Youngster S K, Saari W S, Heikkila R E
Department of Neurology, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson, Medical School, Piscataway 08854-5635.
Neurosci Lett. 1987 Aug 18;79(1-2):151-6. doi: 10.1016/0304-3940(87)90688-4.
1-Methyl-4-cyclohexyl-1,2,3,6-tetrahydropyridine (MCTP), an analog of MPTP, was found to be an MPTP-like neurotoxin. MCTP administration caused extensive losses of neostriatal dopamine and its major metabolites in male Swiss-Webster mice. Under similar experimental conditions, MCTP was approximately as potent as MPTP. Like MPTP, MCTP was a good substrate for monoamine oxidase-B (MAO-B) and its neurotoxicity was prevented in mice by AGN-1135, a selective inhibitor of MAO-B. The neurotoxicity of MCTP and of MPTP was also prevented by the dopamine uptake inhibitor mazindol. 1-Methyl-4-cyclohexylpyridinium ion (MCP+), the 4-electron oxidation product of MCTP, caused release of previously accumulated [3H]dopamine from mouse neostriatal synaptosomes. This release was blocked by mazindol, which indicates that MCP+, like 1-methyl-4-phenylpyridinium ion (MPP+), the 4-electron oxidation product of MPTP, is a substrate for the dopamine transport system. Like MPP+, MCP+ was found to inhibit the mitochondrial oxidation of NADH-linked substrates. It appears that conjugation between the tetrahydropyridine ring and a 4-substituent is not a requirement for an MPTP analog to possess neurotoxicity.
1-甲基-4-环己基-1,2,3,6-四氢吡啶（MCTP）是MPTP的类似物，被发现是一种类似MPTP的神经毒素。给雄性瑞士-韦伯斯特小鼠施用MCTP会导致新纹状体多巴胺及其主要代谢产物大量损失。在相似的实验条件下，MCTP的效力与MPTP大致相当。与MPTP一样，MCTP是单胺氧化酶-B（MAO-B）的良好底物，其神经毒性在小鼠中可被MAO-B的选择性抑制剂AGN-1135所预防。多巴胺摄取抑制剂吗茚酮也可预防MCTP和MPTP的神经毒性。MCTP的4电子氧化产物1-甲基-4-环己基吡啶离子（MCP+）可使先前积累在小鼠新纹状体突触体中的[3H]多巴胺释放。这种释放被吗茚酮所阻断，这表明MCP+与MPTP的4电子氧化产物1-甲基-4-苯基吡啶离子（MPP+）一样，是多巴胺转运系统的底物。与MPP+一样，发现MCP+可抑制NADH连接底物的线粒体氧化。看来四氢吡啶环与4-取代基之间的共轭并非MPTP类似物具有神经毒性的必要条件。
