Excess administration of miR-340-5p ameliorates spinal cord injury-induced neuroinflammation and apoptosis by modulating the P38-MAPK signaling pathway
Excess administration of miR-340-5p ameliorates spinal cord injury-induced neuroinflammation and apoptosis by modulating the P38-MAPK signaling pathway
复制标题
过量施用 miR-340-5p 通过调节 P38-MAPK 信号通路改善脊髓损伤诱导的神经炎症和细胞凋亡
DOI：
10.1016/j.bbi.2020.01.025
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发表时间：
2020-07-01
影响因子：
15.1
通讯作者：
Cao, Xiaojian
中科院分区：
文献类型：
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作者：
Qian, Zhanyang;Chang, Jie;Cao, Xiaojian
脊髓损伤(SCI)是一种破坏性的多发性神经病，可导致感觉运动功能丧失和括约肌功能障碍，危重时甚至死亡。MicroRNAs(MiRs)是一系列参与转录调控的非编码RNA分子。以往的研究表明，多个MIR的调节参与了脊髓损伤后神经功能的恢复。然而，miR-340-5p在脊髓损伤中的作用仍不明确。因此，我们探讨了miR-340-5p对脊髓损伤大鼠体内、外小胶质细胞的治疗作用及其机制。采用逆转录定量聚合酶链式反应(RT-qPCR)和免疫印迹法检测脊髓损伤后miR-340-5p和P38蛋白表达的变化。通过荧光素酶报告分析、免疫荧光分析和Western blotting确定小胶质细胞中的miR-340-5p靶点。建立脊髓损伤模型，给予miR-340-5P治疗。通过免疫荧光、免疫组织化学和组织学分析，评价miR-340-5p对脊髓损伤后炎症、氧化应激和细胞凋亡的改善作用。最后用Basso、Beattie、Bresna han评定量表判定运动功能恢复情况。在我们的研究中，表达谱和荧光素酶检测结果表明，P38是miR-340-5P的靶标，与P38-MAPK信号通路的激活有关。MiR-340-5p的升高降低了P38的表达，从而抑制了炎症反应。MiR-340-5P治疗可减轻脊髓损伤后继发性神经炎症。此外，通过控制神经炎症，miR-340-5p水平的增加可能会对抗氧化应激，降低细胞凋亡程度。我们还观察到，在脊髓损伤的慢性期，胶质增生和胶质瘢痕形成减少，神经营养因子表达增加。总之，miR-340-5P治疗的这些潜在作用最终改善了脊髓损伤大鼠的运动功能恢复。
Spinal cord injury (SCI) is a destructive polyneuropathy that can result in loss of sensorimotor function and sphincter dysfunction, and even death in critical situations. MicroRNAs (miRs) are a series of non-coding RNA molecules that are involved in transcriptional regulation. Previous studies have demonstrated that modulation of multiple miRs is involved in neurological recovery after SCI. However, the functions of miR-340-5p in SCI remain uncertain. Therefore, we probed the therapeutic effect and mechanism of miR-340-5p in microglia in vitro and in vivo in SCI rats. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were employed to examine the alterations in miR-340-5p and P38 levels in SCI rats. miR-340-5p targets in microglia were ascertained using luciferase reporter assays, immunofluorescence analyses, and western blotting. We also established an SCI model and administered miR-340-5p. The effects of miR-340-5p on the amelioration of inflammation, oxidative stress, and apoptosis following SCI were assessed using immunofluorescence, immunohistochemistry, and histological analyses. Finally, locomotor function recovery was determined using the Basso, Beattie, Bresnahan rating scale. In our study, the expression profiles and luciferase assay results clarified that P38 was a target of miR-340-5p, which was associated with activation of the P38-MAPK signaling pathway. Elevation of miR-340-5p decreased P38 expression, subsequently inhibiting the inflammatory reaction. SCI-induced secondary neuroinflammation was relieved under miR-340-5p treatment. Moreover, by controlling neuroinflammation, the increased levels of miR-340-5p might counter oxidative stress and reduce the degree of apoptosis. We also observed decreasing gliosis and glial scar formation and increasing neurotrophin expression at the chronic stage of SCI. Together, these potential effects of miR-340-5p treatment ultimately improved locomotor function recovery in SCI rats.