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The Protective Effects of Juglanin in Cerebral Ischemia Reduce Blood-Brain Barrier Permeability via Inhibition of VEGF/VEGFR2 Signaling.
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-08-05 , DOI: 10.2147/dddt.s250904
Jia Liu 1 , Lei Chen 2 , Xin Zhang 1 , Lixiao Pan 1 , Lili Jiang 1
Affiliation  

Introduction: Ischemic brain injury due to stroke or other pathologies is a major contributor to disability and mortality worldwide. Upon the occurrence of stroke, neuronal cells undergo apoptosis due to the deprivation of oxygen and nutrients and failure of the blood–brain barrier (BBB). In the moments immediately following a stroke, widespread perfusion resulting from hyperpermeability is accompanied by an acute inflammatory response, which induces neovascularization and often permanent neurological injury. Vascular endothelial growth factor (VEGF) and its receptor VEGF receptor 2 (VEGFR2) have been targeted to suppress cerebral ischemia. Recently, natural products including flavonoids, such as juglanin, have been receiving increasing attention for their impressive physiological effects.
Methods: Twenty mg/kg body weight juglanin was administrated for 3 weeks before inducing middle cerebral artery occlusion (MCAO) in mice. The animal brain infarction volume, neurological deficit score, blood–brain barrier permeability, and the expression of tight junction proteins were evaluated. Endothelial permeability and tight junction protein expression were also assessed in brain microvascular endothelial cells (HMBVECs) exposed to oxygen–glucose deprivation/reperfusion (OGD/R).
Results: Juglanin significantly reduced occlusion-induced infarct volume and improved neurological score by suppressing BBB hyperpermeability. Juglanin inhibited both the mRNA and protein expression of VEGF and VEGFR2 and restored the normal expression of occludin and zonula occludens-1 (ZO-1), two important tight junction proteins, in MCAO mice. Meanwhile, the results of in vitro experiments show that the protective effects of juglanin against increased BBB permeability and reduced tight junction functionality are dependent on the VEGF/VEGFR2 signaling pathway, as evidenced by the capacity of exogenous VEGF-A to abolish the effects of juglanin.
Conclusion: Our findings indicate a potent ability of juglanin to prevent neuronal injury resulting from cerebral ischemia by modulating the VEGF/VEGFR2 signaling pathway. Further research will help elucidate the exact mechanisms behind the protective effects of juglanin.

Keywords: cerebral ischemia, stroke, juglanin, VEGF, VEGFR2, tight junction proteins, blood–brain barrier, BBB permeability


中文翻译:

胡桃苷在脑缺血中的保护作用通过抑制 VEGF/VEGFR2 信号传导降低血脑屏障通透性。

简介:中风或其他疾病引起的缺血性脑损伤是全球残疾和死亡率的主要原因。中风发生后,由于氧气和营养物质的缺乏以及血脑屏障(BBB)的失效,神经元细胞会发生凋亡。在中风后的瞬间,由高渗透性导致的广泛灌注伴随着急性炎症反应,这会导致新血管形成和通常的永久性神经损伤。血管内皮生长因子 (VEGF) 及其受体 VEGF 受体 2 (VEGFR2) 已被靶向用于抑制脑缺血。最近,包括胡桃苷等类黄酮在内的天然产物因其令人印象深刻的生理作用而受到越来越多的关注。
方法:在小鼠中诱导大脑中动脉闭塞 (MCAO) 之前,给予 20 mg/kg 体重胡桃苷 3 周。评估动物脑梗死体积、神经功能缺损评分、血脑屏障通透性和紧密连接蛋白的表达。还在暴露于氧-葡萄糖剥夺/再灌注 (OGD/R) 的脑微血管内皮细胞 (HMBVEC) 中评估了内皮通透性和紧密连接蛋白的表达。
结果:Juglanin 通过抑制 BBB 高渗透性显着减少闭塞诱导的梗塞体积并改善神经系统评分。Juglanin 抑制 VEGF 和 VEGFR2 的 mRNA 和蛋白质表达,并恢复 MCAO 小鼠中两种重要的紧密连接蛋白 occludin 和 zonula occludens-1 (ZO-1) 的正常表达。同时,体外实验结果表明胡桃苷对 BBB 通透性增加和紧密连接功能降低的保护作用依赖于 VEGF/VEGFR2 信号通路,外源性 VEGF-A 消除胡桃苷作用的能力证明了这一点。 .
结论:我们的研究结果表明胡桃苷具有通过调节 VEGF/VEGFR2 信号通路来预防脑缺血引起的神经元损伤的强大能力。进一步的研究将有助于阐明胡桃苷保护作用背后的确切机制。

关键词:脑缺血, 中风, 胡桃苷, VEGF, VEGFR2, 紧密连接蛋白, 血脑屏障, BBB 通透性
更新日期:2020-08-05
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