中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (12): 2733-2742.doi: 10.4103/1673-5374.373676

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

贝沙罗汀改善脊髓损伤后运动功能的机制

  

  • 出版日期:2023-12-15 发布日期:2023-06-15
  • 基金资助:
    浙江省医药卫生科技项目（2021KY214）；浙江省中医药科技项目（2021ZB183）

Bexarotene improves motor function after spinal cord injury in mice

Xingyu Wang1, 2, 3, Zhihao Shen1, 2, 3, Haojie Zhang1, 2, 3, Hao-Jie Zhang1, 2, 3, Feida Li1, 2, 3, Letian Yu4, Hua Chen1, 2, 3, Kailiang Zhou1, 2, 3, *, Hui Xu1, 2, 3, *, Sunren Sheng1, 2, 3, *   

  1. 1Department of Orthopedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; 2Zhejiang Provincial Key Laboratory of Orthopedics, Wenzhou, Zhejiang Province, China; 3The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; 4Renji College of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
  • Online:2023-12-15 Published:2023-06-15
  • Contact: Kailiang Zhou, MD, PhD, zhoukailiang@wmu.edu.cn; Hui Xu, MD, PhD; Sunren Sheng, MD, PhD, shengsunren82330@126.com.
  • Supported by:
    This study was supported by grants from Zhejiang Provincial Medicine and Health Technology Project, No. 2021KY214 (to SS); and Zhejiang Provincial Science and Technology Project of Traditional Chinese Medicine, No. 2021ZB183 (to HX).

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摘要：

贝沙罗汀已被证明能促进自噬，但其尚未应用于脊髓损伤的治疗中。为了解其对脊髓损伤的影响，实验建立了小鼠T11-T12脊髓挫伤模型，然后连续5d腹腔注射贝沙罗汀进行治疗。结果发现，贝沙罗汀可有效减少损伤脊髓中胶原沉积和病变神经元数量，增加神经细胞突触数量，减轻氧化应激，抑制细胞焦亡，促进运动功能的恢复，减少小鼠死亡。进一步研究发现，以3-甲基腺嘌呤抑制自噬可逆转贝沙罗汀对脊髓损伤的作用。同时贝沙罗汀还可增强促进脊髓损伤后转录因子E3的激活和核易位，并激活AMPK-SKP2-CARM1和AMPK-mTOR信号通路，而静脉注射TFE3 shRNA或腹腔注射AMPK抑制剂化合物C均可抑制贝沙罗汀的作用。提示贝沙罗汀可通过AMPK-SKP2-CARM1和AMPK-mTOR信号通路调节转录因子E3核易位，促进细胞自噬，以降低活性氧平，并抑制细胞焦亡，最终改善脊髓损伤后运动功能。

https://orcid.org/0000-0001-7795-576X (Kailiang Zhou); https://orcid.org/0000-0001-8277-7590 (Sunren Sheng); https://orcid.org/0000-0003-0540-4250 (Xingyu Wang); https://orcid.org/0009-0007-9455-5961 (Haojie Zhang); https://orcid.org/0000-0003-1395-3364 (Hao-Jie Zhang)

关键词: 脊髓损伤, 贝沙罗汀, 转录因子E3, 自噬, 焦亡, 氧化应激, 有丝分裂, 活性氧, AMP依赖的蛋白激酶, 3-甲基腺嘌呤

Abstract: Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system. Therefore, early treatment to prevent lesion expansion is crucial for the management of patients with spinal cord injury. Bexarotene, a type of retinoid, exerts therapeutic effects on patients with cutaneous T-cell lymphoma and Parkinson’s disease. Bexarotene has been proven to promote autophagy, but it has not been used in the treatment of spinal cord injury. To investigate the effects of bexarotene on spinal cord injury, we established a mouse model of T11–T12 spinal cord contusion and performed daily intraperitoneal injection of bexarotene for 5 consecutive days. We found that bexarotene effectively reduced the deposition of collagen and the number of pathological neurons in the injured spinal cord, increased the number of synapses of nerve cells, reduced oxidative stress, inhibited pyroptosis, promoted the recovery of motor function, and reduced death. Inhibition of autophagy with 3-methyladenine reversed the effects of bexarotene on spinal cord injury. Bexarotene enhanced the nuclear translocation of transcription factor E3, which further activated AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signaling pathways. Intravenous injection of transcription factor E3 shRNA or intraperitoneal injection of compound C, an AMP-activated protein kinase blocker, inhibited the effects of bexarotene. These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways, promotes autophagy, decreases reactive oxygen species level, inhibits pyroptosis, and improves motor function after spinal cord injury.

Key words: 3‐methyladenine, AMP-activated protein kinase, autophagy, bexarotene, mitophagy, oxidative stress, pyroptosis, reactive oxygen species, spinal cord injury, transcription factor E3