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Differential Cytotoxicities of N‐Methyl‐β‐Carbolinium Analogues of MPP+ in PC12 Cells: Insights into Potential Neurotoxicants in Parkinson's Disease

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.