中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (3): 532-541.doi: 10.4103/1673-5374.245480

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

去铁胺抑制铁死亡可促进创伤性脊髓损伤恢复

  

  • 出版日期:2019-03-15 发布日期:2019-03-15
  • 基金资助:

    国家自然科学基金(81672171，81330042，81620108018，81772342)；国家重点药物化学实验室(南开大学)项目(2017027)

Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis

Xue Yao1, 2, 3, Yan Zhang1, 3, Jian Hao1, 4, Hui-Quan Duan1, 3, Chen-Xi Zhao1, 3, Chao Sun1, 3, Bo Li1, 3, Bao-You Fan1, 3, Xu Wang1, 3, Wen-Xiang Li1, 3, Xuan-Hao Fu1, 3, Yong Hu5, Chang Liu6, Xiao-Hong Kong6, Shi-Qing Feng1, 3, 7   

  1. 1 Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
    2 State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
    3 International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin, China
    4 Department of Orthopedics, Nankai Hospital, Tianjin, China
    5 Department of Orthopedic and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
    6 School of Medicine, Nankai University, Tianjin, China
    7 Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China
  • Online:2019-03-15 Published:2019-03-15
  • Contact: Shi-Qing Feng, sqfeng@tmu.edu.cn.
  • Supported by:

    This study was supported by the National Natural Science Foundation of China, No. 81672171 (to XY), 81330042 (to SQF),81620108018 (to SQF), 81772342; the State Key Laboratory of Medicinal Chemical Biology (Nankai University), China, No. 2017027.

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摘要：

铁死亡是一种依赖铁的细胞死亡方式，谷胱甘肽过氧化物酶4(GPX4)、谷氨酸/半胱氨酸转运体(xCT)在铁死亡中扮演重要角色，但铁死亡在脊髓损伤中的作用至今尚无报道。为阐明去铁胺能否通过抑制铁死亡修复脊髓损伤，以及铁死亡在脊髓损伤中作用，实验用Allen法重物自由落体打击法构建胸10(T10)节段脊髓建立脊髓损伤模型大鼠，90只8周龄雌性Wistar大鼠购自中国北京军事医学科学院实验动物中心，损伤前半小时腹腔注射去铁胺(100 mg/kg)，设为实验组，同时设假手术组和SCI组作对照，连续给药7 d。(1) 电镜结果显示：与假手术组相比，脊髓损伤后SCI组出现了溶血现象，可导致铁过载，同时在SCI组损伤后1 h和24 h均观察到了铁死亡的显著特征性变化，即线粒体皱缩；(2) BBB评分显示：损伤后1，2，4，8周，实验组大鼠后肢功能恢复明显优于SCI组；(3) 铁离子浓度检测显示：实验组在损伤后1，4，24 h铁离子浓度明显低于SCI组；(4) Western blot结果显示：与SCI组相比，实验组GPX4、xCT及谷胱甘肽(GSH)蛋白表达在脊髓损伤后2，7 d显著升高；(5) RT-qPCR结果显示：相比于SCI组，损伤后1，8 h实验组铁死亡相关基因乙酰辅酶A合成酶2(Acsf2)、铁反应元件结合蛋白(Ireb2)的mRNA水平在脊髓损伤后明显升高；(6)苏木精-伊红染色显示：与SCI组相比，损伤后2，8周，实验组局部损伤组织存活神经元增多，同时去铁胺对胶质增生具有抑制作用；(7)上述数据说明，去铁胺可通过上调Xc-/GPX4通路抑制铁死亡修复脊髓损伤，我们认为，抑制铁死亡可作为治疗脊髓损伤的一个新方法进行深入探讨。

orcid: 0000-0001-9437-7674(Shi-Qing Feng)

关键词: 铁, 脊髓损伤, 继发性损伤, 铁死亡, 去铁胺, 谷胱甘肽过氧化物酶4, 谷氨酸半胱氨酸转运体, 治疗, 胶质细胞增生, 脂质过氧化反应, 神经再生

Abstract:

Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen’s method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows: (1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group. (2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferox¬amine group than in the spinal cord injury group. (3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury. (4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group. (5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2 (ACSF2) and iron-responsive element-binding protein 2 (IREB2) were up-regulated in the Deferoxamine group. (6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.

Key words: nerve regeneration, iron, spinal cord injury, secondary injury, ferroptosis, deferoxamine, GPX4, xCT, treatment, astrogliosis, lipid peroxidation, neural regeneration