Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (12): 2733-2742.doi: 10.4103/1673-5374.373676

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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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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