中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (3): 642-649.doi: 10.4103/1673-5374.380904

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

β-谷甾醇改善脑缺血再灌注损伤:抑制胆固醇过载、内质网应激以及凋亡

  

  • 出版日期:2024-03-15 发布日期:2023-09-02
  • 基金资助:
    国家自然科学基金项目(82104158,31800887,31972902,82001422);中国博士后科学基金项目(2020M683750);陕西省高校科协青年人才基金项目(20200307)

Treatment with β-sitosterol ameliorates the effects of cerebral ischemia/reperfusion injury by suppressing cholesterol overload, endoplasmic reticulum stress, and apoptosis

Xiuling Tang1, #, Tao Yan1, #, Saiying Wang1, #, Qingqing Liu1, Qi Yang1, Yongqiang Zhang1, Yujiao Li2, Yumei Wu3, Shuibing Liu3, #br# Yulong Ma4, *, Le Yang1, 5, *#br#   

  1. 1Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China; 2Department of Clinical Pharmacy, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China; 3Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi’an, Shaanxi Province, China; 4Department of Anesthesiology, The First Medical Center of Chinese PLA General Hospital, Beijing, China; 5Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, Air Force Medical University, Xi’an, Shaanxi Province, China
  • Online:2024-03-15 Published:2023-09-02
  • Contact: Yulong Ma, PhD, yulongma123@163.com; Le Yang, PhD, yanglefmmu@163.com.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China, Nos. 82104158 (to XT), 31800887 (to LY), 31972902 (to LY), 82001422 (to YL), China Postdoctoral Science Foundation, No. 2020M683750 (to LY), and partially by Young Talent Fund of University Association for Science and Technology in Shaanxi Province of China, No. 20200307 (to LY).

摘要:

β-谷甾醇是一种植物类甾醇,既往研究显示,其具有抗氧化、抗高血脂、抗炎、免疫调节、抗肿瘤等方面的作用,但未见其治疗缺血性脑卒中方面的报道。体内实验首先发现,β-谷甾醇可减轻大脑中动脉闭塞建立的缺血性脑卒中小鼠模型脑梗死体积以及脑水肿,减少脑组织中神经元凋亡,缓解神经功能障碍;且β-谷甾醇也能增加氧糖剥夺大脑皮质神经元活性,并减少细胞凋亡。进一步研究发现,β-谷甾醇的神经保护作用可能与抑制缺血性脑卒中后细胞内胆固醇积累引起的内质网应激有关。此外,β-谷甾醇具有作为胆固醇的关键转运蛋白NPC1L1拮抗剂的高亲和力。由此提示,β-谷甾醇可能通过抑制神经元内胆固醇过载、内质网应激以及凋亡信号通路,在治疗缺血性脑卒中中发挥作用。

https://orcid.org/0009-0002-1999-4503 (Le Yang)

关键词:

细胞凋亡, 血脑屏障, β-谷甾醇, 脑缺血再灌注损伤, 胆固醇过载, 内质网应激, 缺血性脑卒中, 分子对接, NPC1L1, 胆固醇转运

Abstract: β-Sitosterol is a type of phytosterol that occurs naturally in plants. Previous studies have shown that it has anti-oxidant, anti-hyperlipidemic, anti-inflammatory, immunomodulatory, and anti-tumor effects, but it is unknown whether β-sitosterol treatment reduces the effects of ischemic stroke. Here we found that, in a mouse model of ischemic stroke induced by middle cerebral artery occlusion, β-sitosterol reduced the volume of cerebral infarction and brain edema, reduced neuronal apoptosis in brain tissue, and alleviated neurological dysfunction; moreover, β-sitosterol increased the activity of oxygen- and glucose-deprived cerebral cortex neurons and reduced apoptosis. Further investigation showed that the neuroprotective effects of β-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke. In addition, β-sitosterol showed high affinity for NPC1L1, a key transporter of cholesterol, and antagonized its activity. In conclusion, β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.

Key words: apoptosis, blood-brain barrier, β-sitosterol, cerebral ischemia/reperfusion injury, cholesterol overload, cholesterol transport, endoplasmic reticulum stress, ischemic stroke, molecular docking, NPC1L1