agonists. Paradoxically, we show here that millimolar thiol can protect from acute exposure to micromolar SNHC that is normally neurotoxic. This finding can be best explained by the fact that although S-nitrosothiols undergo homolytic cleavage to produce NO and subsequent neurotoxicity, adding thiol stabilizes S-nitrosothiols, effectively preventing this cleavage. Thus, the equilibrium between thiol and nitrosothiol determines outcome in studies of neuronal degeneration.