Possible role of salsolinol quinone methide in the decrease of RCSN-3 cell survival.
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.
Martinez-Alvarado
P
P
Programme of Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.
Dagnino-Subiabre
A
A
Paris
I
I
Metodiewa
D
D
Welch
C J
CJ
Olea-Azar
C
C
Caviedes
P
P
Caviedes
R
R
Segura-Aguilar
J
J
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002374:Catalase / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D001728:Dicumarol / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005979:Glutathione Peroxidase / Q000235:genetics; D045563:Indolequinones; D007211:Indoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D045563:Indolequinones; D007211:Indoles; D007546:Isoquinolines; D011809:Quinones; D012333:RNA, Messenger; C068040:quinone methide; D001728:Dicumarol; C036617:salsolinol; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D004298:Dopamine