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

Hemant Kumar, Min Jae Jo, Hyemin Choi, Manjunatha S. Muttigi, Seil Shon, Byung Joo Kim, Soo Hong Lee, In Bo Han

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2577-2590
Number of pages14
JournalMolecular Neurobiology
Volume55
Issue number3
DOIs
Publication statusPublished - 01-03-2018

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

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