Cuadrado Antonio, Moreno-Murciano Paz, Pedraza-Chaverri José
Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC, Ciber de Enfermedades Neurodegenerativas, Departamento de Bioquímica, Facultad de Medicina Universidad Autónoma de Madrid, Madrid, Spain.
Expert Opin Ther Targets. 2009 Mar;13(3):319-29. doi: 10.1517/13543780802716501.
In recent years, it has been accepted that oxidative stress is critically involved in the etiopathology of Parkinson's disease (PD) and as a result new therapeutic targets for reduction of oxidant injury and neuroprotection can be defined. Here we discuss the potential use of the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), as a pharmacological target for neuroprotective therapy in PD. Data generated by various groups indicate that Nrf2 induces the expression of a group of cytoprotective, antixenobiotic and antioxidant enzymes that include heme oxygenase-1, NAD(P)H:quinone oxidoreductase and enzymes of glutathione (GSH) metabolism such as gamma-glutamyl cysteine ligase, GSH transferases and so on. Two strategies are known to increase Nrf2 transcriptional activity in PD: i) use of certain catechol-derived quinones for selective inhibition of the Nrf2 repressor Kelch-like ECH-associated protein to increase of Nrf2 protein levels; and ii) use of glycogen synthase kinase 3beta inhibitors to maintain high protein and activity levels of Nrf2 in the nucleus. This review provides a rationale for drug design of appropriate molecules that might endorse a neuroprotective strategy to PD on the basis of attenuation of oxidative stress.
近年来，人们已经认识到氧化应激在帕金森病（PD）的病因病理中起着关键作用，因此可以确定减少氧化损伤和神经保护的新治疗靶点。在此，我们讨论转录因子核因子红细胞2相关因子2（Nrf2）作为PD神经保护治疗药理学靶点的潜在用途。不同研究小组得出的数据表明，Nrf2可诱导一组细胞保护、抗外源性物质和抗氧化酶的表达，这些酶包括血红素加氧酶-1、NAD（P）H：醌氧化还原酶以及谷胱甘肽（GSH）代谢相关酶，如γ-谷氨酰半胱氨酸连接酶、GSH转移酶等。已知有两种策略可增加PD中Nrf2的转录活性：i）使用某些儿茶酚衍生的醌类物质选择性抑制Nrf2阻遏物 Kelch样ECH相关蛋白，以提高Nrf2蛋白水平；ii）使用糖原合酶激酶3β抑制剂维持细胞核中Nrf2的高蛋白水平和活性。本综述为设计合适分子的药物提供了理论依据，这些分子可能基于减轻氧化应激为PD支持一种神经保护策略。
