Andrews A M, Murphy D L
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892.
J Neurochem. 1993 Mar;60(3):1167-70. doi: 10.1111/j.1471-4159.1993.tb03271.x.
Unlike 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces consistent decreases in levels of striatal dopamine (DA) with considerably smaller and more variable effects on mouse brain levels of serotonin (5-HT) and norepinephrine (NE), a novel amine-substituted MPTP analogue, 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP), administered in a standard mouse dosing paradigm for MPTP (20 mg/kg x 4) did not affect striatal DA but led to marked reductions (60-70%) in levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and NE measured in frontal cortex and hippocampus 1 week after treatment. Another 2'-substituted MPTP analogue, 1-methyl-4-(2'-methylphenyl)-1,2,3,6- tetrahydropyridine, affected cortical and hippocampal 5-HT, 5-HIAA, and NE only minimally, while markedly reducing the DA content in striatum (90%), thus indicating that the substituent (-NH2 versus -CH3) at the 2' position is important for the differential effects of these MPTP analogues. In a replication study with a 3-week end point, hippocampal and cortical 5-HT, 5-HIAA,, and NE levels remained depressed with no indication of recovery. These results suggest that 2'-NH2-MPTP may be a novel, regionally selective neurotoxin for serotonergic and noradrenergic nerve terminals.
与1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）不同，MPTP会使纹状体多巴胺（DA）水平持续下降，而对小鼠脑内血清素（5-HT）和去甲肾上腺素（NE）水平的影响则小得多且变化更大。一种新型的胺取代MPTP类似物，1-甲基-4-（2'-氨基苯基）-1,2,3,6-四氢吡啶（2'-NH2-MPTP），按照MPTP的标准小鼠给药方案（20mg/kg×4）给药，并未影响纹状体DA，但在治疗1周后，额叶皮质和海马体中测得的5-HT、5-羟吲哚乙酸（5-HIAA）和NE水平显著降低（60-70%）。另一种2'-取代的MPTP类似物，1-甲基-4-（2'-甲基苯基）-1,2,3,6-四氢吡啶，对皮质和海马体中的5-HT、5-HIAA和NE影响极小，而纹状体中的DA含量则显著降低（90%），这表明2'位的取代基（-NH2对-CH3）对于这些MPTP类似物的差异效应很重要。在一项为期3周终点的重复研究中，海马体和皮质中的5-HT、5-HIAA和NE水平仍然较低，没有恢复的迹象。这些结果表明，2'-NH2-MPTP可能是一种新型的、对血清素能和去甲肾上腺素能神经末梢具有区域选择性的神经毒素。
