Liao Wei-Hao, Hsiao Ming-Yen, Kung Yi, Liu Hao-Li, Béra Jean-Christophe, Inserra Claude, Chen Wen-Shiang
Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
J Adv Res. 2020 Jun 21;26:15-28. doi: 10.1016/j.jare.2020.06.012. eCollection 2020 Nov.
Numerous studies have shown the ability of low-energy acoustic waves such as focused ultrasound or shockwave to transiently open blood-brain barrier (BBB) and facilitate drug delivery to the brain. Preclinical and clinical evidences have well demonstrated the efficacy and safety in treating various brain disorders. However, the molecular mechanisms of acoustic waves on the BBB are still not fully understood.
The present study aimed at exploring the possible molecular mechanisms of acoustic wave stimulation on brains.
The left hemisphere of the rat's brain was treated with pulsed ultrasound from a commercial focused shockwave or a planar ultrasound device, and the right hemisphere served as a control. One hour after the mechanical wave stimulation or overnight, the rats were sacrificed and the brains were harvested for protein or histological analysis. Agonists and antagonists related to the signal transduction pathways of tight junction proteins were used to investigate the possible intracellular mechanisms.
Intracellular signal transduction analysis shows calcium influx through transient receptor potential vanilloid 4 (TRPV4) channels, and the activation of PKC-δ pathway to mediate dissociation of ZO-1 and occludin after acoustic wave stimulation. The activation of TRPV4 or PKC-δ signaling further increased the expression level of TRPV4, suggesting a feedback loop to regulate BBB permeability. Moreover, the tight junction proteins dissociation can be reversed by administration of PKC-δ inhibitor and TRPV4 antagonist.
The present study shows the crucial role of TRPV4 in acoustic wave-mediated BBB permeability, specifically its effect on compromising tight junction proteins, ZO-1 and occludin. Our findings provide a new molecular perspective to explain acoustic wave-mediated BBB opening. Moreover, activation of TRPV4 by agonists may reduce the threshold intensity level of acoustic waves for BBB opening, which may prevent undesirable mechanical damages while maintaining efficient BBB opening.
大量研究表明，聚焦超声或冲击波等低能量声波能够短暂打开血脑屏障（BBB），并促进药物向脑部递送。临床前和临床证据已充分证明其在治疗各种脑部疾病方面的有效性和安全性。然而，声波作用于血脑屏障的分子机制仍未完全明确。
本研究旨在探索声波刺激大脑的可能分子机制。
用商用聚焦冲击波或平面超声设备产生的脉冲超声处理大鼠大脑的左半球，右半球作为对照。在机械波刺激后1小时或过夜后，处死大鼠并取出大脑用于蛋白质或组织学分析。使用与紧密连接蛋白信号转导途径相关的激动剂和拮抗剂来研究可能的细胞内机制。
细胞内信号转导分析显示，声波刺激后，钙通过瞬时受体电位香草酸受体4（TRPV4）通道内流，PKC-δ通路激活，介导ZO-1和闭合蛋白解离。TRPV4或PKC-δ信号的激活进一步增加了TRPV4的表达水平，提示存在一个调节血脑屏障通透性的反馈回路。此外，给予PKC-δ抑制剂和TRPV4拮抗剂可逆转紧密连接蛋白的解离。
本研究表明TRPV4在声波介导的血脑屏障通透性中起关键作用，特别是其对紧密连接蛋白ZO-1和闭合蛋白的破坏作用。我们的研究结果为解释声波介导的血脑屏障开放提供了一个新的分子视角。此外，激动剂激活TRPV4可能会降低声波打开血脑屏障所需的阈值强度水平，这在维持有效的血脑屏障开放的同时，可能会防止不必要的机械损伤。
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