Necrosulfonamide Ameliorates Neurological Impairment in Spinal Cord Injury by Improving Antioxidative Capacity
Necrosulfonamide Ameliorates Neurological Impairment in Spinal Cord Injury by Improving Antioxidative Capacity
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DOI：
10.3389/fphar.2019.01538
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发表时间：
2020-01-09
影响因子：
5.6
通讯作者：
Wu, Minfei
中科院分区：
文献类型：
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作者：
Jiao, Jianhang;Wang, Yang;Wu, Minfei
脊髓损伤(SCI)目前尚无有效的治疗方法。脊髓损伤后的缺氧症是导致组织破坏的关键问题，而脊髓损伤后的低氧在引起炎症的同时也会导致细胞损伤。混合系激酶区样蛋白(MLKL)是坏死性下垂的关键信号分子，线粒体功能障碍被认为是脊髓损伤后最关键的事件之一。基于MLKL在细胞损伤中的重要作用和线粒体功能障碍的潜在作用，我们的研究重点是NSA在缺氧缺糖(OGD)诱导的细胞损伤和脊髓损伤小鼠线粒体功能障碍中对MLKL的调节作用，从而特异性地阻断MLKL。我们的结果表明，NSA可以保护线粒体膜电位、三磷酸腺苷、谷胱甘肽和超氧化物歧化酶水平的下降，以及活性氧和丙二醛水平的增加。NSA还通过不依赖于受体相互作用蛋白激酶3(RIP3)的磷酸化抑制MLKL的激活来改善脊髓损伤小鼠的运动功能和OGD诱导的脊髓神经元损伤。除了保护作用外，NSA还展示了一个治疗窗口。脊髓损伤模型的最佳治疗时间为伤后12h内。总之，我们的数据表明，抑制p-MLKL的NSA水平不依赖于RIP3的磷酸化，与通过提高脊髓损伤后的抗氧化能力而诱导的神经损伤之间存在密切的联系。NSA通过抑制MLKL依赖的坏死性下垂改善脊髓损伤后的神经功能损害。为NSA在脊髓损伤治疗中的进一步研究和应用提供了理论依据。
Currently, there is no efficient therapy for spinal cord injury (SCI). Anoxemia after SCI is a key problem, which leads to tissue destruction, while hypoxia after SCI induces cell injury along with inflammation. Mixed-lineage kinase domain-like protein (MLKL) is a critical signal molecule of necroptosis, and mitochondrial dysfunction is regarded as one of the most pivotal events after SCI. Based on the important role of MLKL in cell damage and potential role of mitochondrial dysfunction, our study focuses on the regulation of MLKL by Necrosulfonamide (NSA) in mitochondrial dysfunction of oxygen-glucose deprivation (OGD)-induced cell damage and SCI-mice, which specifically blocks the MLKL. Our results showed that NSA protected against a decrease in the mitochondrial membrane potential, adenosine triphosphate, glutathione, and superoxide dismutase levels and an increase in reactive oxygen species and malonyldialdehyde levels. NSA also improved the locomotor function in SCI-mice and OGD-induced spinal neuron injury through inhibition of MLKL activation independently of receptor-interacting protein kinase 3 (RIP3) phosphorylation. Besides the protective effects, NSA exhibited a therapeutic window. The optimal treatment time was within 12 h after the injury in the SCI-mice model. In conclusion, our data suggest a close association between the NSA level inhibiting p-MLKL independently of RIP3 phosphorylation and induction of neurological impairment by improving antioxidative capacity after SCI. NSA ameliorates neurological impairment in SCI through inhibiting MLKL-dependent necroptosis. It also provides a theoretical basis for further research and application of NSA in the treatment of SCI.