Neurotoxicity of Endogenous Cysteinylcatechols

• Published in: Experimental neurology Vol. 148; no. 1; pp. 26 - 33
• Main Authors: Montine, T.J., Picklo, M.J., Amarnath, V., Whetsell, W.O., Graham, D.G.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.11.1997; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain Chemistry; Carcinoma, Embryonal - pathology; Catechols - metabolism; Catechols - toxicity; Cells, Cultured; Culture Media; Cysteine - analogs & derivatives; Cysteine - metabolism; Cysteine - toxicity; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine - metabolism; Electron Transport - drug effects; Excitatory Amino Acid Antagonists - pharmacology; Hippocampus - drug effects; Magnetic Resonance Spectroscopy; Medical sciences; N-Methylaspartate - antagonists & inhibitors; NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors; Neuroglia - drug effects; Neurology; Oxidation-Reduction; Parkinson Disease - metabolism; Pyramidal Cells - drug effects; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Glutamate - drug effects; Receptors, N-Methyl-D-Aspartate - drug effects; Tumor Cells, Cultured; Cell culture; Nervous system diseases; Pathogenesis; Central nervous system; Parkinson disease; Cytotoxicity; Pyrocatechol; Cerebral disorder; Endogenous; Central nervous system disease; Neurotoxin; Degenerative disease; Oxidation; Hippocampus; Extrapyramidal syndrome
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.1997.6662

Progression of Parkinson's disease has been associated with several biochemical changes in the substantia nigra including increased oxidative challenge, catechol oxidation, and inhibition of mitochondrial complex I activity. Cysteinylcatechols, formed by nucleophilic addition of cysteine to oxidized catechols, have been identified as markers of catechol oxidation in brain tissue. We have examined the neurotoxicity of a series of cysteinylcatechols. Of the compounds examined, only 5-S-cysteinyl-3,4-dihydroxyphenylacetate (cysdopac) was specifically cytotoxic to differentiated P19 neuroglial cultures. Cysdopac also was neurotoxic to pyramidal neurons in organotypic cultures of hippocampus, and this effect was ablated by selectiveN-methyl-d-aspartate (NMDA) receptor antagonists.In vitro,cysdopac was a potent inhibitor of mitochondrial complex I activity. However, electrophysiologic experiments failed to demonstrate NMDA receptor agonist activity for cysdopac, nor did cysdopac inhibit glutamate uptake. These results showed that cysdopac was the most potent neurotoxin of this series of cysteinylcatechols and suggest that cysdopac may function as an indirect excitotoxin, potentially via inhibition of mitochondrial respiration.