Striatal dopaminergic toxicity following intranigral injection in rats of 2-methyl-norharman, a beta-carbolinium analog of N-methyl-4-phenylpyridinium ion (MPP+).
Striatal dopaminergic toxicity following intranigral injection in rats of 2-methyl-norharman, a beta-carbolinium analog of N-methyl-4-phenylpyridinium ion (MPP+).
复制标题
大鼠黑质内注射 2-甲基-去甲哈曼（N-甲基-4-苯基吡啶鎓离子 (MPP) 的 β-碳啉类似物）后纹状体多巴胺能毒性。
DOI：
10.1016/0304-3940(89)90645-9
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发表时间：
1989
影响因子：
2.5
通讯作者：
Collins,MA
中科院分区：
文献类型：
--
作者：
Neafsey,EJ;Drucker,G;Raikoff,K;Collins,MA
甲基化β-卡波林化合物是哺乳动物吲哚代谢物，由于其结构与多巴胺能毒素n -甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的活性氧化产物MPP+相似，我们提出了内源性神经毒素。几个实验室已经证明MPP+进入大鼠的黑质或中前脑束会导致纹状体多巴胺及其代谢物的大量消耗。我们现在报道，在黑质内注射β-卡波林、2-甲基-诺哈曼、纹状体多巴胺、DOPAC和同侧香草酸（HVA）浓度三周后，与车注射对照组相比，同侧注射浓度降低了41-64%；在个体动物中，多巴胺消耗率达到96%。另外，在黑质2-甲基诺哈曼注射部位，光镜下可见明显的大病变和胶质瘤。这是第一次直接证明2-甲基β-碳鎓离子具有神经毒性。这进一步证实了MPP+样β-碳碱可能是帕金森病的内源性病原体的假设。
Methylated β-carboline compounds are mammalian indole metabolites that we have proposed to be endogenous neurotoxins due to their structural similarity to MPP+, the active oxidized product of the dopaminergic toxin,N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Several laboratories have demonstrated that MPP+administration into the substantia nigra or median forebrain bundle of rats results in extensive depletion of striatal dopamine and its metabolites. We now report that three weeks after intranigral injection of the β-carboline, 2-methyl-norharman, striatal dopamine, DOPAC, and homovanillic acid (HVA) concentrations ipsilateral to the injection are reduced 41–64% compared to vehicle-injected controls; in individual animals dopamine depletions of 96% were achieved. In addition, at the 2-methylnorharman injection site in the substantia nigra, large lesions and gliosis were apparent under light microscopic examination. This is the first direct demonstration that a 2-methyl-β-carbolinium ion is neurotoxic. It lends further validity to the hypothesis that MPP+-like β-carbolines may be endogenous causative agents in Parkinson's disease.