中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (4): 881-888.doi: 10.4103/1673-5374.353496

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

促红细胞生成素可抑制铁死亡改善脊髓损伤后的神经功能

  

  • 出版日期:2023-04-15 发布日期:2022-10-29
  • 基金资助:
    国家自然科学基金项目(81871785,81672161)

Erythropoietin inhibits ferroptosis and ameliorates neurological function after spinal cord injury

Yu Kang, Rui Zhu, Shuang Li, Kun-Peng Qin, Hao Tang, Wen-Shan Shan, Zong-Sheng Yin*   

  1. Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
  • Online:2023-04-15 Published:2022-10-29
  • Contact: Zong-Sheng Yin, MD, ahmu_zsyin@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81871785 and 81672161 (both to ZSY).

摘要:

铁死亡是脊髓损伤的重要病理事件之一。有研究认为促红细胞生成素可改善脊髓损伤的恢复,然而铁死亡是否参与促红细胞生成素对脊髓损伤的神经保护作用尚有待研究。实验建立了改良的重物坠落法建立的脊髓损伤模型大鼠,在其腹腔注射1000和5000 IU/kg促红细胞生成素,每周1次,持续2周。(1)发现两种剂量的促红细胞生成素均能促进脊髓损伤大鼠后肢功能恢复,且高剂量的效果更好。高剂量组对损伤脊髓内铁超负荷的抑制效果强于低剂量组。将促红细胞生成素与铁死亡抑制剂Fer-1进行对比发现,对于脊髓损伤大鼠,促红细胞生成素抑制铁死亡相关蛋白表达以及恢复线粒体形态的效果与Fer-1接近,而且其作用可被铁死亡激活剂RSL3削弱。(2)体外实验结果表明,促红细胞生成素可抑制RSL3诱导的PC12细胞铁死亡,提高细胞中胱氨酸/谷氨酸反向转运体及谷胱甘肽过氧化物酶的表达,表明胱氨酸/谷氨酸反向转运体/谷胱甘肽过氧化物酶4通路参与介导了促红细胞生成素对脊髓损伤的神经保护作用。(3)该研究揭示了红细胞生成素潜在的抗铁死亡作用,为治疗脊髓损伤提供了一种潜在的治疗策略。

https://orcid.org/0000-0001-9295-3623 (Yu Kang); 

https://orcid.org/0000-0003-3569-5861 (Rui Zhu); 

https://orcid.org/0000-0003-4284-1193 (Shuang Li); 
https://orcid.org/0000-0002-0605-8129 (Kun-Peng Qin); 

https://orcid.org/0000-0002-8756-3732 (Hao Tang); 

https://orcid.org/0000-0002-1577-694X (Wen-Shan Shan); 
https://orcid.org/0000-0002-4862-5443 (Zong-Sheng Yin)

关键词: 促红细胞生成素, 脊髓损伤, 铁死亡, 神经功能, 胱氨酸/谷氨酸反向转运体, 谷胱甘肽过氧化物酶4, 铁过载, 脂质过氧化, 神经元, PC12细胞

Abstract: Ferroptosis is one of the critical pathological events in spinal cord injury. Erythropoietin has been reported to improve the recovery of spinal cord injury. However, whether ferroptosis is involved in the neuroprotective effects of erythropoietin on spinal cord injury has not been examined. In this study, we established rat models of spinal cord injury by modified Allen’s method and intraperitoneally administered 1000 and 5000 IU/kg erythropoietin once a week for 2 successive weeks. Both low and high doses of erythropoietin promoted recovery of hindlimb function, and the high dose of erythropoietin led to better outcome. High dose of erythropoietin exhibited a stronger suppressive effect on ferroptosis relative to the low dose of erythropoietin. The effects of erythropoietin on inhibiting ferroptosis-related protein expression and restoring mitochondrial morphology were similar to those of Fer-1 (a ferroptosis suppressor), and the effects of erythropoietin were largely diminished by RSL3 (ferroptosis activator). In vitro experiments showed that erythropoietin inhibited RSL3-induced ferroptosis in PC12 cells and increased the expression of xCT and Gpx4. This suggests that xCT and Gpx4 are involved in the neuroprotective effects of erythropoietin on spinal cord injury. Our findings reveal the underlying anti-ferroptosis role of erythropoietin and provide a potential therapeutic strategy for treating spinal cord injury.

Key words: erythropoietin, ferroptosis, Gpx4, iron overload, lipid peroxidation, mechanism, neurological function recovery, spinal cord injury, spinal neuron, xCT