Differential cytotoxicities of N-methyl-beta-carbolinium analogues of MPP+ in PC12 cells: insights into potential neurotoxicants in Parkinson's disease.
N-Methylated beta-carbolinium cations that can form in vivo from environmental or endogenous beta-carbolines are putative neurotoxic factors in Parkinson's disease. The cytotoxicities of 11 N-methylated beta-carbolinium cations and N-methyl-4-phenylpyridinium cation (MPP+), the experimental parkinsonian neurotoxicant which the carbolinium cations structurally resemble, were examined using rat pheochromocytoma (PC12) cells cultured in "low energy" N-5 medium; cell death was estimated by released lactate dehydrogenase activity and viable cell protein. Of the eight N2-monomethylated beta-carbolinium cations utilized, only 2-methyl-harmalinium (harmaline-2-methiodide) was as cytotoxic as MPP+. Also, three N2(beta), N9(indole)-dimethylated beta-carbolinium cations displayed cytotoxic effects, with the simplest, 2,9-dimethylnorharmanium, approaching the effectiveness of MPP+ in PC12 cells cultured in N-5 medium. However, when PC12 cells grown in higher energy Dulbecco's modified Eagle's medium were utilized with selected effective cations, it was observed that the cultures were relatively resistant to MPP+ and 2,9-dimethylnorharmanium, but remained vulnerable to 2-methylharmalinium. The results are interpreted to mean that different cytotoxic mechanisms exist for the two most potent beta-carbolinium cations--namely, a mechanism for the 2,9-dimethyl-beta-carbolinium species that, as with MPP+, is conditional on mitochondrial ATP depletion, but a different (or additional) mechanism for 2-methylharmalinium that is independent of mitochondrial inhibition. The possible accumulation of these cytotoxic cations in Parkinson's disease is discussed in the context of these findings.
Cobuzzi
R J
RJ
Department of Molecular and Cellular Biochemistry, Loyola University Stritch School of Medicine, Maywood, Illinois.
Neafsey
E J
EJ
Collins
M A
MA
D015655:1-Methyl-4-phenylpyridinium / Q000031:analogs & derivatives* / Q000633:toxicity*; D000818:Animals; D002412:Cations; D016923:Cell Death / Q000187:drug effects; D003470:Culture Media; D004734:Energy Metabolism; D006246:Harmaline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008745:Methylation; D015394:Molecular Structure; D016716:PC12 Cells / Q000187:drug effects*; D010300:Parkinson Disease / Q000209:etiology; D051381:Rats
D002412:Cations; D003470:Culture Media; C086310:2-methylharmalinium; D006246:Harmaline; D007770:L-Lactate Dehydrogenase; D015655:1-Methyl-4-phenylpyridinium