Department of Pharmacy, The First Affiliated Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Department of Neurosurgery, The First Affiliated Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Neurochem Res. 2024 Nov 18;50(1):17. doi: 10.1007/s11064-024-04259-w.
Protection against blood-brain barrier (BBB) dysfunction is key to reduce the cerebral ischemia injury as its breakdown causes edema formation and extravasation of blood components and immune cells. The maintenance of BBB integrity requires the GSK-3β/β-catenin pathway activity. Naringenin (NAR), an effective monomer from Chinese herbal medicine, had potent protective effect on brain inflammatory and oxidative injury. However, whether NAR could protect the integrity of BBB during cerebral ischemia injury and the involvement of GSK-3β/β-catenin pathway in the beneficial effect of NAR was unknown. Therefore, mouse middle cerebral artery occlusion/reperfusion (IR) model was employed to answer these questions. NAR was intraperitoneally administrated once daily for 6 days immediately after IR with the dose of 10 mg/kg. BBB damage was evaluated with Evans blue. Protein levels of GSK-3β and β-catenin in vascular endothelial cells at penumbra were assessed with western blotting and immunofluorescence. The experimental data suggested that NAR improved neurological deficits, decreased the percentage of infarct volumes and neuronal apoptosis at 7d after IR. NAR improved BBB damage as evidenced by a lower permeability of Evans blue dye and upregulation of tight junction proteins such as zonula occludens-1(ZO-1), Occludin and Claudin-5. Importantly, GSK-3β/β-catenin pathway activity was related to the improvement of BBB integrity rendered by NAR. Our findings demonstrated that NAR might become a potential therapeutic drug for IR.
保护血脑屏障（BBB）功能是减少脑缺血损伤的关键，因为其破坏会导致脑水肿形成和血液成分及免疫细胞的外渗。维持 BBB 的完整性需要 GSK-3β/β-catenin 通路的活性。柚皮素（NAR）是中药中的一种有效单体，对脑炎症和氧化损伤具有强大的保护作用。然而，NAR 是否能在脑缺血损伤期间保护 BBB 的完整性，以及 GSK-3β/β-catenin 通路在 NAR 的有益作用中的参与情况尚不清楚。因此，采用小鼠大脑中动脉闭塞/再灌注（IR）模型来回答这些问题。NAR 以 10mg/kg 的剂量每天腹腔注射一次，连续 6 天，在 IR 后立即进行。用伊文思蓝评估 BBB 损伤。用 Western blot 和免疫荧光法检测血管内皮细胞中 GSK-3β和β-catenin 的蛋白水平。实验数据表明，NAR 改善了神经功能缺损，降低了 IR 后 7d 的梗死体积百分比和神经元凋亡。NAR 改善了 BBB 损伤，表现为 Evans 蓝染料的通透性降低，以及紧密连接蛋白（如 ZO-1、Occludin 和 Claudin-5）的上调。重要的是，GSK-3β/β-catenin 通路的活性与 NAR 改善 BBB 完整性有关。我们的研究结果表明，NAR 可能成为 IR 的一种潜在治疗药物。
