Huenchuguala Sandro, Segura-Aguilar Juan
Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Santiago 8370003, Chile.
Molecular & Clinical Pharmacology, Instituto de Ciencias Biomédicas (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
Antioxidants (Basel). 2024 Sep 18;13(9):1125. doi: 10.3390/antiox13091125.
Recently, a single-neuron degeneration model has been proposed to understand the development of idiopathic Parkinson's disease based on (i) the extremely slow development of the degenerative process before the onset of motor symptoms and during the progression of the disease and (ii) the fact that it is triggered by an endogenous neurotoxin that does not have an expansive character, limiting its neurotoxic effect to single neuromelanin-containing dopaminergic neurons. It has been proposed that aminochrome is the endogenous neurotoxin that triggers the neurodegenerative process in idiopathic Parkinson's disease by triggering mitochondrial dysfunction, oxidative stress, neuroinflammation, dysfunction of both lysosomal and proteasomal protein degradation, endoplasmic reticulum stress and formation of neurotoxic alpha-synuclein oligomers. Aminochrome is an endogenous neurotoxin that is rapidly reduced by flavoenzymes and/or forms adducts with proteins, which implies that it is impossible for it to have a propagative neurotoxic effect on neighboring neurons. Interestingly, the enzymes DT-diaphorase and glutathione transferase M2-2 prevent the neurotoxic effects of aminochrome. Natural compounds present in fruits, vegetables and other plant products have been shown to activate the KEAP1/Nrf2 signaling pathway by increasing the expression of antioxidant enzymes including DT-diaphorase and glutathione transferase. This review analyzes the possibility of searching for natural compounds that increase the expression of DT-diaphorase and glutathione transferase through activation of the KEAP1/Nrf2 signaling pathway.
最近，基于以下两点提出了一种单神经元退化模型来理解特发性帕金森病的发展过程：（i）在运动症状出现之前以及疾病进展过程中，退化过程发展极其缓慢；（ii）该疾病由一种不具有扩散特性的内源性神经毒素引发，其神经毒性作用仅限于单个含神经黑色素的多巴胺能神经元。有人提出氨基色素是引发特发性帕金森病神经退行性过程的内源性神经毒素，它通过引发线粒体功能障碍、氧化应激、神经炎症、溶酶体和蛋白酶体蛋白质降解功能障碍、内质网应激以及神经毒性α-突触核蛋白寡聚体的形成来实现。氨基色素是一种内源性神经毒素，可被黄素酶迅速还原和/或与蛋白质形成加合物，这意味着它不可能对邻近神经元产生传播性神经毒性作用。有趣的是，DT-黄递酶和谷胱甘肽转移酶M2-2可预防氨基色素的神经毒性作用。水果、蔬菜和其他植物产品中存在的天然化合物已被证明可通过增加包括DT-黄递酶和谷胱甘肽转移酶在内的抗氧化酶的表达来激活KEAP1/Nrf2信号通路。本综述分析了寻找通过激活KEAP1/Nrf2信号通路来增加DT-黄递酶和谷胱甘肽转移酶表达的天然化合物的可能性。
