中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (11): 2424-2428.doi: 10.4103/1673-5374.371366

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

3-正丁基苯酞对脑卒中的神经保护机制:调节缺氧诱导因子1α泛素化减轻氧化应激诱导细胞凋亡

  

  • 出版日期:2023-11-15 发布日期:2023-05-04

Dl-3-n-butylphthalide exerts neuroprotective effects by modulating hypoxia-inducible factor 1-alpha ubiquitination to attenuate oxidative stress-induced apoptosis

Shuai Li1, #, Jingyuan Zhao2, #, Yan Xi1, #, Jiaqi Ren1, Yanna Zhu1, Yan Lu3, *, Deshi Dong1, *   

  1. 1Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China; 2Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China; 3Department of Cardiology, Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
  • Online:2023-11-15 Published:2023-05-04
  • Contact: Deshi Dong, PhD, cpu200613@163.com; Yan Lu, PhD, Yan_lu439@126.com.

摘要:

小分子药物3-正丁基苯酞可用于治疗轻中度急性缺血性脑卒中,但其具体作用机制仍需进一步研究。为此,实验以过氧化氢诱导PC12细胞和RAW 264.7细胞损伤,以体外模拟脑卒中神经元氧化应激损伤,3-正丁基苯酞预处理24h进行干预。结果显示,3-正丁基苯酞预处理可明显抑制过氧化氢诱导的神经细胞活性下降以及活性氧产生,并对细胞凋亡起到抑制作用。进一步染色质免疫沉淀和泛素化分析结果显示,3-正丁基苯酞预处理可抑制促凋亡基因BAX和BNIP3的表达,而缺氧诱导因子1α是调节上述基因的关键转录因子,同时3-正丁基苯酞预处理可促进缺氧诱导因子1α的泛素化和降解。由此证实,3-正丁基苯酞可能通过促进缺氧诱导因子1α泛素化,抑制细胞凋亡,从而发挥对脑卒中的神经保护作用。

https://orcid.org/0000-0002-4943-6898 (Deshi Dong)

关键词: 3-正丁基苯酞, 神经保护, 氧化应激, 缺氧诱导因子1α, 泛素化, 转录因子, 脑卒中, 线粒体, 活性氧, 血脑屏障, 体外实验

Abstract: Dl-3-n-butylphthalide is used to treat mild and moderate acute ischemic stroke. However, the precise underlying mechanism requires further investigation. In this study, we investigated the molecular mechanism of Dl-3-n-butylphthalide action by various means. We used hydrogen peroxide to induce injury to PC12 cells and RAW264.7 cells to mimic neuronal oxidative stress injury in stroke in vitro and examined the effects of Dl-3-n-butylphthalide. We found that Dl-3-n-butylphthalide pretreatment markedly inhibited the reduction in viability and reactive oxygen species production in PC12 cells caused by hydrogen peroxide and inhibited cell apoptosis. Furthermore, Dl-3-n-butylphthalide pretreatment inhibited the expression of the pro-apoptotic genes Bax and Bnip3. Dl-3-n-butylphthalide also promoted ubiquitination and degradation of hypoxia inducible factor 1α, the key transcription factor that regulates Bax and Bnip3 genes. These findings suggest that Dl-3-n-butylphthalide exhibits a neuroprotective effect on stroke by promoting hypoxia inducible factor-1α ubiquitination and degradation and inhibiting cell apoptosis. 

Key words: blood-brain barrier, Dl-3-n-butylphthalide, hypoxia inducible factor 1α, mitochondria, neuroprotection, oxidative stress, reactive oxygen species, stroke, transcription factor, ubiquitination