NEUROTOXICITY OF ENDOGENOUS CYSTEINYLCATECHOLS

Progression of Parkinson's disease has been associated with several bi ochemical changes in the substantia nigra including increased oxidativ e challenge, catechol oxidation, and inhibition of mitochondrial compl ex I activity. Cysteinylcatechols, formed by nucleophilic addition of cysteine to oxidized catechols, have been identified as markers of cat echol oxidation in brain tissue. We have examined the neurotoxicity of a series of cysteinylcatechols. Of the compounds examined only, 5-S-c ysteinyl-3,4-dihydroxyphenylacetate (cysdopac) was specifically cytoto xic to differentiated P19 neuroglial cultures. Cysdopac also was neuro toxic to pyramidal neurons in organotypic cultures of hippocampus, and this effect was ablated by selective N-methyl-D-aspartate (NMDA) rece ptor antagonists. In vitro, cysdopac was a potent inhibitor of mitocho ndrial complex I activity. However, electrophysiologic experiments fai led to demonstrate NMDA receptor agonist activity for cysdopac, nor di d cysdopac inhibit glutamate uptake. These results showed that cysdopa c was the most potent neurotoxin of this series of cysteinylcatechols and suggest that cysdopac may function as an indirect excitotoxin, pot entially via inhibition of mitochondrial respiration. (C) 1997 Academi c Press.