Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway
Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway
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DOI：
10.1124/jpet.111.190132
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发表时间：
2012-04-01
影响因子：
3.5
通讯作者：
Rhodes, Kenneth J.
中科院分区：
文献类型：
--
作者：
Scannevin, Robert H.;Chollate, Sowmya;Rhodes, Kenneth J.
氧化应激是包括多发性硬化症在内的几种神经退行性疾病病理的核心，旨在增强抗氧化潜力的治疗方法可能具有临床价值。本研究的目的是研究富马酸二甲酯(DMF)及其主要代谢物富马酸单甲酯(MMF)对原代培养的中枢神经系统(CNS)细胞氧化损伤抵抗的潜在直接神经保护作用，并进一步探讨核因子(红系衍生2)样2(Nrf2)途径在这一过程中的依赖性和作用。用DMF或MMF处理动物或原代培养的CNS细胞后，活性Nrf2的核水平增加，随后规范的抗氧化靶基因上调。体内依赖DMF的抗氧化基因上调在缺乏Nrf2[Nrf2(-/-)]的小鼠中丢失。DMF或MMF以浓度依赖的方式增加细胞氧化还原电位、谷胱甘肽、三磷酸腺苷水平和线粒体膜电位。用DMF或MMF处理星形胶质细胞或神经元也能显著提高毒性氧化攻击后的细胞存活率，且呈浓度依赖关系。在消除或减少Nrf2的细胞中，这种对活性的影响消失了。这些数据表明，DMF和MMF对神经元和星形胶质细胞具有细胞保护作用，防止氧化应激诱导的细胞损伤和丢失，可能是通过上调Nrf2依赖的抗氧化反应来实现的。这些数据还表明，DMF和MMF可能通过改善线粒体功能而发挥作用。DMF在多发性硬化症中的临床应用正在通过BG-12的III期试验进行探索，BG-12是一种含有DMF作为活性成分的口服疗法。
Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis, and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels of active Nrf2, with subsequent up-regulation of canonical antioxidant target genes. DMF-dependent up-regulation of antioxidant genes in vivo was lost in mice lacking Nrf2 [Nrf2(-/-)]. DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels, and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2. These data suggest that DMF and MMF are cytoprotective for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via up-regulation of an Nrf2dependent antioxidant response. These data also suggest DMF and MMF may function through improving mitochondrial function. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic containing DMF as the active ingredient.