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.
- 10.Zhao, Y., J. Zhao, M. Zhang, et al. 2017. Involvement of toll like receptor 2 signaling in secondary injury during experimental diffuse axonal injury in rats. Mediators of Inflammation 1570917: 2017.Google Scholar
- 11.Ramirez, S.H., D. Heilman, B. Morsey, R. Potula, J. Haorah, and Y. Persidsky. 2008. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) suppresses Rho GTPases in human brain microvascular endothelial cells and inhibits adhesion and transendothelial migration of HIV-1 infected monocytes. Journal of Immunology 180 (3): 1854–1865.CrossRefGoogle Scholar
- 12.Lombardi, A., G. Cantini, E. Piscitelli, S. Gelmini, M. Francalanci, T. Mello, E. Ceni, G. Varano, G. Forti, M. Rotondi, A. Galli, M. Serio, and M. Luconi. 2008. A new mechanism involving ERK contributes to rosiglitazone inhibition of tumor necrosis factor-alpha and interferon-gamma inflammatory effects in human endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology 28 (4): 718–724.CrossRefGoogle Scholar
- 14.Gu, Y., G. Zheng, M. Xu, Y. Li, X. Chen, W. Zhu, Y. Tong, S.K. Chung, K.J. Liu, and J. Shen. 2012. Caveolin-1 regulates nitric oxide-mediated matrix metalloproteinases activity and blood-brain barrier permeability in focal cerebral ischemia and reperfusion injury. Journal of Neurochemistry 120 (1): 147–156.CrossRefGoogle Scholar
- 15.Ye, L.B., X.C. Yu, Q.H. Xia, Y. Yang, D.Q. Chen, F. Wu, X.J. Wei, X. Zhang, B.B. Zheng, X.B. Fu, H.Z. Xu, X.K. Li, J. Xiao, and H.Y. Zhang. 2016. Regulation of caveolin-1 and junction proteins by bFGF contributes to the integrity of blood-spinal cord barrier and functional recovery. Neurotherapeutics 13 (4): 844–858.CrossRefGoogle Scholar
- 17.Dong, H.J., C.Z. Shang, D.W. Peng, J. Xu, P.X. Xu, L. Zhan, and P. Wang. 2014. Curcumin attenuates ischemia-like injury induced IL-1beta elevation in brain microvascular endothelial cells via inhibiting MAPK pathways and nuclear factor-kappaB activation. Neurological Sciences 35 (9): 1387–1392.CrossRefGoogle Scholar
- 21.Lin, M.N., D.S. Shang, W. Sun, B. Li, X. Xu, W.G. Fang, W.D. Zhao, L. Cao, and Y.H. Chen. 2013. Involvement of PI3K and ROCK signaling pathways in migration of bone marrow-derived mesenchymal stem cells through human brain microvascular endothelial cell monolayers. Brain Research 1513: 1–8.CrossRefGoogle Scholar
- 25.Cunningham, T.L., Cartagena, C.M., Lu, X.-C., et al. 2013. Correlations between blood-brain barrier disruption and neuroinflammation in an experimental model of penetrating ballistic-like brain injury.Google Scholar
- 30.Uchida, T., M. Mori, A. Uzawa, H. Masuda, M. Muto, R. Ohtani, and S. Kuwabara. 2017. Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood-brain barrier disruption. Multiple Sclerosis 23 (8): 1072–1084.CrossRefGoogle Scholar
- 34.Delerive, P., F. Martin-Nizard, G. Chinetti, et al. 1999. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circulation Research 85 (5): 394–402.CrossRefGoogle Scholar
- 37.Werion, A., V. Joris, M. Hepp, L. Papasokrati, L. Marique, C. de Ville de Goyet, V. van Regemorter, M. Mourad, B. Lengelé, C. Daumerie, E. Marbaix, S. Brichard, M.C. Many, and J. Craps. 2016. Pioglitazone, a PPARgamma agonist, upregulates the expression of caveolin-1 and catalase, essential for thyroid cell homeostasis: a clue to the pathogenesis of Hashimoto's thyroiditis. Thyroid 26 (9): 1320–1331.CrossRefGoogle Scholar
- 38.Yang, K., W. Lu, Q. Jiang, X. Yun, M. Zhao, H. Jiang, and J. Wang. 2015. Peroxisome proliferator-activated receptor gamma-mediated inhibition on hypoxia-triggered store-operated calcium entry. A caveolin-1-dependent mechanism. American Journal of Respiratory Cell and Molecular Biology 53 (6): 882–892.CrossRefGoogle Scholar