中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (1): 192-198.doi: 10.4103/1673-5374.290098

• 原著:视神经损伤修复保护与再生 • 上一篇    

氩气抑制视网膜缺血再灌注损伤后小胶质细胞活化和炎性细胞因子的表达

  

  • 出版日期:2021-01-15 发布日期:2020-11-26
  • 基金资助:

    这项工作得到了德国弗莱堡大学医学中心麻醉学和重症监护系的财政支持; 物品处理费由巴登-符腾堡州科学,研究与艺术部和弗莱堡大学在开放获取出版计划中资助

Argon reduces microglial activation and inflammatory cytokine expression in retinal ischemia/reperfusion injury

Ulrich Goebel, Stefanie Scheid, Sashko Spassov, Nils Schallner, Jakob Wollborn, Hartmut Buerkle, Felix Ulbrich*   

  1. Department of Anesthesiology and Critical Care, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Online:2021-01-15 Published:2020-11-26
  • Contact: Felix Ulbrich, MD, felix.ulbrich@uniklinik-freiburg.de.
  • Supported by:
    This work was financially supported by the Department of Anesthesiology and Critical Care, Medical Center - University of Freiburg, Germany. The article processing charge was funded by the Baden-Württemberg Ministry of Science, Research and Art and the University of Freiburg in the funding programme Open Access Publishing.

摘要:

已经研究显示,稀有气体氩有神经保护作用,但确切作用机制仍不清楚。实验应用鱼藤酮干预4h诱导损伤人类神经母细胞瘤细胞损伤,然后在氩气(75 vol%)的条件下作用2 h。另外进行的体内实验通过增加大鼠眼内压1h诱发视网膜缺血再灌注损伤,并再灌注后,吸入2h氩气。发现氩气减少了人类神经母细胞瘤细胞中涉及神经元损伤调节的多种转录因子:信号转导子和转录激活因子3、核因子κB、激活蛋白1和核转录因子E2 相关因子2的结合活力,并下调了细胞表面Fas配体的表达。toll 样受体TLR2和TLR4抑制剂OxPAPC可部分消除这些调节作用。氩气抑制了视网膜缺血再灌注损伤后的小胶质细胞活化,以及促炎性细胞因子白细胞介素1α,白细胞介素1ß,白细胞介素6,肿瘤坏死因子α和诱导型一氧化氮合酶mRNA的表达。实验结果表明,氩气可通过抑制对小胶质细胞活化至关重要的转录因子的活性,减轻了视网膜缺血再灌注损伤后视网膜神经元的炎症反应。氩气没有已知的副作用或麻醉特性;因此,这种稀有气体的治疗用途似乎可能成为治疗视网膜缺血/再灌注损伤中神经元受损患者的理想选择。

https://orcid.org/0000-0003-1175-9736 (Felix Ulbrich)

关键词:

氩气, 缺血再灌注损伤, 小胶质细胞, 神经炎症, 稀有气体, SH-SY5Y, toll样受体, 转录因子, 神经保护

Abstract: We previously found that argon exerts its neuroprotective effect in part by inhibition of the toll-like receptors (TLR) 2 and 4. The downstream transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) are also affected by argon and may play a role in neuroprotection. It also has been demonstrated that argon treatment could mitigate brain damage, reduce excessive microglial activation, and subsequently attenuate brain inflammation. Despite intensive research, the further exact mechanism remains unclear. In this study, human neuroblastoma cells were damaged in vitro with rotenone over a period of 4 hours (to mimic cerebral ischemia and reperfusion damage), followed by a 2-hour post-conditioning with argon (75%). In a separate in vivo experiment, retinal ischemia/reperfusion injury was induced in rats by increasing intraocular pressure for 1 hour. Upon reperfusion, argon was administered by inhalation for 2 hours. Argon reduced the binding of the transcription factors signal transducer and activator of transcription 3, nuclear factor kappa B, activator protein 1, and nuclear factor erythroid 2-related factor 2, which are involved in regulation of neuronal damage. Flow cytometry analysis showed that argon downregulated the Fas ligand. Some transcription factors were regulated by toll-like receptors; therefore, their effects could be eliminated, at least in part, by the TLR2 and TLR4 inhibitor oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC). Argon treatment reduced microglial activation after retinal ischemia/reperfusion injury. Subsequent quantitative polymerase chain reaction analysis revealed a reduction in the pro-inflammatory cytokines interleukin (IL-1α), IL-1β, IL-6, tumor necrosis factor α, and inducible nitric oxide synthase. Our results suggest that argon reduced the extent of inflammation in retinal neurons after ischemia/reperfusion injury by suppression of transcription factors crucial for microglial activation. Argon has no known side effects or narcotic properties; therefore, therapeutic use of this noble gas appears ideal for treatment of patients with neuronal damage in retinal ischemia/reperfusion injury. The animal experiments were approved by the Commission for Animal Care of the University of Freiburg (approval No. 35-9185.81/G14-122) on October 19, 2012. 

Key words: argon, ischemia/reperfusion injury, microglia, neuroinflammation, neuroprotection, noble gas, SH-SY5Y, toll-like receptor, transcription factor