Differential Cytotoxicities of N-Methyl-β-Carbolinium Analogues of MPP+ in PC12 Cells: Insights into Potential Neurotoxicants in Parkinson's Disease |
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Authors: | Robert J Cobuzzi Jr Edward J Neafsey Michael A Collins |
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Institution: | Department of Molecular and Cellular Biochemistry, Maywood, Illinois, U.S.A.;Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Stritch School of Medicine, Maywood, Illinois, U.S.A. |
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Abstract: | N-Methylated β-carbolinium cations that can form in vivo from environmental or endogenous β-carbolines are putative neurotoxic factors in Parkinson's disease. The cytotoxicities of 11 N-methylated β-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 N-monomethylated β-carbolinium cations utilized, only 2-methyl-harmalinium (harmaline-2- methiodide) was as cytotoxic as MPP+. Also, three N2(β), N8(indole)-dimethylated β-carbolinium cations displayed cytotoxic effects, with the simplest, 2,9-dimethylnorhar- manium, 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 β-carbolinium cations—namely, a mechanism for the 2,9-dimethyl-β-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. |
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Keywords: | β-Carbolines Neurodegen- eration MPP+ N-Methylated indoles Harmaline- methiodide |
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