Neurotoxicity of endogenous cysteinylcatechols.
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 selective N-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.
Montine
T J
TJ
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Picklo
M J
MJ
Amarnath
V
V
Whetsell
W O
WO
Graham
D G
DG
D000818:Animals; D001923:Brain Chemistry; D018236:Carcinoma, Embryonal / Q000473:pathology; D002396:Catechols / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D003470:Culture Media; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D004298:Dopamine / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D009457:Neuroglia / Q000187:drug effects*; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D017470:Receptors, Glutamate / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D014407:Tumor Cells, Cultured
D002396:Catechols; D003470:Culture Media; D018691:Excitatory Amino Acid Antagonists; D017382:Reactive Oxygen Species; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C109504:cysdopac; D016202:N-Methylaspartate; D016660:NAD(P)H Dehydrogenase (Quinone); D003545:Cysteine; D004298:Dopamine