Skip to main content

Advertisement

SpringerLink
Log in

Deficiency of Tenascin-C Alleviates Neuronal Apoptosis and Neuroinflammation After Experimental Subarachnoid Hemorrhage in Mice

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Tenascin-C (TNC), a matricellular protein, is upregulated in brain parenchyma after experimental subarachnoid hemorrhage (SAH). Recent studies emphasize that early brain injury (EBI) should be overcome to improve post-SAH outcomes. The aim of this study was to investigate effects of TNC knockout (TNKO) on neuronal apoptosis and neuroinflammation, both of which are important constituents of EBI after SAH. C57BL/6 wild-type (WT) mice or TNKO mice underwent sham or filament perforation SAH modeling. Twenty-five WT mice and 25 TNKO mice were randomly divided into sham+WT (n = 10), sham+TNKO (n = 8), SAH+WT (n = 15), and SAH+TNKO (n = 17) groups. Beam balance test, neurological score, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, immunostaining of Toll-like receptor 4 (TLR4), and Western blotting were performed to evaluate neurobehavioral impairments, neuronal apoptosis, and neuroinflammation at 24 h post-SAH. Deficiency of TNC significantly alleviated post-SAH neurobehavioral impairments and neuronal apoptosis. The protective effects of TNKO on neurons were associated with the inhibition of a caspase-dependent apoptotic pathway, which was at least partly mediated by TLR4/nuclear factor-κB/interleukin-1β and interleukin-6 signaling cascades. This study first provided the direct evidence that TNC causes post-SAH neuronal apoptosis and neuroinflammation, potentially leading to the development of a new molecular targeted therapy against EBI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Zacharia BE, Hickman ZL, Grobelny BT, DeRosa P, Kotchetkov I, Ducruet AF, Connolly ES Jr (2010) Epidemiology of aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am 21(2):221–233. https://doi.org/10.1016/j.nec.2009.10.002

    Article  PubMed  Google Scholar 

  2. Chen S, Feng H, Sherchan P, Klebe D, Zhao G, Sun X, Zhang J, Tang J et al (2014) Controversies and evolving new mechanisms in subarachnoid hemorrhage. Prog Neurobiol 115:64–91. https://doi.org/10.1016/j.pneurobio.2013.09.002

    Article  PubMed  Google Scholar 

  3. Sehba FA, Hou J, Pluta RM, Zhang JH (2012) The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol 97(1):14–37. https://doi.org/10.1016/j.pneurobio.2012.02.003

    Article  PubMed  PubMed Central  Google Scholar 

  4. Midwood KS, Chiquet M, Tucker RP, Orend G (2016) Tenascin-C at a glance. J Cell Sci 129(23):4321–4327. https://doi.org/10.1242/jcs.190546

    Article  CAS  PubMed  Google Scholar 

  5. Udalova IA, Ruhmann M, Thomson SJ, Midwood KS (2011) Expression and immune function of tenascin-C. Crit Rev Immunol 31(2):115–145

    Article  CAS  Google Scholar 

  6. Liu L, Kawakita F, Fujimoto M, Nakano F, Imanaka-Yoshida K, Yoshida T, Suzuki H (2017) Role of periostin in early brain injury after subarachnoid hemorrhage in mice. Stroke 48(4):1108–1111. https://doi.org/10.1161/STROKEAHA.117.016629

    Article  CAS  PubMed  Google Scholar 

  7. Suzuki H, Kinoshita N, Imanaka-Yoshida K, Yoshida T, Taki W (2008) Cerebrospinal fluid tenascin-C increases preceding the development of chronic shunt-dependent hydrocephalus after subarachnoid hemorrhage. Stroke 39(5):1610–1612. https://doi.org/10.1161/STROKEAHA.107.505735

    Article  CAS  PubMed  Google Scholar 

  8. Suzuki H, Kanamaru K, Shiba M, Fujimoto M, Imanaka-Yoshida K, Yoshida T, Taki W (2011) Cerebrospinal fluid tenascin-C in cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol 23(4):310–317. https://doi.org/10.1097/ANA.0b013e31822aa1f2

    Article  PubMed  Google Scholar 

  9. Liu L, Fujimoto M, Kawakita F, Nakano F, Imanaka-Yoshida K, Yoshida T, Suzuki H (2016) Anti-vascular endothelial growth factor treatment suppresses early brain injury after subarachnoid hemorrhage in mice. Mol Neurobiol 53(7):4529–4538. https://doi.org/10.1007/s12035-015-9386-9

