DIFFERENTIAL CYTOTOXICITIES OF N-METHYL-BETA-CARBOLINIUM ANALOGS OF MPP- INSIGHTS INTO POTENTIAL NEUROTOXICANTS IN PARKINSONS-DISEASE( IN PC12 CELLS )

N-Methylated beta-carbolinium cations that can form in vivo from envir onmental or endogenous beta-carbolines are putative neurotoxic factors in Parkinson's disease. The cytotoxicities of 11 N-methylated beta-ca rbolinium cations and N-methyl-4-phenylpyridinium cation (MPP+), the e xperimental parkinsonian neurotoxicant which the carbolinium cations s tructurally 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 cation s displayed cytotoxic effects, with the simplest, 2,9-dimethylnorharma nium, 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 MPPand 2,9-dimethylnorharmanium, but remained vulnerable to 2-methylharma linium. The results are interpreted to mean that different cytotoxic m echanisms exist for the two most potent beta-carbolinium cations-namel y, a mechanism for the 2,9-dimethyl-beta-carbolinium species that, as with MPP+, is conditional on mitochondrial ATP depletion, but a differ ent (or additional) mechanism for 2-methylharmalinium that is independ ent of mitochondrial inhibition. The possible accumulation of these cy totoxic cations in Parkinson's disease is discussed in the context of these findings.