Division of Neurocritical Care, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Neurotrauma. 2023 Jul;40(13-14):1470-1480. doi: 10.1089/neu.2022.0468. Epub 2023 May 4.
Cerebrovascular dysfunction following traumatic brain injury (TBI) is a well-characterized phenomenon. Given the therapeutic potential of xenon, we aimed to study its effects after localized delivery to the brain using microbubbles. We designed xenon-containing microbubbles stabilized by dibehenoylphosphatidylcholine (DBPC) and polyethylene glycol (PEG) attached to saturated phospholipid (DPSE-PEG5000). Using a pig model of TBI, these microbubbles were intravenously injected, and ultrasound was used to release xenon at the level of the carotid artery. The control group received perfluorobutane containing microbubbles. Diffusion tensor imaging (DTI) showed areas of higher fractional anisotropy for pigs receiving xenon microbubbles compared to the control group at 1 day after injury. Radial diffusivity analysis showed that this effect was mainly the result of acute edema. Pigs were euthanized at 5 days, and the brain tissues of xenon-treated animals showed reduction of perivascular inflammation and blood-brain barrier disruption. Endothelial cell culture experiments showed that glutamate reduces tight junction protein zona occludens-1 (ZO-1), but treatment with xenon microbubbles attenuates this effect. Xenon treatment protects cerebrovasculature and reduces astroglial reactivity after TBI. Further, these data support the future use of localized delivery of various therapeutic agents for brain injury using microbubbles in order to limit systemic side effects and reduce costs.
创伤性脑损伤 (TBI) 后的脑血管功能障碍是一种特征明显的现象。鉴于氙气的治疗潜力，我们旨在研究使用微泡将其局部递送至大脑后的效果。我们设计了含有氙气的微泡，由二硬脂酰基磷脂酰胆碱 (DBPC) 和聚乙二醇 (PEG) 稳定，连接饱和磷脂 (DPSE-PEG5000)。使用 TBI 的猪模型，将这些微泡静脉注射，并使用超声在颈动脉水平释放氙气。对照组接受含有全氟丁烷的微泡。弥散张量成像 (DTI) 显示，与对照组相比，受伤后 1 天接受氙气微泡的猪的各向异性分数更高。径向扩散率分析表明，这种作用主要是急性水肿的结果。猪在 5 天被安乐死，氙气处理动物的脑组织显示血管周围炎症和血脑屏障破坏减少。内皮细胞培养实验表明，谷氨酸减少紧密连接蛋白封闭蛋白-1 (ZO-1)，但氙气微泡处理可减弱这种作用。氙气治疗可保护 TBI 后的脑血管并减少星形胶质细胞反应。此外，这些数据支持未来使用微泡局部递送来治疗各种脑损伤的治疗剂，以限制全身副作用并降低成本。
