Advertisement

Acetyl-11-keto-β-boswellic acid (AKBA) Attenuates Oxidative Stress, Inflammation, Complement Activation and Cell Death in Brain Endothelial Cells Following OGD/Reperfusion

  • Saif AhmadEmail author
  • Shah Alam Khan
  • Adam Kindelin
  • Tasha Mohseni
  • Kanchan Bhatia
  • Md Nasrul Hoda
  • Andrew F. DucruetEmail author
Original Paper

Abstract

Brain endothelial cells play an important role in maintaining blood flow homeostasis in the brain. Cerebral ischemia is a major cause of endothelial dysfunction which can disrupt the blood–brain barrier (BBB). Oxygen–glucose deprivation (OGD)/reperfusion promote cell death and BBB breakdown in brain endothelial cells. Acetyl-11-keto-β-boswellic acid (AKBA), a biologically active phytoconstituent of the medicinal plant Boswellia serrata, has been shown to be protective against various inflammatory diseases as well as ischemic brain injury. The molecular mechanisms underlying these beneficial characteristics of AKBA are poorly understood. We subjected bEND.3 cells to OGD/reperfusion to investigate the protective role of AKBA in this model. We found that AKBA treatment attenuated endothelial cell death and oxidative stress assessed by means of TUNEL assay, cleaved-caspase-3, and dihydroethidium (DHE) staining. Furthermore, OGD downregulated tight junction proteins ZO-1 and Occludin levels, and increased the expressions of inflammatory cytokines TNF-α, ICAM-1, and complement C3a receptor (C3aR). We also noticed the increased phosphorylation of ERK 1/2 in bEND.3 cells in OGD group. AKBA treatment significantly attenuated expression levels of these inflammatory proteins and prevented the degradation of ZO-1 and Occludin following OGD. In conclusion, AKBA treatment provides protection against endothelial cell dysfunction following OGD by attenuating oxidative stress and inflammation.

Keywords

bEND.3 AKBA OGD BBB Inflammation Complement C3a receptor 

Notes

Acknowledgements

This study was supported by the Barrow Neurological Foundation (BNF).

Compliance with Ethical Standards

Conflict of interest

None of the authors have any conflicts of interest to disclose.

