Low-intensity focused ultrasound (LIFU) combined with intravenously circulating microbubbles has recently emerged as a novel approach for increasing delivery through the blood-brain barrier (BBB). This technique safely and transiently enables therapeutic agents to overcome the BBB, which typically poses a significant obstacle for treatment of brain disorders. However, the full impact of LIFU on the entire neurovascular unit (NVU), as well as the mechanisms and factors involved in restoring BBB integrity still require further elucidation.We conducted immunohistochemical analyses of the putamen in non-human primates to monitor changes over time [immediately post-treatment (3 h) and at 7- and 30-days post-BBB opening] in vascular, glial, and immune cells. Additionally, we examined the dynamic interactions among these elements and their role in the restorative process at the BBB level.A mild inflammatory response primarily involving microglia, astrocytes, and T- and B-lymphocytes was observed in the treated putamen acutely after BBB opening. These cells, recruited in response to the vascular changes, stimulate upregulation of PDGFRβ, a pericyte-specific marker, and VEGF-A, a pro-angiogenic factor. This was associated with vascular sprouting by 7 days post-BBB opening. Importantly, no notable long-term alterations were observed in the NVU 30 days post-BBB opening.These results offer further evidence regarding the efficacy and safety of LIFU in achieving BBB opening in the primate brain, indicating that nearly all changes in the NVU revert to baseline within 30 days post-treatment. This also suggests that angiogenesis may play an important role in restoring vascular integrity after BBB opening.

中文翻译：

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非人灵长类动物壳核血脑屏障打开后神经血管单位变化的时间动力学


低强度聚焦超声 （LIFU） 与静脉内循环微泡相结合，最近成为一种增加通过血脑屏障 （BBB） 输送的新方法。这项技术可以安全、瞬时地使治疗剂克服 BBB，而 BBB 通常会对脑部疾病的治疗构成重大障碍。然而，LIFU 对整个神经血管单位 （NVU） 的全面影响，以及恢复 BBB 完整性所涉及的机制和因素仍需要进一步阐明。我们对非人灵长类动物的壳核进行了免疫组织化学分析，以监测血管、神经胶质细胞和免疫细胞随时间的变化 [治疗后立即 （3 小时） 以及 BBB 开放后 7 天和 30 天]。此外，我们还在 BBB 水平检查了这些元素之间的动态相互作用及其在 BBB 水平恢复过程中的作用。在 BBB 开放后急性在治疗壳核中观察到主要涉及小胶质细胞、星形胶质细胞以及 T 和 B 淋巴细胞的轻度炎症反应。这些细胞响应血管变化而被募集，刺激 PDGFRβ（一种周细胞特异性标志物）和 VEGF-A（一种促血管生成因子）的上调。这与 BBB 开放后 7 天的维管发芽有关。重要的是，在 BBB 打开后 30 天内，NVU 未观察到明显的长期变化。这些结果提供了关于 LIFU 在灵长类动物大脑中实现 BBB 开放的有效性和安全性的进一步证据，表明 NVU 的几乎所有变化在治疗后 30 天内都恢复到基线。这也表明血管生成可能在恢复 BBB 开放后血管完整性方面发挥重要作用。