依达拉奉右莰醇下调中性粒细胞胞外诱捕网表达并改善急性缺血性脑卒中血脑屏障通透性。
Edaravone Dexborneol Downregulates Neutrophil Extracellular Trap Expression and Ameliorates Blood-Brain Barrier Permeability in Acute Ischemic Stroke.
机构信息
Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
Hebei Key Laboratory of Vascular Homeostasis and Hebei Collaborative Innovation Center for Cardio-Cerebrovascular Disease, Shijiazhuang 050000, China.
出版信息
Mediators Inflamm. 2022 Aug 18;2022:3855698. doi: 10.1155/2022/3855698. eCollection 2022.
BACKGROUND
Our previous work has shown that inflammatory processes play a detrimental role in the pathophysiology of acute ischemic stroke (AIS). Neutrophil extracellular traps (NETs) have been recognized as a key contributor to the proinflammatory response in AIS and could aggravate blood-brain barrier (BBB) damage. Recently, experimental and clinical researches showed that Edaravone Dexborneol (Eda.B), which is comprised of two active ingredients, Edaravone and (+)-Borneol, was effective in treatment of AIS. However, it is not clear whether the effects of Eda.B against AIS are related to NETs and BBB permeability.
METHODS
Experiment 1 was to detect the effects of Eda.B in AIS patients. Serum samples of volunteers and AIS patients were collected before and 3 days after Edaravone Dexborneol treatment. Markers of NETs and occludin were detected by ELISA kit. Experiment 2 was to explore the effects of Eda.B on experimental stroke mice. Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (MCAO) and treated with vehicle, Eda.B, or DeoxyribonueleaseI (DNase I). After stroke, the neurobehavioral tests, infarct volume, and cerebral blood flow evaluation were determined. Leakage of Evans blue was to assess the integrity of BBB. Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence were used to examine the expression of NETs and tight junction- (TJ-) associated proteins.
RESULTS
Eda.B significantly improved neurological function and cerebral blood flow but reduced infarct volume after experimental stroke. Eda.B downregulated level of NETs in serum samples of AIS patients and tissue samples of MCAO mouse cortex. Eda.B and DNase I alleviated BBB permeability by upregulating TJ-associated proteins.
CONCLUSION
NETs are related to the early stage of AIS. Eda.B exerted neuroprotective effects and ameliorated BBB permeability after AIS.
背景
我们之前的工作表明，炎症过程在急性缺血性脑卒中（AIS）的病理生理学中起着有害作用。中性粒细胞胞外诱捕网（NETs）已被认为是 AIS 中促炎反应的关键因素，并可能加重血脑屏障（BBB）损伤。最近，实验和临床研究表明，由两种活性成分依达拉奉和（+）-冰片组成的依达拉奉右莰醇（Eda.B）对 AIS 治疗有效。然而，尚不清楚 Eda.B 对 AIS 的作用是否与 NETs 和 BBB 通透性有关。
方法
实验 1 旨在检测 Eda.B 在 AIS 患者中的作用。收集志愿者和 AIS 患者治疗前和治疗后 3 天的血清样本。通过 ELISA 试剂盒检测 NETs 和 occludin 标志物。实验 2 旨在探讨 Eda.B 对实验性中风小鼠的作用。雄性 C57BL/6 小鼠接受大脑中动脉闭塞（MCAO），并用载体、Eda.B 或脱氧核糖核酸酶 I（DNase I）治疗。中风后，进行神经行为学测试、梗死体积和脑血流评估。伊文思蓝渗漏用于评估 BBB 的完整性。Western blot、实时定量聚合酶链反应（RT-qPCR）和免疫荧光用于检测 NETs 和紧密连接相关蛋白的表达。
结果
Eda.B 显著改善了实验性中风后神经功能和脑血流，但减少了梗死体积。Eda.B 下调了 AIS 患者血清样本和 MCAO 小鼠皮质组织样本中 NETs 的水平。Eda.B 和 DNase I 通过上调 TJ 相关蛋白来减轻 BBB 通透性。
结论
NETs 与 AIS 的早期阶段有关。Eda.B 在 AIS 后发挥神经保护作用并改善 BBB 通透性。
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