Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China.
State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
Exp Neurol. 2024 Sep;379:114849. doi: 10.1016/j.expneurol.2024.114849. Epub 2024 Jun 8.
Cerebral ischemic stroke is a serious disease with high mortality and disability rates. However, few neuroprotective drugs have been used for ischemic stroke in the clinic. Two main reasons may be responsible for this failure: difficulty in penetrating the blood-brain barrier (BBB) and easily inactivated in the blood circulation. Ferroptosis, a lipid oxidation-related cell death, plays significant roles in cerebral ischemia-reperfusion injury. We utilized RVG29, a peptide derived from Rabies virus glycoprotein, to obtain BBB-targeted lipid nanoparticles (T-LNPs) in order to investigate whether T-LNPs improved the neuroprotective effects of Ferrostatin-1 (Fer1, an inhibitor of ferroptosis) against cerebral ischemic damage. T-LNPs significantly increased BBB penetration following oxygen/glucose deprivation exposure in an in vitro BBB model and enhanced the fluorescence distribution in brain tissues at 6 h post-administration in a cerebral ischemic murine model. Moreover, T-LNPs encapsulated Fer1 (T-LNPs-Fer1) significantly enhanced the inhibitory effects of Fer1 on ferroptosis by maintaining the homeostasis of NADPH oxidase 4 (NOX4) and glutathione peroxidase 4 (GPX4) signals in neuronal cells after cerebral ischemia. T-LNPs-Fer1 significantly suppressed oxidative stress [heme oxygenase-1 expression and malondialdehyde (the product of lipid ROS reaction)] in neurons and alleviated ischemia-induced neuronal cell death, compared to Fer1 alone without encapsulation. Furthermore, T-LNPs-Fer1 significantly reduced cerebral infarction and improved behavior functions compared to Fer1-treated cerebral ischemic mice after 45-min ischemia/24-h reperfusion. These findings showed that the T-LNPs helped Fer1 penetrate the BBB and improved the neuroprotection of Fer1 against cerebral ischemic damage in experimental stroke, providing a feasible translational strategy for the development of clinical drugs for the treatment of ischemic stroke.
脑缺血性中风是一种死亡率和致残率都很高的严重疾病。然而，临床上用于缺血性中风的神经保护药物很少。造成这种失败的主要有两个原因：难以穿透血脑屏障（BBB）和在血液循环中容易失活。铁死亡，一种与脂质氧化相关的细胞死亡，在脑缺血再灌注损伤中发挥重要作用。我们利用 RVG29（一种来源于狂犬病毒糖蛋白的肽）来获得靶向 BBB 的脂质纳米颗粒（T-LNPs），以研究 T-LNPs 是否能提高 Ferrostatin-1（一种铁死亡抑制剂）对脑缺血损伤的神经保护作用。T-LNPs 在体外 BBB 模型中氧/葡萄糖剥夺暴露后显著增加 BBB 通透性，并在脑缺血小鼠模型中给药后 6 小时增强脑组织中的荧光分布。此外，T-LNPs 包封 Fer1（T-LNPs-Fer1）在脑缺血后通过维持 NADPH 氧化酶 4（NOX4）和谷胱甘肽过氧化物酶 4（GPX4）信号的稳态，显著增强了 Fer1 对铁死亡的抑制作用。与未包封的 Fer1 相比，T-LNPs-Fer1 显著抑制神经元中的氧化应激[血红素加氧酶-1 表达和丙二醛（脂质 ROS 反应产物）]，并减轻缺血诱导的神经元细胞死亡。此外，与 Fer1 治疗的脑缺血小鼠相比，T-LNPs-Fer1 在 45 分钟缺血/24 小时再灌注后显著减少脑梗死面积，并改善行为功能。这些发现表明，T-LNPs 有助于 Fer1 穿透 BBB，并改善 Fer1 对实验性中风中脑缺血损伤的神经保护作用，为缺血性中风治疗的临床药物开发提供了一种可行的转化策略。
