Inflammation

, Volume 39, Issue 4, pp 1503–1513 | Cite as

Salvianolic Acid B Ameliorates Cerebral Ischemia/Reperfusion Injury Through Inhibiting TLR4/MyD88 Signaling Pathway

  • Yujue Wang
  • Guang Chen
  • Xiangdong Yu
  • Yunchao Li
  • Li Zhang
  • Zongze He
  • Nannan Zhang
  • Xiuping Yang
  • Yansheng Zhao
  • Na Li
  • Hong Qiu
ORIGINAL ARTICLE

ABSTRACT

Ischemic stroke can activate multiple transcription factors and cause inflammatory reactions, which involve pattern recognition receptors with immunostimulatory effects. Toll-like receptor 4 (TLR4) is one of the receptors related to innate immunity and several inflammatory reactions. The promising anti- inflammatory activity of salvianolic acid B (SAB) had been previously reported, but its effect on ischemic stroke remains unknown. An oxygen-glucose deprivation and reoxygenation (OGD/R) model in vitro and a middle cerebral artery occlusion (MCAO) model in vivo were used in this paper, and the results showned that SAB remarkably increased the viabilities of PC12 cells and primary cortical neurons after OGD/R injury and notably prevented cerebral ischemia/reperfusion (I/R) injury. SAB also significantly ameliorated NeuN release from primary cortical neurons. Further research indicated that the neuroprotection of SAB was completed through inhibiting the TLR4/MyD88/TRAF6 signaling pathway. The blocking of TLR4 by SAB also restrained NF-kB transcriptional activity and pro-inflammatory cytokine responses (IL-1β, IL-6, and TNF-α). These findings supply a new insight that will aid in clarifying the effect of SAB against cerebral I/R injury and provide the development of SAB as a potential candidate for treating ischemic stroke.

