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核因子E2相关因子2-抗氧化反应元件通路：治疗神经退行性疾病的一个有价值的治疗靶点。

The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases.

作者信息

Joshi Gururaj, Johnson Jeffrey A

机构信息

Division of Pharmaceutical Sciences, School of Pharmacy, 6125 Rennebohm Hall, 777 Highland Avenue, University of Wisconsin, Madison, WI 53705, USA.

出版信息

Recent Pat CNS Drug Discov. 2012 Dec;7(3):218-29. doi: 10.2174/157488912803252023.

DOI:10.2174/157488912803252023
PMID:22742419
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3625035/
Abstract

Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders. The overexpression of Nrf2 has become a potential therapeutic avenue for various neurodegenerative disorders such as Parkinson, Amyotrophic lateral sclerosis, and Alzheimer's disease. The expression of phase II detoxification enzymes is governed by the cis-acting regulatory element known as antioxidant response element (ARE). The transcription factor Nrf2 binds to ARE thereby transcribing multitude of antioxidant genes. Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 can increase the endogenous antioxidant capacity of the brain thereby rendering protection against oxidative stress in neurodegenerative disorders. This review primarily focuses on recent patents that target Nrf2 overexpression as a promising therapeutic strategy for the treatment of neurodegenerative disorders.

摘要

在多种神经退行性疾病中已显示出对核因子E2相关因子2（Nrf2）的调节作用。Nrf2的过表达已成为治疗帕金森病、肌萎缩侧索硬化症和阿尔茨海默病等各种神经退行性疾病的潜在治疗途径。II期解毒酶的表达受称为抗氧化反应元件（ARE）的顺式作用调节元件控制。转录因子Nrf2与ARE结合，从而转录多种抗氧化基因。Keap1是一种基于culin 3的E3连接酶，靶向Nrf2进行降解，将Nrf2隔离在细胞质中。Keap1-Nrf2相互作用的破坏或Nrf2的基因过表达可增加大脑的内源性抗氧化能力，从而在神经退行性疾病中抵御氧化应激。本综述主要关注以Nrf2过表达为治疗神经退行性疾病的有前景治疗策略的近期专利。

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