References

  1. Ahmad, S., Fatteh, N., El-Sherbiny, N. M., Naime, M., Ibrahim, A. S., El-Sherbini, A. M., et al. (2013). Potential role of A2A adenosine receptor in traumatic optic neuropathy. Journal of Neuroimmunology, 264(1–2), 54–64.  https://doi.org/10.1016/j.jneuroim.2013.09.015.CrossRefGoogle Scholar
  2. Ahmad, S., Kindelin, A., Khan, S. A., Ahmed, M., Hoda, M. N., Bhatia, K., et al. (2019). C3a receptor inhibition protects brain endothelial cells against oxygen-glucose deprivation/reperfusion. Experimental Neurobiology, 28(2), 216–228.  https://doi.org/10.5607/en.2019.28.2.216.CrossRefGoogle Scholar
  3. Alluri, H., Anasooya Shaji, C., Davis, M. L., & Tharakan, B. (2015). Oxygen-glucose deprivation and reoxygenation as an in vitro ischemia-reperfusion injury model for studying blood–brain barrier dysfunction. Journal of Visualized Experiments.  https://doi.org/10.3791/52699.Google Scholar
  4. Alluri, H., Stagg, H. W., Wilson, R. L., Clayton, R. P., Sawant, D. A., Koneru, M., et al. (2014). Reactive oxygen species-caspase-3 relationship in mediating blood–brain barrier endothelial cell hyperpermeability following oxygen-glucose deprivation and reoxygenation. Microcirculation, 21(2), 187–195.  https://doi.org/10.1111/micc.12110.CrossRefGoogle Scholar
  5. Arumugam, T. V., Woodruff, T. M., Lathia, J. D., Selvaraj, P. K., Mattson, M. P., & Taylor, S. M. (2009). Neuroprotection in stroke by complement inhibition and immunoglobulin therapy. Neuroscience, 158(3), 1074–1089.  https://doi.org/10.1016/j.neuroscience.2008.07.015.CrossRefGoogle Scholar
  6. Beghelli, D., Isani, G., Roncada, P., Andreani, G., Bistoni, O., Bertocchi, M., et al. (2017). Antioxidant and ex vivo immune system regulatory properties of Boswellia serrata extracts. Oxidative Medicine and Cellular Longevity, 2017, 7468064.  https://doi.org/10.1155/2017/7468064.CrossRefGoogle Scholar
  7. Bertocchi, M., Isani, G., Medici, F., Andreani, G., Tubon Usca, I., Roncada, P., et al. (2018). Anti-inflammatory activity of Boswellia serrata extracts: An in vitro study on porcine aortic endothelial cells. Oxidative Medicine and Cellular Longevity, 2018, 2504305.  https://doi.org/10.1155/2018/2504305.CrossRefGoogle Scholar
  8. Chen, S. L., Deng, Y. Y., Wang, Q. S., Han, Y. L., Jiang, W. Q., Fang, M., et al. (2017). Hypertonic saline protects brain endothelial cells against hypoxia correlated to the levels of epidermal growth factor receptor and interleukin-1beta. Medicine (Baltimore), 96(1), e5786.  https://doi.org/10.1097/MD.0000000000005786.CrossRefGoogle Scholar
  9. Cuaz-Perolin, C., Billiet, L., Bauge, E., Copin, C., Scott-Algara, D., Genze, F., et al. (2008). Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-β-boswellic acid in LPS-challenged ApoE-/- mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(2), 272–277.  https://doi.org/10.1161/ATVBAHA.107.155606.CrossRefGoogle Scholar
  10. Ding, Y., Chen, M., Wang, M., Wang, M., Zhang, T., Park, J., et al. (2014). Neuroprotection by acetyl-11-keto-β-boswellic acid, in ischemic brain injury involves the Nrf2/HO-1 defense pathway. Scientific Reports, 4, 7002.  https://doi.org/10.1038/srep07002.CrossRefGoogle Scholar
  11. Ding, Y., Qiao, Y., Wang, M., Zhang, H., Li, L., Zhang, Y., et al. (2016). Enhanced neuroprotection of acetyl-11-keto-β-boswellic acid (AKBA)-loaded O-carboxymethyl chitosan nanoparticles through antioxidant and anti-inflammatory pathways. Molecular Neurobiology, 53(6), 3842–3853.  https://doi.org/10.1007/s12035-015-9333-9.CrossRefGoogle Scholar
  12. Ducruet, A. F., Zacharia, B. E., Sosunov, S. A., Gigante, P. R., Yeh, M. L., Gorski, J. W., et al. (2012). Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke. PLoS ONE, 7(6), e38664.  https://doi.org/10.1371/journal.pone.0038664.CrossRefGoogle Scholar
  13. Eltzschig, H. K., & Eckle, T. (2011). Ischemia and reperfusion—From mechanism to translation. Nature Medicine, 17(11), 1391–1401.  https://doi.org/10.1038/nm.2507.CrossRefGoogle Scholar
