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首页> 外文期刊>Life sciences >Neurotoxicity studies with the monoamine oxidase B substrate 1-methyl-3-phenyl-3-pyrroline
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Neurotoxicity studies with the monoamine oxidase B substrate 1-methyl-3-phenyl-3-pyrroline

机译：单胺氧化酶B底物1-甲基-3-苯基-3-吡咯啉的神经毒性研究

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摘要

The neurotoxic properties of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are dependent on its metabolic activation in a reaction catalyzed by centrally located monoamine oxidase B (MAO-13). This reaction ultimately leads to the permanently charged 1-methyl-4-phenylpyridinium species MW, a 4-electron oxidation product of MPTP and a potent mitochondrial toxin. The corresponding 5-membered analogue, 1-methyl-3-phenyt-3-pyrroline, is also a selective MAO-13 substrate. Unlike MPTP, the MAO-B-catalyzed oxidation of 1-methyl-3-phenyl-3-pyrroline is a 2-electron process that leads to the neutral 1-methyl-3-phenylpyrrole. MPP+ is thought to exert its toxic effects only after accumulating in the mitochondria, a process driven by the transmembrane electrochemical gradient. Since this energy-dependent accumulation of MPP+ relies upon its permanent charge, 1-methyl-3-phenyl-3-pyrrolines and their pyrrolyl oxidation products should not be neurotoxic. We have tested this hypothesis by examining the neurotoxic potential of 1-methyl-3-phenyl-3-pyrroline and 1-methyl-3-(4chlorophenyl)-3-pyrroline in the C57BL/6 mouse model. These pyrrolines did not deplete striatal dopamine while analogous treatment with MPTP resulted in 65-73% depletion. Kinetic studies revealed that both 1-methyl-3-phenyl-3-pyrroline and its pyrrolyl oxidation product were present in the brain in relatively high concentrations. Unlike MPP+, however, 1-methyl-3-phenylpyrrole was cleared from the brain quickly. These results suggest that the brain MAO-B-catalyzed oxidation of xenobiotic amines is not, in itself, sufficient to account for the neurodegenerative properties of a compound like MPTP. The rapid clearance of 1-methyl-3-phenylpyrroles from the brain may contribute to their lack of neurotoxicity. (c) 2007 Elsevier Inc. All rights reserved.
机译：帕金森氏病诱导剂1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的神经毒性取决于其在中心定位的单胺氧化酶B（MAO-13）催化的反应中的代谢活化。该反应最终导致永久充电的1-甲基-4-苯基吡啶鎓类物质MW，MPTP的4-电子氧化产物和有效的线粒体毒素。相应的5元类似物1-甲基-3-苯基-3-吡咯啉也是MAO-13的选择性底物。与MPTP不同，MAO-B催化的1-甲基-3-苯基-3-吡咯啉的氧化是一种2电子过程，导致生成中性的1-甲基-3-苯基吡咯。据认为，MPP +仅在线粒体中积累后才发挥其毒性作用，该过程是由跨膜电化学梯度驱动的。由于这种依赖能量的MPP +积累依赖于其永久电荷，因此1-甲基-3-苯基-3-吡咯啉及其吡咯基氧化产物不应具有神经毒性。我们通过检查在C57BL / 6小鼠模型中1-甲基-3-苯基-3-吡咯啉和1-甲基-3-（4-氯苯基）-3-吡咯啉的神经毒性潜力来检验该假设。这些吡咯啉没有耗尽纹状体多巴胺，而MPTP的类似治疗导致65-73％的消耗。动力学研究表明，1-甲基-3-苯基-3-吡咯啉及其吡咯基氧化产物均以相对较高的浓度存在于大脑中。但是，与MPP +不同，1-甲基-3-苯基吡咯可从大脑中迅速清除。这些结果表明，大脑MAO-B催化的异种生物胺的氧化本身不足以解释MPTP等化合物的神经变性特性。 1-甲基-3-苯基吡咯从大脑中快速清除可能导致它们缺乏神经毒性。 （c）2007 Elsevier Inc.保留所有权利。

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