Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson's disease.
Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson's disease.
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DOI：
10.1186/s13024-015-0067-y
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发表时间：
2016-01-13
影响因子：
15.1
通讯作者：
Sperlágh B
中科院分区：
文献类型：
--
作者：
Baranyi M;Porceddu PF;Gölöncsér F;Kulcsár S;Otrokocsi L;Kittel Á;Pinna A;Frau L;Huleatt PB;Khoo ML;Chai CL;Dunkel P;Mátyus P;Morelli M;Sperlágh B
线粒体功能障碍、氧化应激及其相互作用是帕金森病的核心病理特征。在多巴胺能神经元中，单胺及其代谢产物在其被单胺氧化酶或自氧化分解期间提供了反应性自由基的额外来源。此外，线粒体功能障碍和氧化应激对多巴胺的病理性细胞质积累及其随后的释放具有超加性影响。在这里，我们报告了一系列新的有效的和选择性的MAO-B抑制性（杂）芳基烯基炔丙胺化合物对线粒体功能障碍和氧化应激的超加和效应具有保护性能的影响。（杂）芳基烯基炔丙胺进行了测试，在体外，急性大鼠纹状体切片，预处理与复合物I抑制剂鱼藤酮和体内，使用1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的急性，亚慢性和慢性帕金森氏病的小鼠实验模型。所述化合物表现出一致的保护作用，对抗i）在鱼藤酮处理后，体外氧化应激诱导的大鼠纹状体中的病理性多巴胺释放和毒性多巴胺醌的形成以及黑质中的酪氨酸羟化酶阳性神经元的拯救; ii）使用急性和亚慢性、延迟施用方案，在小鼠中体内MPTP诱导的纹状体多巴胺耗竭和运动功能障碍。还检查了一种化合物（SZV 558），并证明其在MPTP加丙磺舒（MPTPp）给药的慢性小鼠模型中具有保护作用，所述MPTP加丙磺舒给药诱导黑质纹状体多巴胺能神经元的进行性损失。同时抑制MAO-B和氧化应激诱导的病理性多巴胺释放的新型炔丙胺在动物模型中是保护性的，似乎是一个合理的策略，以打击帕金森氏病。本文的在线版本（doi：10.1186/s13024-015-0067-y）包含补充材料，可供授权用户使用。
Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson’s disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress. The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson’s disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons. Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson’s disease. The online version of this article (doi:10.1186/s13024-015-0067-y) contains supplementary material, which is available to authorized users.