Wang Xingyu, Shen Zhihao, Zhang Haojie, Zhang Hao-Jie, Li Feida, Yu Letian, Chen Hua, Zhou Kailiang, Xu Hui, Sheng Sunren
Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University; Zhejiang Provincial Key Laboratory of Orthopedics; The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
Renji College of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
Neural Regen Res. 2023 Dec;18(12):2733-2742. doi: 10.4103/1673-5374.373676.
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.
脊髓损伤是骨科领域的一项挑战，因为它会对中枢神经系统造成不可逆的损害。因此，早期治疗以防止损伤扩大对于脊髓损伤患者的管理至关重要。贝沙罗汀是一种类视黄醇，对皮肤T细胞淋巴瘤和帕金森病患者具有治疗作用。贝沙罗汀已被证明可促进自噬，但尚未用于治疗脊髓损伤。为了研究贝沙罗汀对脊髓损伤的影响，我们建立了T11 - T12脊髓挫伤小鼠模型，并连续5天每天腹腔注射贝沙罗汀。我们发现，贝沙罗汀有效减少了损伤脊髓中胶原蛋白的沉积和病理性神经元的数量，增加了神经细胞的突触数量，降低了氧化应激，抑制了细胞焦亡，促进了运动功能的恢复，并减少了死亡。用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。贝沙罗汀增强了转录因子E3的核转位，进而激活了AMP激活的蛋白激酶 - S期激酶相关蛋白2 - 共激活因子相关精氨酸甲基转移酶1和AMP激活的蛋白激酶 - 雷帕霉素哺乳动物靶标信号通路。静脉注射转录因子E3的短发夹RNA或腹腔注射AMP激活的蛋白激酶阻滞剂化合物C可抑制贝沙罗汀的作用。这些发现表明，贝沙罗汀通过AMP激活的蛋白激酶 - S期激酶相关蛋白2 - 共激活因子相关精氨酸甲基转移酶1和AMP激活的蛋白激酶 - 雷帕霉素哺乳动物靶标信号通路调节转录因子E3的核转位，促进自噬，降低活性氧水平，抑制细胞焦亡，并改善脊髓损伤后的运动功能。
