中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (11): 2429-2435.doi: 10.4103/1673-5374.371367

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

环状活性多肽Cyclo(MQCNS)有治疗缺血性脑卒中的潜力

  

  • 出版日期:2023-11-15 发布日期:2023-05-04

Cyclo (MQCNS) has the potential to treat ischemic stroke

Zhibing Song1, 2, Xinyu Li1, Mengting Lv1, Yuchen Guo3, Shanshan Deng1, Yuefan Zhang1, *, Tiejun Li1, *   

  1. 1School of Medicine, Shanghai University, Shanghai, China; 2College of Biological and Medical Engineering, Donghua University, Shanghai, China; 3College of Pharmacology, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
  • Online:2023-11-15 Published:2023-05-04
  • Contact: Tiejun Li, PhD, ltj204@163.com; Yuefan Zhang, PhD, yuefanzhang@shu.edu.cn.

摘要:

作者既往研究发现,单核细胞迁移抑制因子对脑卒中急性期缺血性损伤有神经保护作用,因此对抗炎五肽—单核细胞迁移抑制因子进行结构修饰,构建出一种结构及药理活性更优环状活性多肽Cyclo (MQCNS)(LZ-3),拟探索其对缺血性脑卒中的干预效果。实验首先以大脑中动脉闭塞方法构建了缺血性脑卒中模型,然后连续7d尾静脉注射LZ-3(2或4 mg/kg)进行治疗,结果显示,LZ-3能显著缩小脑梗死体积,减少皮质中神经细胞死亡,改善大鼠神经神经功能,减轻大脑皮质和海马组织病理损伤,降低血清和脑组织中炎性因子的水平。实验进一步在氧糖剥夺复氧诱导的BV2细胞模型中发现,LZ-3(100μM)可抑制JAK1-STAT6信号通路。最后发现LZ-3可调节缺血性脑卒中大鼠大脑皮质中小胶质细胞从M1到M2的极化,并可通过JAK1/STAT6信号通路抑制损伤BV2细胞的吞噬和迁移能力。因此得出LZ-3可通过抑制JAK1/STAT6信号通路调节小胶质细胞的活化,进而促进缺血性脑卒中后神经功能的恢复。

https://orcid.org/0000-0002-8319-8125 (Tiejun Li); https://orcid.org/0000-0003-3676-3280 (Zhibing Song)

关键词: LZ-3, 单核细胞移动抑制因子, 脑卒中, 功能恢复, 皮质, 小胶质细胞, 巨噬细胞, JAK1, STAT6, 极化, 吞噬

Abstract: We previously found that monocyte locomotion inhibitory factor has a neuroprotective effect on ischemic brain injury during the acute phase of stroke. Therefore, we modified the structure of an anti-inflammatory monocyte locomotion inhibitory factor peptide to construct an active cyclic peptide—Cyclo (MQCNS) (LZ-3)—and investigated its effects on ischemic stroke. In this study, we established a rat model of ischemic stroke by occluding the middle cerebral artery and then administered LZ-3 (2 or 4 mg/kg) via the tail vein for 7 consecutive days. Our results showed that LZ-3 (2 or 4 mg/kg) substantially decreased infarct volume, reduced cortical nerve cell death, improved neurological function, reduced cortical and hippocampal injury, and decreased the levels of inflammatory factors in the blood and brain tissues. In a well-differentiated, oxygen-glucose deprivation/reoxygenation-induced BV2 cell model of post-stroke, LZ-3 (100 μM) inhibited the JAK1-STAT6 signaling pathway. LZ-3 regulated microglia/macrophage polarization from the M1 to the M2 type and inhibited microglia/macrophage phagocytosis and migration via the JAK1/STAT6 signaling pathway. To conclude, LZ-3 regulates microglial activation by inhibiting the JAK1/STAT6 signaling pathway and improves functional recovery post-stroke.

Key words: cortex, functional recovery, JAK1, LZ-3, macrophage, microglia, monocyte locomotion inhibitory factor, phagocytosis, polarization, post-stroke, STAT6