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Matrix Metalloproteinase-8 Inhibition Prevents Disruption of Blood–Spinal Cord Barrier and Attenuates Inflammation in Rat Model of Spinal Cord Injury

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Abstract

After spinal cord injury (SCI), tight junction (TJ) protein degradation increases permeability and disrupts the blood–spinal cord barrier (BSCB). The BSCB is primarily formed of endothelial cell, which forms a specialized tight seal due to the presence of TJs. BSCB disruption after SCI allows neutrophil infiltration. Matrix metalloproteinase (MMP)-8 is believed to be mainly expressed by neutrophils and is quickly released upon neutrophil activation. Here, we determined whether MMP-8 is involved in the TJ protein degradation in endothelial cells and also determined its role in the neuroinflammation after SCI. MMP-8 recombinant protein treatment increases the TNF-α expression and decreased the TJ (occludin and zonula occludens-1) protein expression in the endothelial cells. Likewise, specific MMP-8 inhibitor (MMP-8I) significantly prevented the TNF-α-induced decrease in the expression of TJ protein in endothelial cells. Furthermore, MMP-8 expression was significantly increased 1 and 3 days after moderate compression (35 g for 5 min at T10 level) SCI, whereas TJ protein levels decreased as determined qRT-PCR, western blotting, and immunohistochemistry. MMP-8 was inhibited directly using a MMP-8I (5 mg/kg) and indirectly by reducing neutrophil infiltration with sivelestat sodium (50 mg/kg) or using the antioxidant N-acetyl-l-cysteine (100 mg/kg). The MMP-8I significantly decreased TNF-α expression, IL-6, and iNOS expression and increased TJ protein expression after SCI. In addition, MMP-8I significantly lessens the amount of Evans blue dye extravasation observed after injury. Thus, our result suggests that MMP-8 plays an imperative role in inflammation and degradation of TJ proteins. Increased MMP-8 expression was associated with the early inflammatory phase of SCI. Inhibiting MMP-8 significantly attenuated SCI-induced inflammation, BSCB breakdown, and cell injury.

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Acknowledgments

This work was supported by a grant of the National Research Foundation of Korea (NRF) (NRF-2014R1A1A2059118, NRF-2015H1D3A1066543), the Ministry of Science, ICT & Future Planning (NRF-2016R1A2A1A05004987), and the Korea Healthcare Technology Research & Development Project, Ministry for Health & Welfare Affairs, Republic of Korea (HI14C3270, HR16C0002).

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  1. Hemant Kumar and Min-Jae Jo are contributed equally.

Authors and Affiliations

  1. Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea

    Hemant Kumar, Min-Jae Jo, Hyemin Choi, Seil Shon & In-Bo Han

  2. Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea

    Hemant Kumar, Min-Jae Jo, Hyemin Choi, Manjunatha S. Muttigi, Byung-Joo Kim & Soo-Hong Lee

  3. School of Integrative Engineering, Chung-Ang University, Seoul, 06911, Republic of Korea

    Manjunatha S. Muttigi

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Supplementary Fig. 1

Matrix metalloproteinase-8 (MMP-8) expression increases after spinal cord injury (SCI) at the epicenter of the damage. The spinal cord was collected 1, 3, 7, 14, 21 and 28 days (1D, 3D, 7D, 14D, 21D and 28D, respectively) after SCI to determine the expression of MMP-8 (A). Luxol fast blue (LFB) staining was performed at the epicenter of the SCI damage and in sham-injured rats 3H and 1D, 3D, 5D, and 7D, respectively after SCI in longitudinal section (B). (JPEG 86 kb).

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Kumar, H., Jo, MJ., Choi, H. et al. Matrix Metalloproteinase-8 Inhibition Prevents Disruption of Blood–Spinal Cord Barrier and Attenuates Inflammation in Rat Model of Spinal Cord Injury. Mol Neurobiol 55, 2577–2590 (2018). https://doi.org/10.1007/s12035-017-0509-3

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