  14. Frey, R. S., Ushio-Fukai, M., & Malik, A. B. (2009). NADPH oxidase-dependent signaling in endothelial cells: Role in physiology and pathophysiology. Antioxidants & Redox Signaling, 11(4), 791–810.  https://doi.org/10.1089/ARS.2008.2220.CrossRefGoogle Scholar
  15. Guo, S., Stins, M., Ning, M., & Lo, E. H. (2010). Amelioration of inflammation and cytotoxicity by dipyridamole in brain endothelial cells. Cerebrovascular Diseases, 30(3), 290–296.  https://doi.org/10.1159/000319072.CrossRefGoogle Scholar
  16. Huang, S. H., Wang, L., Chi, F., Wu, C. H., Cao, H., Zhang, A., et al. (2013). Circulating brain microvascular endothelial cells (cBMECs) as potential biomarkers of the blood–brain barrier disorders caused by microbial and non-microbial factors. PLoS ONE, 8(4), e62164.  https://doi.org/10.1371/journal.pone.0062164.CrossRefGoogle Scholar
  17. Jiao, H., Wang, Z., Liu, Y., Wang, P., & Xue, Y. (2011). Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood–brain barrier in a focal cerebral ischemic insult. Journal of Molecular Neuroscience, 44(2), 130–139.  https://doi.org/10.1007/s12031-011-9496-4.CrossRefGoogle Scholar
  18. Khatri, R., McKinney, A. M., Swenson, B., & Janardhan, V. (2012). Blood–brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke. Neurology, 79(13 Suppl 1), S52–S57.  https://doi.org/10.1212/WNL.0b013e3182697e70.CrossRefGoogle Scholar
  19. Liao, L. X., Zhao, M. B., Dong, X., Jiang, Y., Zeng, K. W., & Tu, P. F. (2016). TDB protects vascular endothelial cells against oxygen-glucose deprivation/reperfusion-induced injury by targeting miR-34a to increase Bcl-2 expression. Scientific Reports, 6, 37959.  https://doi.org/10.1038/srep37959.CrossRefGoogle Scholar
  20. Ma, X., Zhang, H., Pan, Q., Zhao, Y., Chen, J., Zhao, B., et al. (2013). Hypoxia/Aglycemia-induced endothelial barrier dysfunction and tight junction protein downregulation can be ameliorated by citicoline. PLoS ONE, 8(12), e82604.  https://doi.org/10.1371/journal.pone.0082604.CrossRefGoogle Scholar
  21. Narasimhan, P., Liu, J., Song, Y. S., Massengale, J. L., & Chan, P. H. (2009). VEGF Stimulates the ERK 1/2 signaling pathway and apoptosis in cerebral endothelial cells after ischemic conditions. Stroke, 40(4), 1467–1473.  https://doi.org/10.1161/STROKEAHA.108.534644.CrossRefGoogle Scholar
  22. Ni, Y., Teng, T., Li, R., Simonyi, A., Sun, G. Y., & Lee, J. C. (2017). TNFalpha alters occludin and cerebral endothelial permeability: Role of p38MAPK. PLoS ONE, 12(2), e0170346.  https://doi.org/10.1371/journal.pone.0170346.CrossRefGoogle Scholar
  23. Pan, R., Yu, K., Weatherwax, T., Zheng, H., Liu, W., & Liu, K. J. (2017). Blood occludin level as a potential biomarker for early blood brain barrier damage following ischemic stroke. Scientific Reports, 7, 40331.  https://doi.org/10.1038/srep40331.CrossRefGoogle Scholar
  24. Park, Y. S., Lee, J. H., Bondar, J., Harwalkar, J. A., Safayhi, H., & Golubic, M. (2002). Cytotoxic action of acetyl-11-keto-beta-boswellic acid (AKBA) on meningioma cells. Planta Medica, 68(5), 397–401.  https://doi.org/10.1055/s-2002-32090.CrossRefGoogle Scholar
  25. Roy, S., Khanna, S., Krishnaraju, A. V., Subbaraju, G. V., Yasmin, T., Bagchi, D., et al. (2006). Regulation of vascular responses to inflammation: inducible matrix metalloproteinase-3 expression in human microvascular endothelial cells is sensitive to antiinflammatory Boswellia. Antioxidants & Redox Signaling, 8(3–4), 653–660.  https://doi.org/10.1089/ars.2006.8.653.CrossRefGoogle Scholar
  26. Sadeghnia, H. R., Arjmand, F., & Ghorbani, A. (2017). Neuroprotective effect of Boswellia serrata and its active constituent acetyl-11-keto-β-boswellic acid against oxygen-glucose-serum deprivation-induced cell injury. Acta Poloniae Pharmaceutica, 74(3), 911–920.Google Scholar
  27. Salvador, E., Burek, M., & Forster, C. Y. (2015). Stretch and/or oxygen glucose deprivation (OGD) in an in vitro traumatic brain injury (TBI) model induces calcium alteration and inflammatory cascade. Frontiers in Cellular Neuroscience, 9, 323.  https://doi.org/10.3389/fncel.2015.00323.Google Scholar