KEY WORDS

cerebral I/R injury inflammation ischemic stroke SAB TLR4 

REFERENCES

  1. 1.
    Eltzschig, H.K., and T. Eckle. 2011. Ischemia and reperfusion—from mechanism to translation. Nature Medicine 17(11): 1391–1401.CrossRefPubMedGoogle Scholar
  2. 2.
    Flynn, R.W., R.S. MacWalter, and A.S. Doney. 2008. The cost of cerebral ischaemia. Neuropharmacology 55(3): 250–256.CrossRefPubMedGoogle Scholar
  3. 3.
    Lu, C., T. Ha, X. Wang, L. Liu, X. Zhang, E.O. Kimbrough, Z. Sha, M. Guan, J. Schweitzer, J. Kalbfleisch, D. Williams, and C. Li. 2014. The TLR9 ligand, CpG-ODN, induces protection against cerebral ischemia/reperfusion injury via activation of PI3K/Akt signaling. Journal of the American Heart Association 3(2): e000629.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Cuzzocrea, S., D.P. Riley, A.P. Caputi, and D. Salvemini. 2001. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacological Reviews 53(1): 135–159.PubMedGoogle Scholar
  5. 5.
    Iadecola, C., and J. Anrather. 2011. The immunology of stroke: from mechanisms to translation. Nature Medicine 17(7): 796–808.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lu, X., L. Ma, L. Ruan, Y. Kong, H. Mou, Z. Zhang, Z. Wang, J.M. Wang, and Y. Le. 2010. Resveratrol differentially modulates inflammatory responses of microglia and astrocytes. Journal of Neuroinflammation 7: 46.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Marin-Prida, J., N. Pavon-Fuentes, A. Llopiz-Arzuaga, J.R. Fernandez-Masso, L. Delgado-Roche, Y. Mendoza-Mari, S.P. Santana, A. Cruz-Ramirez, C. Valenzuela-Silva, M. Nazabal-Galvez, A. Cintado-Benitez, G.L. Pardo-Andreu, N. Polentarutti, F. Riva, E. Penton-Arias, and G. Penton-Rol. 2013. Phycocyanobilin promotes PC12 cell survival and modulates immune and inflammatory genes and oxidative stress markers in acute cerebral hypoperfusion in rats. Toxicology and Applied Pharmacology 272(1): 49–60.CrossRefPubMedGoogle Scholar
  8. 8.
    Eskes, C., L. Juillerat-Jeanneret, G. Leuba, P. Honegger, and F. Monnet-Tschudi. 2003. Involvement of microglia-neuron interactions in the tumor necrosis factor-alpha release, microglial activation, and neurodegeneration induced by trimethyltin. Journal of Neuroscience Research 71(4): 583–590.CrossRefPubMedGoogle Scholar
  9. 9.
    Hanke, M.L., and T. Kielian. 2011. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clinical Science (London) 121(9): 367–387.CrossRefGoogle Scholar
  10. 10.
    Gao, Y., X. Fang, Y. Tong, Y. Liu, and B. Zhang. 2009. TLR4-mediated MyD88-dependent signaling pathway is activated by cerebral ischemia-reperfusion in cortex in mice. Biomedicine and Pharmacotherapy 63(6): 442–450.CrossRefPubMedGoogle Scholar
  11. 11.
    Akira, S., K. Takeda, and T. Kaisho. 2001. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunology 2(8): 675–680.CrossRefPubMedGoogle Scholar
  12. 12.
    Wang, P.F., H. Fang, J. Chen, S. Lin, Y. Liu, X.Y. Xiong, Y.C. Wang, R.P. Xiong, F.L. Lv, J. Wang, and Q.W. Yang. 2014. Polyinosinic-polycytidylic acid has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3. Journal of Immunology 192(10): 4783–4794.CrossRefGoogle Scholar
  13. 13.
    Michelsen, K.S., M.H. Wong, P.K. Shah, W. Zhang, J. Yano, T.M. Doherty, S. Akira, T.B. Rajavashisth, and M. Arditi. 2004. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proceedings of the National Academy of Sciences of the United States of America 101(29): 10679–10684.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Cao, C.X., Q.W. Yang, F.L. Lv, J. Cui, H.B. Fu, and J.Z. Wang. 2007. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochemical and Biophysical Research Communications 353(2): 509–514.CrossRefPubMedGoogle Scholar
  15. 15.
    Caso, J.R., J.M. Pradillo, O. Hurtado, J.C. Leza, M.A. Moro, and I. Lizasoain. 2008. Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke. Stroke 39(4): 1314–1320.CrossRefPubMedGoogle Scholar
  16. 16.
    Ridder, D.A., and M. Schwaninger. 2009. NF-kappaB signaling in cerebral ischemia. Neuroscience 158(3): 995–1006.CrossRefPubMedGoogle Scholar
  17. 17.
    Tao, X., X. Sun, L. Yin, X. Han, L. Xu, Y. Qi, Y. Xu, H. Li, Y. Lin, K. Liu, and J. Peng. 2015. Dioscin ameliorates cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via HMGB-1 inhibition. Free Radical Biology and Medicine 84: 103–115.CrossRefPubMedGoogle Scholar
  18. 18.
    Chen, Q., and Y. Zeng. 2000. Anisodamine protects against neuronal death following cerebral ischemia in gerbils. Chinese Medical Journal 113(7): 636–639.PubMedGoogle Scholar
  19. 19.
    Wu, X., J. Su, L. Chen, B. Ma, X. Gu, and L. Zhu. 2015. Ginkgolide B protects neurons from ischemic injury by inhibiting the expression of RTP801. Cellular and Molecular Neurobiology 35(7): 943–952.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhao, Q., M. Yang, Y. Deng, H. Yu, L. Wang, F. Teng, K. Cho, H. Ma, P. Wu, X. Li, W. Wu, X. Liu, F. Xu, B. Jiang, and D.A. Guo. 2015. The safety evaluation of SAB and ginsenoside Rg1 combination on mice. International Journal of Molecular Sciences 16(12): 29345–29356.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhao, Y., Y. Guo, and X. Gu. 2011. SAB, a potential chemopreventive agent, for head and neck squamous cell cancer. Journal of Oncology 2011: 534548.CrossRefPubMedGoogle Scholar
  22. 22.
