dicumarol and quinone-methide

The endogenous dopamine-derived neurotoxin salsolinol was found to decrease survival in the dopaminergic neuronal cell line RCSN-3, derived from adult rat substantia nigra in a concentration-dependent manner (208 microM salsolinol induced a 50% survival decrease). Incubation of RCSN-3 cells with 100 micro;M dicoumarol and salsolinol significantly decreased cell survival by 2.5-fold (P < 0.001), contrasting with a negligible effect on RCHT cells, which exhibited nearly a 5-fold lower nomifensine-insensitive dopamine uptake. The levels of catalase and glutathione peroxidase mRNA were decreased when RCSN-3 cells were treated with 100 microM salsolinol alone or in the presence of 100 microM dicoumarol. In vitro oxidation of salsolinol to o-quinone catalyzed by lactoperoxidase gave the quinone methide and 1,2-dihydro-1-methyl-6,7-isoquinoline diol as final products of salsolinol oxidation as determined by NMR analysis. Evidence of the formation of salsolinol o-semiquinone radical has been provided by ESR studies during one-electron oxidation of salsolinol catalyzed by lactoperoxidase.

Topics: Animals; Biological Transport; Catalase; Cell Line; Cell Survival; Dicumarol; Dopamine; Electron Spin Resonance Spectroscopy; Gene Expression Regulation, Enzymologic; Glutathione Peroxidase; Indolequinones; Indoles; Isoquinolines; Neurons; Quinones; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Substantia Nigra; Superoxide Dismutase; Transcription, Genetic