Monomethyl fumarate promotes Nrf2-dependent neuroprotection in retinal ischemia-reperfusion.
Monomethyl fumarate promotes Nrf2-dependent neuroprotection in retinal ischemia-reperfusion.
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DOI：
10.1186/s12974-015-0452-z
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发表时间：
2015-12-21
影响因子：
9.3
通讯作者：
Duh EJ
中科院分区：
文献类型：
--
作者：
Cho H;Hartsock MJ;Xu Z;He M;Duh EJ
视网膜缺血导致神经元变性，是多种致盲疾病的发病机制之一。最近，富马酸酯富马酸二甲酯（DMF）已被fda批准用于治疗多发性硬化症，基于其神经保护和抗炎作用。它作为视网膜疾病的神经保护剂的潜在作用很少受到关注。此外，DMF的作用方式尚不清楚，尽管研究表明核因子红细胞2相关因子2 （Nrf2）激活是一个重要的机制。本文研究了富马酸单甲基（MMF）的生物活性代谢物在视网膜缺血再灌注（I/R）损伤中的神经保护作用，并研究了Nrf2在介导MMF作用中的作用。野生型C57BL/6J和Nrf2敲除（KO）小鼠进行90 min的视网膜缺血再灌注。小鼠每天腹腔注射MMF。在I/R损伤后48 h，采用定量反转录PCR （qRT-PCR）检测炎症基因表达。I/R后第7天，行Nrf2靶基因表达qRT-PCR检测，神经节细胞层（GCL）神经胶质化和细胞丢失免疫染色检测，视网膜电图检测视网膜功能。本研究结果证实MMF以nrf2依赖的方式减少视网膜神经变性。MMF处理显著增加了nrf2调控的抗氧化基因的表达，抑制了炎症基因的表达，减少了<s:1> ller细胞胶质细胞增生，减少了GCL中神经元细胞的损失，改善了野生型小鼠视网膜I/R损伤后视网膜电图（ERG）的视网膜功能。重要的是，这些mmf介导的有益作用未在Nrf2 KO小鼠中观察到。这些结果表明富马酸酯（FAEs）在视网膜I/R模型中发挥神经元保护功能，进一步验证了Nrf2调节是FAEs的主要作用方式。这表明DMF和FAEs可能是激活视网膜和可能的全身性疾病中Nrf2通路的潜在治疗剂。本文的在线版本（doi:10.1186/s12974-015-0452-z）包含补充材料，可供授权用户使用。
Retinal ischemia results in neuronal degeneration and contributes to the pathogenesis of multiple blinding diseases. Recently, the fumaric acid ester dimethyl fumarate (DMF) has been FDA-approved for the treatment of multiple sclerosis, based on its neuroprotective and anti-inflammatory effects. Its potential role as a neuroprotective agent for retinal diseases has received little attention. In addition, DMF’s mode of action remains elusive, although studies have suggested nuclear factor erythroid 2-related factor 2 (Nrf2) activation as an important mechanism. Here we investigated the neuroprotective role of monomethyl fumarate (MMF), the biologically active metabolite of DMF, in retinal ischemia-reperfusion (I/R) injury, and examined the role of Nrf2 in mediating MMF action. Wild-type C57BL/6J and Nrf2 knockout (KO) mice were subjected to 90 min of retinal ischemia followed by reperfusion. Mice received daily intraperitoneal injection of MMF. Inflammatory gene expression was measured using quantitative reverse transcription PCR (qRT-PCR) at 48 h after I/R injury. Seven days after I/R, qRT-PCR for Nrf2 target gene expression, immunostaining for Müller cell gliosis and cell loss in the ganglion cell layer (GCL), and electroretinography for retinal function were performed. The results of this study confirmed that MMF reduces retinal neurodegeneration in an Nrf2-dependent manner. MMF treatment significantly increased the expression of Nrf2-regulated antioxidative genes, suppressed inflammatory gene expression, reduced Müller cell gliosis, decreased neuronal cell loss in the GCL, and improved retinal function measured by electroretinogram (ERG) after retinal I/R injury in wild-type mice. Importantly, these MMF-mediated beneficial effects were not observed in Nrf2 KO mice. These results indicate that fumaric acid esters (FAEs) exert a neuronal protective function in the retinal I/R model and further validate Nrf2 modulation as a major mode of action of FAEs. This suggests that DMF and FAEs could be a potential therapeutic agent for activation of the Nrf2 pathway in retinal and possibly systemic diseases. The online version of this article (doi:10.1186/s12974-015-0452-z) contains supplementary material, which is available to authorized users.