Specific Frequency Electroacupuncture Stimulation Transiently Enhances the Permeability of the Blood-Brain Barrier and Induces Tight Junction Changes.
Specific Frequency Electroacupuncture Stimulation Transiently Enhances the Permeability of the Blood-Brain Barrier and Induces Tight Junction Changes.
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特定频率电针刺激短暂增强血脑屏障的通透性并引起紧密连接变化
DOI：
10.3389/fnins.2020.582324
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发表时间：
2020
影响因子：
4.3
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Zhang S;Gong P;Zhang J;Mao X;Zhao Y;Wang H;Gan L;Lin X
血脑屏障（blood-brain barrier，BBB）在脑的生理状态和药理状态中都起着重要作用。暂时增强BBB的通透性可能允许使用更多类型的药物治疗神经精神疾病。我们以前的研究表明，电针（EA）刺激在一定的参数可以提高BBB的通透性在Sprague-Dawley大鼠，但这种现象并没有得到很好的表征。我们认为，特定频率电针可以短暂开放血脑屏障，并可能与紧密连接（TJ）的变化有关。为了在常用的电针频率中寻找最佳的电针频率，并初步探讨其作用机制，本实验通过测定大脑皮层伊文思蓝和20 kDa FITC-葡聚糖荧光强度来检测血脑屏障通透性。然后，我们使用激光光谱仪，免疫荧光，免疫印迹，透射电镜检测血脑屏障开放的机制。最后测定脑组织含水量、AQP 4、GFAP、Iba 1，并采用DeadEndTM荧光原位末端标记（TUNEL）系统明确刺激是否引起明显的负性效应。结果表明：2/100 Hz电针刺激可使血脑屏障通透性最大化，电针停止后12 h血脑屏障关闭。电针刺激增加了大脑皮层的血液灌注、c-fos水平和P物质表达，降低了ZO-1和occludin水平，并诱导了TJ形态的超微结构变化。在特定参数下的EA刺激不会引起脑水肿、胶质细胞活化或细胞凋亡。这项研究表明，EA刺激引起可逆的，频率依赖性的BBB通透性的改变，并提出了一个假设的机制，BBB开放相关的血管舒张和TJ中断。在特定参数下用EA瞬时增强BBB的通透性可能是将治疗剂递送到中枢神经系统的新策略。需要对这项技术进行进一步的研究。
The blood-brain barrier (BBB) plays an important role in both the physiological state and pharmacological state of the brain. Transiently enhancing the permeability of the BBB may allow the use of more types of medications for neuropsychiatric diseases. Our previous research revealed that electroacupuncture (EA) stimulation at certain parameters can enhance the permeability of the BBB in Sprague-Dawley rats, but this phenomenon is not well characterized. We propose that specific frequency EA can transiently open the BBB and may be related to the change of tight junctions (TJ). To find the best EA frequency among commonly used frequencies, preliminarily explore the mechanism, we detected BBB permeability by measuring the intensity of Evans Blue and 20 kDa FITC-dextran fluorescence in the cerebral cortex. Then, we used a laser spectrometer, immunofluorescence, western blotting, and transmission electron microscopy to detect the mechanism of BBB opening. Finally, measured brain water content, AQP4, GFAP, Iba1, and used the DeadEndTM Fluorometric TUNEL System to clear whether the stimulation caused obvious negative effects. The results show that EA stimulation at 2/100 Hz maximally increased BBB permeability, and the BBB closed within 12 h after EA stimulation was removed. EA stimulation increased blood perfusion, c-fos levels, and Substance P expression in the cerebral cortex, decreased ZO-1 and occludin levels and induced ultrastructural changes in TJ morphology. EA stimulation at specific parameters did not cause brain edema, activation of glial cells, or cell apoptosis. This study shows that EA stimulation induces a reversible, frequency-dependent alteration of BBB permeability and proposes a hypothetical mechanism of BBB opening related to vasodilation and TJ disruption. Transiently enhancing the permeability of the BBB with EA at specific parameters may be a new strategies for delivering therapeutics to the central nervous system. Further study of this technology is needed.
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