Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway
Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway
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DOI：
10.1093/brain/awq386
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发表时间：
2011-03-01
期刊：
影响因子：
14.5
通讯作者：
Gold, Ralf
中科院分区：
文献类型：
--
作者：
Linker, Ralf A.;Lee, De-Hyung;Gold, Ralf
炎症和氧化应激被认为会促进多发性硬化症的组织损伤。因此，增强细胞对自由基的抵抗力的新疗法可以证明对多发性硬化症治疗有用。BG 00012是富马酸二甲酯的口服制剂。在一项II期多发性硬化症试验中，BG 00012对复发率和指示炎症的磁共振成像标志物以及轴突破坏具有有益作用。首先，我们研究了富马酸二甲酯对慢性多发性硬化症动物模型（C57 BL/6小鼠中髓鞘少突胶质细胞糖蛋白诱导的实验性自身免疫性脑脊髓炎）的病程、中枢神经系统、组织完整性和分子作用机制的影响。在实验性自身免疫性脑脊髓炎的慢性期，预防性或治疗性应用富马酸二甲酯可改善病程，并改善髓鞘、轴突和神经元的保存。在体外实验中，应用阿托伐他汀可增加小鼠神经元存活率，并保护人类或啮齿动物星形胶质细胞免受氧化应激。富马酸二甲酯的应用导致转录因子核因子（红细胞衍生2）相关因子2的稳定、核因子（红细胞衍生2）相关因子2依赖性转录活性的激活和NADP（H）喹啉氧化还原酶-1作为原型靶基因的蓄积。此外，富马酸二甲酯的直接代谢产物富马酸单甲酯导致核因子（红细胞衍生2）相关因子2抑制剂Kelch样ECH相关蛋白1在半胱氨酸残基151处的直接修饰。反过来，增加水平的核因子（红细胞衍生2）相关的因子2和减少蛋白质亚硝基化检测到在中枢神经系统的二甲双胍治疗的小鼠。未经治疗的多发性硬化症患者尸检标本的脊髓中核因子（红细胞衍生2）相关因子2也上调。在二甲双胍治疗的小鼠患有实验性自身免疫性脑脊髓炎，核因子（红细胞衍生2）相关因子2的免疫反应性增加检测共聚焦显微镜在运动皮质和脑干的神经元，以及在少突胶质细胞和星形胶质细胞。在具有相同遗传背景的核因子（红细胞衍生2）相关因子2缺陷小鼠中，富马酸二甲酯介导的对临床病程、轴突保存和星形胶质细胞活化的有益作用几乎完全消除，从而证明了该转录因子与神经保护作用机制的功能相关性。我们得出结论，富马酸二甲酯激活核因子（红细胞衍生2）相关因子2的能力可能提供一种新的细胞保护方式，进一步增强多发性硬化组织中的天然抗氧化反应，尚未被其他多发性硬化症治疗靶向。
Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.