中国神经再生研究(英文版) ›› 2017, Vol. 12 ›› Issue (6): 897-901.doi: 10.4103/1673-5374.208560

• 综述:退行性病与再生 • 上一篇    下一篇

内源性神经毒素和帕金森病的神经保护作用

  

  • 收稿日期:2017-05-15 出版日期:2017-06-15 发布日期:2017-06-15
  • 基金资助:

    此项工作得到了科技基金1170033的支持

On the role of endogenous neurotoxins and neuroprotection in Parkinson’s disease

Juan Segura-Aguilar   

  1. Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile
  • Received:2017-05-15 Online:2017-06-15 Published:2017-06-15
  • Contact: Juan Segura-Aguilar, Ph.D., jsegura@med.uchile.cl.
  • Supported by:

    This work was supported by FONDECYT 1170033.

摘要:

环境因素和遗传易感性在帕金森病中的作用已经被讨论了很长时间。特发性帕金森病的平均发病时间约60岁。然而,由锰,铜和农药(百草枯)等环境因素引起的帕金森综合征最相关的特征之一是在接触这些污染物的年轻人中观察到的早期发现。在黑质纹状体系中含有神经丝氨酸的多巴胺能神经元的变性在运动症状明显之前开始多年。由污染物引起的帕金森综合征和家族性帕金森病的退行过程发生率明显更快,这也解释了其在年轻人中的早期发病原因。然而,由金属或农药引起的帕金森综合征以及由特定突变引起的家族性疾病诱发了帕金森病的早发型并与60岁的帕金森病特发性形式的正常发作相反疾病。因此,在运动症状出现之前和疾病进展之前极其缓慢的退行过程似乎是合理的,这取决于内源性神经毒素的形成,例如在多巴胺氧化过程中产生的神经毒性邻醌,α-突触核蛋白神经毒性低聚物和DOPAL氧化成邻醌。有趣的是,有保护多巴胺能神经元的内源性机制,其可阻止这些内源性神经毒素如VMAT-2,DT-心肌黄酶和GSTM2的神经毒性作用。

ORCID:0000-0002-1018-673X(Juan Segura-Aguilar)

Abstract:

For 50 years ago was introduced L-3,4-dihydroxyphenylalanine (L-dopa) in Parkinson’s disease treatment and during this significant advances has been done but what trigger the degeneration of the nigrostriatal system remain unknown. There is a general agreement in the scientific community that mitochondrial dysfunction, protein degradation dysfunction, alpha-synuclein aggregation to neurotoxic oligomers, neuroinflammation, oxidative and endoplasmic reticulum stress are involved in the loss of dopaminergic neurons containing neuromelanin in Parkinson’s disease. The question is what triggers these mechanisms. The age of normal onset in idiopathic Parkinson’s disease suggests that environmental factors such as metals, pollutants or genetic mutations cannot be involved because these factors are related to early onset of Parkinsonism. Therefore, we have to search for endogenous neurotoxins and neuroprotection in order to understand what trigger the loss of dopaminergic neurons. One important feature of Parkinson’s disease is the rate of the degenerative process before the motor symptoms are evident and during the disease progression. The extremely slow rate of Parkinson’s disease suggests that the neurotoxins and the neuroprotection have to be related to dopamine metabolism. Possible candidates for endogenous neurotoxins are alpha-synuclein neurotoxic oligomers, 4-dihydroxyphenylacetaldehyde and ortho-quinones formed during dopamine oxidation to neuromelanin. Vesicular monoamine transporter-2, DT-diaphorase and glutathione transferase M2-2 seems to be the most important neuroprotective mechanism to prevent neurotoxic mechanism during dopamine oxidation.

Key words: VMAT-2, monoamine oxidase, 3,4-Dihydroxyphenylacetaldehyde, 3,4-dihydroxyphenylacetic acid, dopamine, L-dopa, aminochrome, neuromelanin