STRUCTURE-NEUROTOXICITY TRENDS OF ANALOGS OF 1-METHYL-4-PHENYLPYRIDINIUM (MPP+), THE CYTOTOXIC METABOLITE OF THE DOPAMINERGIC NEUROTOXIN MPTP
STRUCTURE-NEUROTOXICITY TRENDS OF ANALOGS OF 1-METHYL-4-PHENYLPYRIDINIUM (MPP+), THE CYTOTOXIC METABOLITE OF THE DOPAMINERGIC NEUROTOXIN MPTP
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DOI：
10.1016/0024-3205(90)90018-m
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发表时间：
1990-01-01
期刊：
影响因子：
6.1
通讯作者：
SAYRE, LM
中科院分区：
文献类型：
--
作者：
ARORA, PK;RIACHI, NJ;SAYRE, LM
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的多巴胺能神经毒性源于其代谢为1-甲基-4-苯基吡啶阳离子（MPP+），然后选择性地积累在多巴胺能神经元中。为了评估MPP+细胞毒性的结构要求，我们在MPP+类似物微输注大鼠黑质3周后评估了其多巴胺能毒性。我们还通过测量MPP+类似物诱导特异性多巴胺释放的能力，评估了MPP+类似物对纹状体突触体高亲和力多巴胺摄取的底物适用性。MPP+类似物在体内的神经内毒性主要与它们对线粒体呼吸的体外抑制活性相关，这与mptp诱导细胞死亡的主要机制是细胞能量产生的妥协是一致的。这项研究扩展了结构-神经毒性数据库，超出了使用MPTP类似物可获得的数据库，因为这些类似物中的许多不会代谢成吡啶化合物。这些信息对于评估哪些可能的内源性或外源性化合物可能发挥MPTP/MPP+样毒性至关重要。
The dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) derives from its metabolism to 1-methyl-4-phenylpyridinium cation (MPP+), which is then selectively accumulated in dopaminergic neurons. In an effort to assess the structural requirements governing MPP+ cytotoxicity, we evaluated dopaminergic toxicity of MPP+ analogues 3 weeks after their microinfusion into rat substantia nigra. We also evaluated the substrate suitability of MPP+ analogues for high-affinity dopamine uptake in striatal synaptosomes by measuring their ability to induce specific dopamine release. The intranigral neurotoxicity of MPP+ analogues in vivo correlates mainly with their in vitro inhibitory activity on mitochondrial respiration, consistent with a compromise in cellular energy production as the principal mechanism of MPTP-induced cell death. This study extends the structure-neurotoxicity data base beyond that obtainable using MPTP analogues, since many of these are not metabolized to pyridinium compounds. Such information is crucial to assess which possible endogenous or exogenous compounds may exert MPTP/MPP+-like toxicity.