    Article  CAS  PubMed  Google Scholar 

  10. Shiba M, Suzuki H, Fujimoto M, Shimojo N, Imanaka-Yoshida K, Yoshida T, Kanamaru K, Matsushima S et al (2012) Imatinib mesylate prevents cerebral vasospasm after subarachnoid hemorrhage via inhibiting tenascin-C expression in rats. Neurobiol Dis 46(1):172–179. https://doi.org/10.1016/j.nbd.2012.01.005

    Article  CAS  PubMed  Google Scholar 

  11. Fujimoto M, Shiba M, Kawakita F, Liu L, Shimojo N, Imanaka-Yoshida K, Yoshida T, Suzuki H (2016) Deficiency of tenascin-C and attenuation of blood-brain barrier disruption following experimental subarachnoid hemorrhage in mice. J Neurosurg 124(6):1693–1702. https://doi.org/10.3171/2015.4.JNS15484

    Article  CAS  PubMed  Google Scholar 

  12. Saga Y, Yagi T, Ikawa Y, Sakakura T, Aizawa S (1992) Mice develop normally without tenascin. Genes Dev 6(10):1821–1831

    Article  CAS  Google Scholar 

  13. Suzuki H, Hasegawa Y, Chen W, Kanamaru K, Zhang JH (2010) Recombinant osteopontin in cerebral vasospasm after subarachnoid hemorrhage. Ann Neurol 68(5):650–660. https://doi.org/10.1002/ana.22102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Suzuki H, Zhang JH (2012) Neurobehavioral assessments of subarachnoid hemorrhage. In: Chen J, Xu X-M, Xu ZC, Zhang JH (eds) Springer protocols handbooks. Animal models of acute neurological injuries II. Humana Press, New York, pp. 435–440. https://doi.org/10.1007/978-1-61779-576-3_31

    Chapter  Google Scholar 

  15. Sugawara T, Ayer R, Jadhav V, Zhang JH (2008) A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods 167(2):327–334. https://doi.org/10.1016/j.jneumeth.2007.08.004

    Article  PubMed  Google Scholar 

  16. Shiba M, Fujimoto M, Imanaka-Yoshida K, Yoshida T, Taki W, Suzuki H (2014) Tenascin-C causes neuronal apoptosis after subarachnoid hemorrhage in rats. Transl Stroke Res 5(2):238–247. https://doi.org/10.1007/s12975-014-0333-2

    Article  PubMed  Google Scholar 

  17. Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH (2004) Signaling pathways for early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 24(8):916–925. https://doi.org/10.1097/01.WCB.0000125886.48838.7E

    Article  CAS  PubMed  Google Scholar 

  18. Cahill J, Calvert JW, Zhang JH (2006) Mechanisms of early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 26(11):1341–1353. https://doi.org/10.1038/sj.jcbfm.9600283

    Article  CAS  PubMed  Google Scholar 

  19. Suzuki H, Kawakita F (2016) Tenascin-C in aneurysmal subarachnoid hemorrhage: Deleterious or protective? Neural Regen Res 11(2):230–231. https://doi.org/10.4103/1673-5374.177721

    Article  PubMed  PubMed Central  Google Scholar 

  20. Fujimoto M, Shiba M, Kawakita F, Liu L, Shimojo N, Imanaka-Yoshida K, Yoshida T, Suzuki H (2017) Effects of tenascin-C knockout on cerebral vasospasm after experimental subarachnoid hemorrhage in mice. Mol Neurobiol 55:1951–1958. https://doi.org/10.1007/s12035-017-0466-x

    Article  CAS  PubMed  Google Scholar 

  21. Okada T, Suzuki H (2017) Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage. Neural Regen Res 12(2):193–196. https://doi.org/10.4103/1673-5374.200795

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hanafy KA (2013) The role of microglia and the TLR4 pathway in neuronal apoptosis and vasospasm after subarachnoid hemorrhage. J Neuroinflammation 10:83. https://doi.org/10.1186/1742-2094-10-83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kawakita F, Fujimoto M, Liu L, Nakano F, Nakatsuka Y, Suzuki H (2017) Effects of Toll-like receptor 4 antagonists against cerebral vasospasm after experimental subarachnoid hemorrhage in mice. Mol Neurobiol 54(8):6624–6633. https://doi.org/10.1007/s12035-016-0178-7

    Article  CAS  PubMed  Google Scholar 

  24. Zhou CH, Wang CX, Xie GB, Wu LY, Wei YX, Wang Q, Zhang HS, Hang CH et al (2015) Fisetin alleviates early brain injury following experimental subarachnoid hemorrhage in rats possibly by suppressing TLR4/NF-κB signaling pathway. Brain Res 1629:250–259. https://doi.org/10.1016/j.brainres.2015.10.016

