Izumi Yasuhiko, Koyama Yutaka
Laboratory of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
Antioxidants (Basel). 2024 Dec 13;13(12):1527. doi: 10.3390/antiox13121527.
The NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a potential therapeutic target for central nervous system diseases. This review emphasizes the role of oxidative stress and neuroinflammation in neurodegenerative diseases, highlighting the therapeutic potential of Nrf2 activators such as dimethyl fumarate (DMF). DMF, initially administered for treating psoriasis, has demonstrated efficacy in multiple sclerosis and is metabolized to monomethyl fumarate, which may exert significant therapeutic effects. DMF activates the Nrf2-ARE pathway, and recent studies have indicated that its anti-inflammatory effects occur through Nrf2-independent mechanisms. Electrophilic Nrf2 activators, such as DMF, covalently bind to cysteine residues in proteins and modulate their function. We discuss the implications of cysteine residue modifications by DMF, which may cause both therapeutic benefits and potential off-target effects. Furthermore, we propose a chemical proteomics-based drug discovery approach to achieve desired therapeutic effects by selectively covalently modifying cysteines in target proteins. These findings advocate for a broader understanding of the Nrf2-independent mechanisms of electrophilic Nrf2 activators, thereby improving drug discovery strategies that target neurodegenerative diseases while minimizing toxicity.
核因子E2相关因子2（Nrf2）-抗氧化反应元件（ARE）通路是中枢神经系统疾病潜在的治疗靶点。本综述强调氧化应激和神经炎症在神经退行性疾病中的作用，突出了如富马酸二甲酯（DMF）等Nrf2激活剂的治疗潜力。DMF最初用于治疗银屑病，已在多发性硬化症中显示出疗效，且会代谢为单甲基富马酸酯，后者可能发挥显著的治疗作用。DMF激活Nrf2-ARE通路，近期研究表明其抗炎作用通过Nrf2非依赖机制发生。亲电Nrf2激活剂，如DMF，与蛋白质中的半胱氨酸残基共价结合并调节其功能。我们讨论了DMF对半胱氨酸残基修饰的影响，这可能带来治疗益处和潜在的脱靶效应。此外，我们提出一种基于化学蛋白质组学的药物发现方法，通过选择性地共价修饰靶蛋白中的半胱氨酸来实现预期的治疗效果。这些发现倡导更广泛地理解亲电Nrf2激活剂的Nrf2非依赖机制，从而改进针对神经退行性疾病的药物发现策略，同时将毒性降至最低。
