Edaravone is a candidate agent for spinal muscular atrophy: In vitro analysis using a human induced pluripotent stem cells-derived disease model
Edaravone is a candidate agent for spinal muscular atrophy: In vitro analysis using a human induced pluripotent stem cells-derived disease model
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DOI：
10.1016/j.ejphar.2017.08.005
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发表时间：
2017-11-05
影响因子：
5
通讯作者：
Hara, Hideaki
中科院分区：
文献类型：
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作者：
Ando, Shiori;Funato, Michinori;Hara, Hideaki
脊髓性肌萎缩症(SMA)是一种以脊髓运动神经元进行性丧失为特征的顽固性疾病，可导致骨骼肌无力和萎缩。目前，还没有治疗SMA的药物，尽管它被认为是由于存活运动神经元(SMN)蛋白水平降低所致。此外，为什么SMN蛋白水平降低会导致脊髓运动神经元选择性凋亡尚不清楚。本研究的目的是利用SMA患者的诱导多能干细胞(SMA-IPSCs)来评价自由基清除剂依达拉奉的治疗潜力，并研究氧化应激诱导的脊髓运动神经元的凋亡。我们首次发现依达拉奉可以改善SMA-IPSCs来源的脊髓运动神经元受损的神经发育，但对核SMN蛋白表达的影响有限。此外，依达拉奉还能抑制SMA-IPSCs来源的脊髓运动神经元中活性氧的产生和线粒体的活性氧的上调，并逆转氧化应激诱导的细胞凋亡。在本研究中，我们认为氧化应激可能是SMA病理中脊髓运动神经元选择性凋亡的部分原因，氧化应激诱导的细胞凋亡可能是SMA的治疗靶点。
Spinal muscular atrophy (SMA) is an intractable disease characterized by a progressive loss of spinal motor neurons, which leads to skeletal muscle weakness and atrophy. Currently, there are no curative agents for SMA, although it is understood to be caused by reduced levels of survival motor neuron (SMN) protein. Additionally, why reduced SMN protein level results in selective apoptosis in spinal motor neurons is still not understood. Our purpose in this study was to evaluate the therapeutic potential of edaravone, a free radical scavenger, by using induced pluripotent stem cells from an SMA patient (SMA-iPSCs) and to address oxidative stress-induced apoptosis in spinal motor neurons. We first found that edaravone could improve impaired neural development of SMA-iPSCs-derived spinal motor neurons with limited effect on nuclear SMN protein expression. Furthermore, edaravone inhibited the generation of reactive oxygen species and mitochondrial reactive oxygen species upregulated in SMA-iPSCs-derived spinal motor neurons, and reversed oxidative-stress induced apoptosis. In this study, we suggest that oxidative stress might be partly the reason for selective apoptosis in spinal motor neurons in SMA pathology, and that oxidative stress-induced apoptosis might be the therapeutic target of SMA.