Peroxisome Proliferator-Activated Receptor γ Agonist Rosiglitazone Protects Blood–Brain Barrier Integrity Following Diffuse Axonal Injury by Decreasing the Levels of Inflammatory Mediators Through a Caveolin-1-Dependent Pathway
Peroxisome Proliferator-Activated Receptor γ Agonist Rosiglitazone Protects Blood–Brain Barrier Integrity Following Diffuse Axonal Injury by Decreasing the Levels of Inflammatory Mediators Through a Caveolin-1-Dependent Pathway
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DOI：
10.1007/s10753-018-0940-2
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发表时间：
2018-11
期刊：
影响因子：
5.1
通讯作者：
Yonglin Zhao;Xin Wei;Jinning Song;M. Zhang;Ting-qin Huang;J. Qin
中科院分区：
文献类型：
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作者：
Yonglin Zhao;Xin Wei;Jinning Song;M. Zhang;Ting-qin Huang;J. Qin
我们的早期实验证实，罗格列酮（RSG）是一种过氧化物酶体增殖物激活受体γ（PPAR γ）激动剂，通过抑制淀粉样β前体蛋白的表达，减少tau蛋白的丢失和异常磷酸化，具有治疗弥漫性轴索损伤（DAI）的潜力，但其潜在机制尚未完全明确。在本研究中，我们的目的是探讨过氧化物酶体增殖物激活物受体γ在DAI大鼠模型中保护血脑屏障（BBB）完整性的可能作用及其机制。DAI后腹腔注射PPAR激动剂和拮抗剂。RSG治疗可改善轴突损伤、细胞凋亡、胶质细胞活化以及TNF-α、IL-1 β和IL-6等炎性因子的释放。它还增加紧密连接相关蛋白如ZO-1、claudin-5和occludin-1的表达，而PPAR γ拮抗剂GW9662具有相反的作用。还在BBBin体外模型中研究了这些作用，该模型由单层的经受氧和葡萄糖剥夺（OGD）的人微血管内皮细胞（HBMEC）组成。RSG治疗通过减少炎症因子的释放和维持紧密连接相关蛋白的表达来改善由OGD诱导的BBB完整性的丧失和通透性增加。有趣的是，caveolin-1主要定位于内皮细胞，并且RSG增加了caveolin-1的表达，OGD后caveolin-1的表达下降。相反，在体外BBB模型中，caveolin-1 siRNA取消了RSG的保护作用。总之，我们提供的证据表明，PPAR γ在一系列与DAI相关的过程中起着重要作用，并且PPAR γ激动剂RSG可以通过小窝蛋白-1依赖性途径降低炎症介质的水平来保护BBB的完整性。
Our early experiments confirmed that rosiglitazone (RSG), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, had therapeutic potential for the treatment of diffuse axonal injury (DAI) by inhibiting the expression of amyloid-beta precursor protein and reducing the loss and abnormal phosphorylation of tau, but the underlying mechanisms were not fully defined. In this study, we aimed to investigate a possible role for PPARγ in the protection of blood–brain barrier (BBB) integrity in a rat model of DAI, and the underlying mechanisms. PPAR agonists and antagonists were intraperitoneally injected after DAI. Treatment with RSG ameliorated axonal injury, cell apoptosis, glia activation, and the release of inflammatory factors such as TNF-α, IL-1β, and IL-6. It also increased the expression of tight junction-associated proteins like ZO-1, claudin-5, and occludin-1, whereas the PPARγ antagonist GW9662 had the opposite effects. These effects were also studied in a BBBin vitromodel, consisting of a monolayer of human microvascular endothelial cells (HBMECs) subjected to oxygen and glucose deprivation (OGD). Treatment with RSG ameliorated the loss of BBB integrity and the increased permeability induced by OGD by reducing the release of inflammatory factors and maintaining the expression of tight junction-associated proteins. Interestingly, caveolin-1 was found located mainly in endothelial cells, and RSG increased the expression of caveolin-1, which decreased following OGD. In contrast, caveolin-1 siRNA abrogated the protective effects of RSG in thein vitroBBB model. In conclusion, we provide evidence that PPARγ plays an important role in a series of processes associated with DAI, and that the PPARγ agonist RSG can protect BBB integrity by decreasing the levels of inflammatory mediators through a caveolin-1-dependent pathway.