Differential Cytotoxicities of N‐Methyl‐β‐Carbolinium Analogues of MPP+ in PC12 Cells: Insights into Potential Neurotoxicants in Parkinson's Disease
Differential Cytotoxicities of N‐Methyl‐β‐Carbolinium Analogues of MPP+ in PC12 Cells: Insights into Potential Neurotoxicants in Parkinson's Disease
复制标题
MPP+ 的 N-甲基-β-碳鎓类似物在 PC12 细胞中的差异细胞毒性：帕金森病潜在神经毒物的见解
作者：
R. Cobuzzi;E. Neafsey;M. Collins
可在体内由环境或内源性β-咔啉形成的N-甲基化β-咔啉鎓阳离子是帕金森病的假定神经毒性因子。使用在“低能量”N-5培养基中培养的大鼠嗜铬细胞瘤（PC 12）细胞，检查了11种N-甲基化β-咔啉阳离子和N-甲基-4-苯基吡啶阳离子（MPP+）（咔啉阳离子结构类似的实验性帕金森病神经毒物）的细胞毒性;通过释放的乳酸脱氢酶活性和活细胞蛋白估计细胞死亡。在使用的八种N-单甲基化β-咔啉阳离子中，仅2-甲基-骆驼蓬碱（骆驼蓬碱-2-甲基碘）的细胞毒性与MPP+相同。此外，三种N2（β），N8（吲哚）-二甲基化β-咔啉阳离子显示出细胞毒性作用，其中最简单的2，9-二甲基正甲铵接近MPP+在N-5培养基中培养的PC 12细胞中的有效性。然而，当在较高能量的Dulbecco改良Eagle培养基中生长的PC 12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2，9-二甲基去甲基骆驼蓬碱具有相对抗性，但仍然易受2-甲基骆驼蓬碱的影响。结果解释为两种最有效的β-咔啉阳离子存在不同的细胞毒性机制-即，与MPP+一样，2，9-二甲基-β-咔啉物质的机制取决于线粒体ATP耗竭，但2-甲基骆驼蓬碱的机制不同（或额外），不依赖于线粒体抑制。这些细胞毒性阳离子在帕金森氏病的可能积累的背景下，这些研究结果进行了讨论。
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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2-β-甲基碳啉鎓离子（一种潜在的内源性 MPP 类似物）的体内多巴胺能神经毒性。
影响因子：
5
作者：
Rollema,H;Booth,RG;CastagnoliJr,N
通讯作者：
CastagnoliJr,N
复合物 II 是否参与 N-甲基-4-苯基吡啶鎓阳离子 (MMP) 和 N-甲基-β-咔啉对线粒体呼吸的抑制？
DOI：
10.1042/bj2910673
发表时间：
1993
期刊：
The Biochemical journal
影响因子：
--
作者：
Krueger,MJ;Tan,AK;Ackrell,BA;Singer,TP
通讯作者：
Singer,TP
哈曼对大鼠脑、肺和人类脑脊液的影响：饮酒的影响。
DOI：
10.1016/0741-8329(88)90090-0
发表时间：
1988
期刊：
Alcohol (Fayetteville, N.Y.)
影响因子：
--
作者：
Bosin,TR;Borg,S;Faull,KF
通讯作者：
Faull,KF
DOI：
10.1073/pnas.88.14.6368
发表时间：
1991-07-01
影响因子：
11.1
作者：
DAWSON, VL;DAWSON, TM;SNYDER, SH
通讯作者：
SNYDER, SH
影响因子：
6.1
作者：
ARORA, PK;RIACHI, NJ;SAYRE, LM
通讯作者：
SAYRE, LM