中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (5): 1142-1149.doi: 10.4103/1673-5374.385308

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

溴隐亭保护脊髓损伤神经元免受脂毒性的影响

  

  • 出版日期:2024-05-15 发布日期:2023-11-01

Bromocriptine protects perilesional spinal cord neurons from lipotoxicity after spinal cord injury

Ying Peng1, #, Zhuoxuan Li1, #, Zhiyang Zhang2, #, Yinglun Chen3, Renyuan Wang1, Nixi Xu2, Yuanwu Cao2, Chang Jiang2, *, Zixian Chen2, *, Haodong Lin1, *   

  1. 1Trauma Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China; 3Department of Rehabilitation Medicine, Shanghai Geriatric Medical Center, Shanghai, China
  • Online:2024-05-15 Published:2023-11-01
  • Contact: Chang Jiang, MD, cjiang_fdu@yeah.net; Zixian Chen, PhD, MD, chen.zixian@zs-hospital.sh.cn; Haodong Lin, PhD, MD, haodonglin@hotmail.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82071376 (to ZC) and 82001471 (to CJ) and the Natural Science Foundation of Shanghai, No. 20ZR1410500 (to ZC).

PDF

28

摘要：

最近有研究表明，脑损伤后脂滴可在神经元中积聚，继而引起脂毒性，而损害神经元。然而，脊髓神经元的脂质代谢在脊髓损伤中的作用仍不清楚。此次实验拟研究脊髓损伤后神经元的脂质代谢，并希望筛选出降脂化合物来治疗脊髓损伤。结果发现，小鼠脊髓损伤后，脂滴可在病变周围的神经元中积累，且HT22细胞中的髓鞘碎片可诱导脂滴的积累。在磷脂酶降解髓鞘碎片后，产生了大量游离脂肪酸，进而增加脂滴合成、β-氧化和氧化磷酸化。过量的氧化磷酸化还可增加活性氧的生成，从而导致HT22细胞脂质过氧化和凋亡增加。高通量细胞成像分析系统筛选出溴隐亭，可作为一种降脂化合物，通过减少丝裂原活化蛋白激酶途径中细胞外信号调节激酶1/2的磷酸化来抑制胞质磷脂酶A2的磷酸化，从而抑制胞质磷脂A2对髓鞘碎片的降解，进而减少HT22细胞中脂滴的积累。同时溴隐亭治疗的脊髓损伤小鼠运动功能和神经元存活率也得到明显改善。实验结果提示，溴隐亭可通过细胞外信号调节激酶1/2/胞质磷脂酶A2通路保护脊髓损伤后神经元免受脂毒性损害。

https://orcid.org/0000-0002-7468-3372 (Chang Jiang); https://orcid.org/0000-0002-1784-0896 (Zixian Chen); https://orcid.org/0000-0001-5414-7516 (Haodong Lin)

关键词: 中枢神经系统, 脊髓损伤, 脊髓神经元, 脂滴, 脂毒性, 脂质代谢, 高含量筛选, 溴隐亭, 丝裂原活化蛋白激酶, 胞质磷脂酶A2

Abstract: Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity, damaging the neurons. However, how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear. Herein, we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury. We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice. Lipid droplet accumulation could be induced by myelin debris in HT22 cells. Myelin debris degradation by phospholipase led to massive free fatty acid production, which increased lipid droplet synthesis, β-oxidation, and oxidative phosphorylation. Excessive oxidative phosphorylation increased reactive oxygen species generation, which led to increased lipid peroxidation and HT22 cell apoptosis. Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway, thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells. Motor function, lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury. The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.

Key words: bromocriptine, central nervous system, cytosolic phospholipase A2, high-content screening, lipid droplet, lipid metabolism, lipotoxicity, mitogen-activated protein kinase, spinal cord injury, spinal cord neurons