Biological Sciences, Sunnybrook Research Institute, 2075 Bayview Ave. Toronto, ON, Canada M4N 3M5.
Laboratory Medicine & Pathobiology, University of Toronto, 27 King's College Circle, Toronto, ON, Canada, M5S 1A1.
Int J Med Sci. 2021 Jan 1;18(2):482-493. doi: 10.7150/ijms.36775. eCollection 2021.
Focused ultrasound (FUS) is used to locally and transiently induce blood-brain barrier (BBB) permeability, allowing targeted drug delivery to the brain. The purpose of the current study is to evaluate the potential of Vasculotide to accelerate the recovery of the BBB following FUS disruption in the TgCRND8 mouse model of amyloidosis, characteristic of Alzheimer's disease (AD). Accelerating the restoration of the BBB post-FUS would represent an additional safety procedure, which could be beneficial for clinical applications. TgCRND8 mice and their non-transgenic littermates were treated with Vasculotide (250 ng, intraperitoneal) every 48 hours for 3 months. BBB permeability was induced using FUS, in presence of intravenously injected microbubbles, in TgCRND8 and non-transgenic mice, and confirmed at time 0 by MRI enhancement using the contrast agent gadolinium. BBB closure was assessed at 6, 12 and 20 hours by MRI. In a separate cohort of animals, BBB closure was assessed at 24-hours post-FUS using Evans blue injected intravenously and followed by histological evaluation. Chronic Vasculotide administration significantly reduces the ultra-harmonic threshold required for FUS-induced BBB permeability in the TgCRND8 mice. In addition, Vasculotide treatment led to a faster restoration of the BBB following FUS in TgCRND8 mice. BBB closure after FUS is not significantly different between TgCRND8 and non-transgenic mice. BBB permeability was assessed by gadolinium up to 20-hours post-FUS, demonstrating 87% closure in Vasculotide treated TgCRND8 mice, as opposed to 52% in PBS treated TgCRND8 mice, 58% in PBS treated non-transgenic mice, and 74% in Vasculotide treated non-transgenic mice. In both TgCRND8 mice and non-transgenic littermates the BBB was impermeable to Evans blue dye at 24-hours post-FUS. Vasculotide reduces the pressure required for microbubble ultra-harmonic onset for FUS-induced BBB permeability and it accelerates BBB restoration in a mouse model of amyloidosis, suggesting its potential clinical utility to promote vascular health, plasticity and repair in AD.
聚焦超声（FUS）用于局部和瞬时诱导血脑屏障（BBB）通透性，允许靶向药物递送至大脑。本研究的目的是评估 Vasculotide 加速 TgCRND8 淀粉样变性小鼠模型中 FUS 破坏后 BBB 恢复的潜力，该模型是阿尔茨海默病（AD）的特征。FUS 后 BBB 的快速恢复将代表另一种安全程序，这可能对临床应用有益。TgCRND8 小鼠及其非转基因同窝仔鼠每 48 小时用 Vasculotide（250ng，腹腔内）处理 3 个月。在 TgCRND8 和非转基因小鼠中，通过静脉内注射微泡并用 FUS 诱导 BBB 通透性，并通过 MRI 增强使用造影剂钆在时间 0 时确认。在 6、12 和 20 小时通过 MRI 评估 BBB 关闭。在另一组动物中，在 FUS 后 24 小时通过静脉内注射 Evans 蓝并进行组织学评估评估 BBB 关闭。慢性 Vasculotide 给药可显著降低 TgCRND8 小鼠 FUS 诱导的 BBB 通透性所需的超谐波阈值。此外，Vasculotide 治疗可使 TgCRND8 小鼠在 FUS 后更快地恢复 BBB。FUS 后 TgCRND8 和非转基因小鼠之间的 BBB 关闭没有显著差异。FUS 后直至 20 小时通过钆评估 BBB 通透性，表明 Vasculotide 处理的 TgCRND8 小鼠中 87%的 BBB 关闭，而 PBS 处理的 TgCRND8 小鼠中为 52%，PBS 处理的非转基因小鼠中为 58%，而 Vasculotide 处理的非转基因小鼠中为 74%。在 TgCRND8 小鼠和非转基因同窝仔鼠中，FUS 后 24 小时 BBB 对 Evans 蓝染料不透。Vasculotide 降低了 FUS 诱导的 BBB 通透性所需的微泡超谐波起始压力，并加速了淀粉样变性小鼠模型中 BBB 的恢复，这表明其在促进 AD 中的血管健康、可塑性和修复方面的潜在临床应用。
