Neural Regeneration Research ›› 2019, Vol. 14 ›› Issue (3): 532-541.doi: 10.4103/1673-5374.245480

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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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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