  28. Shang, P., Liu, W., Liu, T., Zhang, Y., Mu, F., Zhu, Z., et al. (2016). Acetyl-11-keto-beta-boswellic acid attenuates prooxidant and profibrotic mechanisms involving transforming growth factor-beta1, and improves vascular remodeling in spontaneously hypertensive rats. Scientific Reports, 6, 39809.  https://doi.org/10.1038/srep39809.CrossRefGoogle Scholar
  29. Sidney, S., Sorel, M. E., Quesenberry, C. P., Jaffe, M. G., Solomon, M. D., Nguyen-Huynh, M. N., et al. (2018). Comparative trends in heart disease, stroke, and all-cause mortality in the United States and a large integrated healthcare delivery system. American Journal of Medicine.  https://doi.org/10.1016/j.amjmed.2018.02.014.Google Scholar
  30. Strazielle, N., & Ghersi-Egea, J. F. (2013). Physiology of blood–brain interfaces in relation to brain disposition of small compounds and macromolecules. Molecular Pharmaceutics, 10(5), 1473–1491.  https://doi.org/10.1021/mp300518e.CrossRefGoogle Scholar
  31. Takada, Y., Ichikawa, H., Badmaev, V., & Aggarwal, B. B. (2006). Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression. The Journal of Immunology, 176(5), 3127–3140.CrossRefGoogle Scholar
  32. Tornabene, E., & Brodin, B. (2016). Stroke and drug delivery—In vitro models of the ischemic blood–brain barrier. Journal of Pharmaceutical Sciences, 105(2), 398–405.  https://doi.org/10.1016/j.xphs.2015.11.041.CrossRefGoogle Scholar
  33. Van Beek, J., Bernaudin, M., Petit, E., Gasque, P., Nouvelot, A., MacKenzie, E. T., et al. (2000). Expression of receptors for complement anaphylatoxins C3a and C5a following permanent focal cerebral ischemia in the mouse. Experimental Neurology, 161(1), 373–382.  https://doi.org/10.1006/exnr.1999.7273.CrossRefGoogle Scholar
  34. Wang, M., Chen, M., Ding, Y., Zhu, Z., Zhang, Y., Wei, P., et al. (2015). Pretreatment with beta-boswellic acid improves blood stasis induced endothelial dysfunction: Role of eNOS activation. Scientific Reports, 5, 15357.  https://doi.org/10.1038/srep15357.CrossRefGoogle Scholar
  35. Watters, O., & O’Connor, J. J. (2011). A role for tumor necrosis factor-alpha in ischemia and ischemic preconditioning. Journal of Neuroinflammation, 8, 87.  https://doi.org/10.1186/1742-2094-8-87.CrossRefGoogle Scholar
  36. Writing Group, M, Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., et al. (2016). Executive summary: Heart disease and stroke statistics—2016 update: A report from the American Heart Association. Circulation, 133(4), 447–454.  https://doi.org/10.1161/CIR.0000000000000366.CrossRefGoogle Scholar
  37. Wu, F., Zou, Q., Ding, X., Shi, D., Zhu, X., Hu, W., et al. (2016). Complement component C3a plays a critical role in endothelial activation and leukocyte recruitment into the brain. Journal of Neuroinflammation, 13, 23.  https://doi.org/10.1186/s12974-016-0485-y.CrossRefGoogle Scholar
  38. Yin, K. J., Chen, S. D., Lee, J. M., Xu, J., & Hsu, C. Y. (2002). ATM gene regulates oxygen-glucose deprivation-induced nuclear factor-kappaB DNA-binding activity and downstream apoptotic cascade in mouse cerebrovascular endothelial cells. Stroke, 33(10), 2471–2477.CrossRefGoogle Scholar
  39. Zhao, X. J., Larkin, T. M., Lauver, M. A., Ahmad, S., & Ducruet, A. F. (2017). Tissue plasminogen activator mediates deleterious complement cascade activation in stroke. PLoS ONE, 12(7), e0180822.  https://doi.org/10.1371/journal.pone.0180822.CrossRefGoogle Scholar
  40. Zhou, P., Lu, S., Luo, Y., Wang, S., Yang, K., Zhai, Y., et al. (2017). Attenuation of TNF-alpha-induced inflammatory injury in endothelial cells by ginsenoside Rb1 via inhibiting NF-kappaB, JNK and p38 signaling pathways. Frontiers in Pharmacology, 8, 464.  https://doi.org/10.3389/fphar.2017.00464.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurosurgeryBarrow Neurological Institute, St. Joseph’s Hospital and Medical Center (SJHMC), Dignity HealthPhoenixUSA
  2. 2.Department of PharmacyOman Medical CollegeMuscatSultanate of Oman
  3. 3.Department of NeurologyBarrow Neurological Institute, St. Joseph’s Hospital and Medical Center (SJHMC), Dignity HealthPhoenixUSA
  4. 4.Department of NeurobiologyBarrow Neurological Institute, St. Joseph’s Hospital and Medical Center (SJHMC), Dignity HealthPhoenixUSA

Personalised recommendations