    Ma, L., Y.Q. Guan, and Z.D. Du. 2015. SAB down-regulates matrix metalloproteinase-9 activity and expression in tumor necrosis factor-alpha-induced human coronary artery endothelial cells. Chinese Medical Journal 128(19): 2658–2663.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Agrawal, M., V. Kumar, A.K. Singh, M.P. Kashyap, V.K. Khanna, M.A. Siddiqui, and A.B. Pant. 2013. Trans-Resveratrol protects ischemic PC12 Cells by inhibiting the hypoxia associated transcription factors and increasing the levels of antioxidant defense enzymes. ACS Chemical Neuroscience 4(2): 285–294.CrossRefPubMedGoogle Scholar
  24. 24.
    Mitsios, N., J. Gaffney, P. Kumar, J. Krupinski, S. Kumar, and M. Slevin. 2006. Pathophysiology of acute ischaemic stroke: an analysis of common signalling mechanisms and identification of new molecular targets. Pathobiology 73(4): 159–175.CrossRefPubMedGoogle Scholar
  25. 25.
    Kanzler, H., F.J. Barrat, E.M. Hessel, and R.L. Coffman. 2007. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nature Medicine 13(5): 552–559.CrossRefPubMedGoogle Scholar
  26. 26.
    Hyakkoku, K., J. Hamanaka, K. Tsuruma, M. Shimazawa, H. Tanaka, S. Uematsu, S. Akira, N. Inagaki, H. Nagai, and H. Hara. 2010. Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia. Neuroscience 171(1): 258–267.CrossRefPubMedGoogle Scholar
  27. 27.
    Gupta, A., Z.A. Cooper, M.E. Tulapurkar, R. Potla, T. Maity, J.D. Hasday, and I.S. Singh. 2013. Toll-like receptor agonists and febrile range hyperthermia synergize to induce heat shock protein 70 expression and extracellular release. Journal of Biological Chemistry 288(4): 2756–2766.CrossRefPubMedGoogle Scholar
  28. 28.
    Hou, S.T., and J.P. MacManus. 2002. Molecular mechanisms of cerebral ischemia-induced neuronal death. International Review of Cytology 221: 93–148.CrossRefPubMedGoogle Scholar
  29. 29.
    Emre, U., K. Rantanen, and T. Tatlisumak. 2007. Antithrombotic treatment in the prevention of ischemic stroke. Current Drug Targets 8(7): 817–823.CrossRefPubMedGoogle Scholar
  30. 30.
    Chiu, B.Y., C.P. Chang, J.W. Lin, J.S. Yu, W.P. Liu, Y.C. Hsu, and M.T. Lin. 2014. Beneficial effect of astragalosides on stroke condition using PC12 cells under oxygen glucose deprivation and reperfusion. Cellular and Molecular Neurobiology 34(6): 825–837.CrossRefPubMedGoogle Scholar
  31. 31.
    Hillion, J.A., K. Takahashi, D. Maric, C. Ruetzler, J.L. Barker, and J.M. Hallenbeck. 2005. Development of an ischemic tolerance model in a PC12 cell line. Journal of Cerebral Blood Flow and Metabolism 25(2): 154–162.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Muzio, M., N. Polentarutti, D. Bosisio, M.K. Prahladan, and A. Mantovani. 2000. Toll-like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes. Journal of Leukocyte Biology 67(4): 450–456.PubMedGoogle Scholar
  33. 33.
    Hoshino, K., O. Takeuchi, T. Kawai, H. Sanjo, T. Ogawa, Y. Takeda, K. Takeda, and S. Akira. 1999. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. Journal of Immunology 162(7): 3749–3752.Google Scholar
  34. 34.
    Tsakiri, N., I. Kimber, N.J. Rothwell, and E. Pinteaux. 2008. Interleukin-1-induced interleukin-6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones. British Journal of Pharmacology 153(4): 775–783.CrossRefPubMedGoogle Scholar
  35. 35.
    Li, B., J. Li, X. Pan, G. Ding, H. Cao, W. Jiang, J. Zheng, and H. Zhou. 2010. Artesunate protects sepsis model mice challenged with Staphylococcus aureus by decreasing TNF-alpha release via inhibition TLR2 and Nod2 mRNA expressions and transcription factor NF-kappaB activation. International Immunopharmacology 10(3): 344–350.CrossRefPubMedGoogle Scholar
  36. 36.
    Liu, T., T. Zhang, H. Yu, H. Shen, and W. Xia. 2014. Adjudin protects against cerebral ischemia reperfusion injury by inhibition of neuroinflammation and blood–brain barrier disruption. Journal of Neuroinflammation 11: 107.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Xin, Q., B. Cheng, Y. Pan, H. Liu, C. Yang, J. Chen, and B. Bai. 2015. Neuroprotective effects of apelin-13 on experimental ischemic stroke through suppression of inflammation. Peptides 63: 55–62.CrossRefPubMedGoogle Scholar
  38. 38.
    Li, H., J. Hu, L. Ma, Z. Yuan, Y. Wang, X. Wang, D. Xing, F. Lei, and L. Du. 2010. Comprehensive study of baicalin down-regulating NOD2 receptor expression of neurons with oxygen-glucose deprivation in vitro and cerebral ischemia-reperfusion in vivo. European Journal of Pharmacology 649(1–3): 92–99.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Yujue Wang
    • 1
  • Guang Chen
    • 1
  • Xiangdong Yu
    • 1
  • Yunchao Li
    • 1
  • Li Zhang
    • 2
  • Zongze He
    • 3
  • Nannan Zhang
    • 4
  • Xiuping Yang
    • 4
  • Yansheng Zhao
    • 5
  • Na Li
    • 6
  • Hong Qiu
    • 1
  1. 1.Department of NeurosurgeryKaiLuan General HospitalTangshanChina
  2. 2.Department of NeurosurgeryTangshan People’s HospitalTangshanChina
  3. 3.Department of NeurosurgeryThe Affiliated Hospital of University of Electronic Science and Technology of China & Sichuan Provincial People’s HospitalChengduChina
  4. 4.Department of NeurologyKaiLuan General HospitalTangshanChina
  5. 5.Department of Nuclear MagneticKaiLuan General HospitalTangshanChina
  6. 6.Department of EmergencyChinese People’s Liberation Army 255 HospitalTangshanChina

Personalised recommendations