Differential cytotoxicities of N-methyl-beta-carbolinium analogues of MPP+ in PC12 cells: insights into potential neurotoxicants in Parkinson's disease.
Differential cytotoxicities of N-methyl-beta-carbolinium analogues of MPP+ in PC12 cells: insights into potential neurotoxicants in Parkinson's disease.
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MPP 的 N-甲基-β-碳类似物在 PC12 细胞中的差异细胞毒性：深入了解帕金森病的潜在神经毒物。
DOI：
10.1046/j.1471-4159.1994.62041503.x
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发表时间：
1994
影响因子：
4.7
通讯作者：
Collins,MA
中科院分区：
文献类型：
--
作者：
CobuzziJr,RJ;Neafsey,EJ;Collins,MA
N-甲基化β-咔啉阳离子可以在体内由环境或内源性β-咔啉形成，被认为是帕金森病的神经毒性因子。使用在“低能量”N-5 培养基中培养的大鼠嗜铬细胞瘤 (PC12) 细胞检查了 11N-甲基化 β-碳啉鎓阳离子和 N-甲基-4-苯基吡啶鎓阳离子 (MPP+)（与碳鎓阳离子结构相似的实验性帕金森病神经毒剂）的细胞毒性；通过释放的乳酸脱氢酶活性和活细胞蛋白来估计细胞死亡。在使用的 8 个 N-单甲基化 β-碳鎓阳离子中，只有 2-甲基-骆驼蓬鎓（骆驼蓬碱-2-甲硫碘）的细胞毒性与 MPP+ 相同。此外，三个 N2(β),N8(吲哚)-二甲基化 β-碳鎓阳离子表现出细胞毒性作用，其中最简单的 2,9-二甲基正鎓离子在 N-5 培养基中培养的 PC12 细胞中接近 MPP+ 的有效性。然而，当在更高能量的 Dulbecco 改良 Eagle 培养基中生长的 PC12 细胞与选定的有效阳离子一起使用时，观察到培养物对 MPP+ 和 2,9-二甲基正铧相对具有抗性，但仍然容易受到 2-甲基铧的影响。结果被解释为意味着两种最有效的 β-carbolinium 阳离子存在不同的细胞毒性机制，即 2,9-二甲基-β-carbolinium 物种的机制，与 MPP+ 一样，以线粒体 ATP 消耗为条件，但 2-methylharmalinium 的机制不同（或额外），独立于线粒体抑制。在这些发现的背景下讨论了这些细胞毒性阳离子在帕金森病中可能的积累。
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 11N‐methylated β‐carbolinium cations andN‐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 eightN‐monomethylated β‐carbolinium cations utilized, only 2‐methyl‐harmalinium (harmaline‐2‐ methiodide) was as cytotoxic as MPP+. Also, threeN2(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.