Selective dopaminergic neurotoxicity of three heterocyclic amine subclasses in primary rat midbrain neurons.
Selective dopaminergic neurotoxicity of three heterocyclic amine subclasses in primary rat midbrain neurons.
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DOI：
10.1016/j.neuro.2018.01.009
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发表时间：
2018-03
期刊：
影响因子：
3.4
通讯作者：
Cannon JR
中科院分区：
文献类型：
--
作者：
Cruz-Hernandez A;Agim ZS;Montenegro PC;McCabe GP;Rochet JC;Cannon JR
杂环胺 (HCA) 主要是在高温肉类烹饪过程中产生的。这些化合物作为诱变剂和致癌剂已被深入研究。然而，一致的数据表明 HCA 也可能具有神经毒性，并可能与帕金森病 (PD) 等神经退行性疾病相关。识别新的潜在病因非常重要，因为大多数 PD 病例都是散发的。我们的小组之前表明，2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）对多巴胺能神经元具有选择性神经毒性。然而，PhIP 是众多 HCA 中的一种，HCA 是一类表现出广泛结构变异性的化合物。本研究的目的是确定三个亚类中最常见和研究最充分的 HCA 的神经毒性：氨基咪唑并氮杂萘 (AIA)、α-咔啉和 β-咔啉。使用 E17 大鼠原代中脑培养物，我们测试了以下化合物引起的多巴胺能和非多巴胺能神经毒性：2-氨基-3-甲基咪唑[4,5-f]喹啉 (IQ)、2-氨基-3,4-二甲基咪唑[4,5-f]喹啉 (MeIQ)、2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉(MeIQx)、2-氨基-3,4,8-三甲基咪唑并[4,5-f]喹喔啉 (4,8-DiMeIQx)、PhIP、1-甲基-9H-吡啶并[3,4-b]吲哚（哈马烷）、9H-吡啶并[3,4-b]吲哚（去甲哈尔曼）和 2-氨基-9H-吡啶并[2,3-b]吲哚(AαC) 浓度范围为 100 nM – 5 µM。所有测试的 HCA 均具有选择性神经毒性，但引起多巴胺能神经元选择性丧失或多巴胺能神经突长度选择性减少所需的剂量是化合物特异性的。非多巴胺能神经元在所有测试剂量下均不受影响。敏感性（由引发选择性神经毒性所需的阈剂量决定）似乎与已发表的诱变效力无关。 AIA 和 α/β-咔啉都会产生氧化损伤，与非多巴胺能神经元相比，氧化损伤在多巴胺能神经元中被放大，这是选择性神经毒性的进一步证据。这些研究预计将促进关于 HCA 暴露在 PD 中潜在作用的临床和机制研究。
Heterocyclic amines (HCAs) are primarily produced during high temperature meat cooking. These compounds have been intensively investigated as mutagens and carcinogens. However, converging data suggest that HCAs may also be neurotoxic and potentially relevant to neurodegenerative diseases such as Parkinson’s disease (PD). The identification of new potential etiological factors is important because most PD cases are sporadic. Our group previously showed that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was selectively neurotoxic to dopaminergic neurons. However, PhIP is one of many HCAs, a class of compounds that exhibits wide structural variability. The goal of this study was to determine the neurotoxicity of the most prevalent and best studied HCAs from three subclasses: aminoimidazoaazarenes (AIA), α-carbolines, and β-carbolines. Using E17 rat primary midbrain cultures, we tested dopaminergic and non-dopaminergic neurotoxicity elicited by the following compounds: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), PhIP, 1-methyl-9H-pyrido[3,4-b]indole (harmane), 9H-pyrido[3,4-b]indole (norharmane) and 2-amino-9H-pyrido[2,3-b]indole (AαC) at concentrations ranging from 100 nM – 5 µM. All tested HCAs were selectively neurotoxic, though the dose required to elicit selective loss of dopaminergic neurons or selective decreases in dopaminergic neurite length was compound specific. Non-dopaminergic neurons were unaffected at all tested doses. The sensitivity (determined by threshold dose required to elicit selective neurotoxicity) appears to be unrelated to published mutagenic potency. Both AIA and α/β-carbolines produced oxidative damage, which was magnified in dopaminergic neurons vs. non-dopaminergic neurons as further evidence of selective neurotoxicity. These studies are expected to prompt clinical and mechanistic studies on the potential role of HCA exposure in PD.
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影响因子：
3.8
作者：
Griggs, Amy M.;Agim, Zeynep S.;Cannon, Jason R.
通讯作者：
Cannon, Jason R.
影响因子：
3.8
作者：
Cannon, Jason R.;Greenamyre, J. Timothy
通讯作者：
Greenamyre, J. Timothy
DOI：
10.1111/j.1749-6632.1992.tb24523.x
发表时间：
1992-05-11
影响因子：
5.2
作者：
GERMAN, DC;MANAYE, KF;BROOKS, BA
通讯作者：
BROOKS, BA
影响因子：
2.4
作者：
Hwang O
通讯作者：
Hwang O
DOI：
10.1016/j.jchromb.2003.10.047
发表时间：
2004-03-25
影响因子：
3
作者：
Keating, GA;Bogen, KT
通讯作者：
Bogen, KT