Segura-Aguilar Juan, Mannervik Bengt
Molecular & Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia, Santiago 8380000, Chile.
Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, SE-10691 Stockholm, Sweden.
Antioxidants (Basel). 2023 Mar 9;12(3):673. doi: 10.3390/antiox12030673.
Investigations of the effect of antioxidants on idiopathic Parkinson's disease have been unsuccessful because the preclinical models used to propose these clinical studies do not accurately represent the neurodegenerative process of the disease. Treatment with certain exogenous neurotoxins induces massive and extremely rapid degeneration; for example, MPTP causes severe Parkinsonism in just three days, while the degenerative process of idiopathic Parkinson´s disease proceeds over many years. The endogenous neurotoxin aminochrome seems to be a good alternative target since it is formed in the nigrostriatal system neurons where the degenerative process occurs. Aminochrome induces all the mechanisms reported to be involved in the degenerative processes of idiopathic Parkinson's disease. The presence of neuromelanin-containing dopaminergic neurons in the postmortem brain of healthy elderly people suggests that neuromelanin synthesis is a normal and harmless process despite the fact that it requires oxidation of dopamine to three ortho-quinones that are potentially toxic, especially aminochrome. The apparent contradiction that neuromelanin synthesis is harmless, despite its formation via neurotoxic ortho-quinones, can be explained by the protective roles of DT-diaphorase and glutathione transferase GSTM2-2 as well as the neuroprotective role of astrocytes secreting exosomes loaded with GSTM2-2. Increasing the expression of DT-diaphorase and GSTM2-2 may be a therapeutic goal to prevent the degeneration of new neuromelanin-containing dopaminergic neurons. Several phytochemicals that induce DT-diaphorase have been discovered and, therefore, an interesting question is whether these phytochemical KEAP1/NRF2 activators can inhibit or decrease aminochrome-induced neurotoxicity.
对抗氧化剂对特发性帕金森病影响的研究一直未取得成功，因为用于开展这些临床研究的临床前模型并不能准确反映该疾病的神经退行性过程。用某些外源性神经毒素进行治疗会导致大量且极其快速的退化；例如，MPTP在短短三天内就会引发严重的帕金森症，而特发性帕金森病的退化过程则会持续多年。内源性神经毒素氨基色素似乎是一个很好的替代靶点，因为它在发生退化过程的黑质纹状体系统神经元中形成。氨基色素会引发所有据报道与特发性帕金森病退化过程相关的机制。健康老年人尸检大脑中存在含神经黑色素的多巴胺能神经元，这表明神经黑色素的合成是一个正常且无害的过程，尽管它需要将多巴胺氧化为三种潜在有毒的邻醌，尤其是氨基色素。尽管神经黑色素通过神经毒性邻醌形成，但它的合成却是无害的，这一明显的矛盾可以通过DT - 黄递酶和谷胱甘肽转移酶GSTM2 - 2的保护作用以及分泌载有GSTM2 - 2的外泌体的星形胶质细胞的神经保护作用来解释。增加DT - 黄递酶和GSTM2 - 2的表达可能是预防新的含神经黑色素的多巴胺能神经元退化的一个治疗目标。已经发现了几种能诱导DT - 黄递酶的植物化学物质，因此，一个有趣的问题是，这些植物化学物质KEAP1/NRF2激活剂是否能抑制或降低氨基色素诱导的神经毒性。
