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
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 BBB in vitro model, 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 the in vitro BBB 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.
KEY WORDSPeroxisome proliferator-activated receptor γ Caveolin-1 Blood–brain barrier Diffuse axonal injury
Yonglin Zhao designed the concept of the work and the experiments, did the experiments, and wrote the manuscript. Jin Qin and Jinning Song contributed to the initial idea and conceived the study design. Ming Zhang and Tingqin Huang helped draft and revise the manuscript. Xing Wei performed the analyses and designed the figures. All authors approved the manuscript.
This work was financially supported by the Natural Science Foundation of Shaanxi Province (Grant No. 2018JQ8063) to Jie Qin.
Compliance with Ethical Standards
All procedures were performed according to the Guidelines and Suggestions for the Care and Use of Laboratory Animals formulated by the Ministry of Science and Technology of the People’s Republic of China (PRC) and the Guidelines for the Care and Use of Laboratory Animals from the National Institutes of Health (NIH Publication no. 80-23). The Biomedical Ethics Committee for Animal Experiments of Shaanxi Province (China) approved this study.
Conflict of Interest
The authors declare that there is no personal or institutional conflict of interest related to the presented research and its publication.
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