    Article  CAS  PubMed  Google Scholar 

  25. Xia DY, Zhang HS, Wu LY, Zhang XS, Zhou ML, Hang CH (2017) Pentoxifylline alleviates early brain injury after experimental subarachnoid hemorrhage in rats: possibly via inhibiting TLR4/NF-κB signaling pathway. Neurochem Res 42(4):963–974. https://doi.org/10.1007/s11064-016-2129-0

    Article  CAS  PubMed  Google Scholar 

  26. Roy A, Srivastava M, Saqib U, Liu D, Faisal SM, Sugathan S, Bishnoi S, Baig MS (2016) Potential therapeutic targets for inflammation in toll-like receptor 4 (TLR4)-mediated signaling pathways. Int Immunopharmacol 40:79–89. https://doi.org/10.1016/j.intimp.2016.08.026

    Article  CAS  PubMed  Google Scholar 

  27. Guadagno J, Swan P, Shaikh R, Cregan SP (2015) Microglia-derived IL-1β triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells. Cell Death Dis 6:e1779. https://doi.org/10.1038/cddis.2015.151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tan Y, Uchida K, Nakajima H, Guerrero AR, Watanabe S, Hirai T, Takeura N, Liu SY et al (2013) Blockade of interleukin 6 signaling improves the survival rate of transplanted bone marrow stromal cells and increases locomotor function in mice with spinal cord injury. J Neuropathol Exp Neurol 72(10):980–993. https://doi.org/10.1097/NEN.0b013e3182a79de9

    Article  CAS  PubMed  Google Scholar 

  29. Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, Drexler S, Sofat N et al (2009) Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 15(7):774–780. https://doi.org/10.1038/nm.1987

    Article  CAS  PubMed  Google Scholar 

  30. Fujimoto M, Suzuki H, Shiba M, Shimojo N, Imanaka-Yoshida K, Yoshida T, Kanamaru K, Matsushima S et al (2013) Tenascin-C induces prolonged constriction of cerebral arteries in rats. Neurobiol Dis 55:104–109. https://doi.org/10.1016/j.nbd.2013.01.007

    Article  CAS  PubMed  Google Scholar 

  31. Fujimoto M, Shiba M, Kawakita F, Liu L, Nakasaki A, Shimojo N, Imanaka-Yoshida K, Yoshida T et al (2016) Epidermal growth factor-like repeats of tenascin-C-induced constriction of cerebral arteries via activation of epidermal growth factor receptors in rats. Brain Res 1642:436–444. https://doi.org/10.1016/j.brainres.2016.04.034

    Article  CAS  PubMed  Google Scholar 

  32. Van Obberghen-Schilling E, Tucker RP, Saupe F, Gasser I, Cseh B, Orend G (2011) Fibronectin and tenascin-C: accomplices in vascular morphogensis during development and tumor growth. Int J Dev Biol 55:511–525. https://doi.org/10.1387/ijdb.103243eo

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms. Chiduru Yamamoto (Department of Neurosurgery, Mie University Graduate School of Medicine) for her technical assistance.

Funding

This study was funded by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science to Dr. Fujimoto (15 K19962), and Mie Medical Research Foundation to Dr. Suzuki.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Lei Liu, Masashi Fujimoto, Fumi Nakano, Hirofumi Nishikawa, Takeshi Okada, Fumihiro Kawakita & Hidenori Suzuki

  2. Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan

    Kyoko Imanaka-Yoshida & Toshimichi Yoshida

  3. Research Center for Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan

    Kyoko Imanaka-Yoshida, Toshimichi Yoshida & Hidenori Suzuki

Authors
  1. Lei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masashi Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fumi Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hirofumi Nishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takeshi Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fumihiro Kawakita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kyoko Imanaka-Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toshimichi Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hidenori Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hidenori Suzuki.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Research Involving Animals

All procedures were approved by the Animal Ethics Review Committee of Mie University and were carried out according to the institution’s Guidelines for Animal Experiments.

Electronic supplementary material

ESM 1

(PDF 961 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, L., Fujimoto, M., Nakano, F. et al. Deficiency of Tenascin-C Alleviates Neuronal Apoptosis and Neuroinflammation After Experimental Subarachnoid Hemorrhage in Mice. Mol Neurobiol 55, 8346–8354 (2018). https://doi.org/10.1007/s12035-018-1006-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1006-z

Keywords

Search

Navigation