Matrix Metalloproteinase-8 Inhibition Prevents Disruption of Blood-Spinal Cord Barrier and Attenuates Inflammation in Rat Model of Spinal Cord Injury
- Authors
- Kumar, Hemant; Jo, Min-Jae; Choi, Hyemin; Muttigi, Manjunatha S.; Shon, Seil; Kim, Byung-Joo; Lee, Soo-Hong; Han, In-Bo
- Issue Date
- Mar-2018
- Publisher
- HUMANA PRESS INC
- Keywords
- MMP-8; Spinal cord injury; Tight junctions; Occludin; Neuroinflammation; Blood-spinal cord barrier
- Citation
- MOLECULAR NEUROBIOLOGY, v.55, no.3, pp 2577 - 2590
- Pages
- 14
- Journal Title
- MOLECULAR NEUROBIOLOGY
- Volume
- 55
- Number
- 3
- Start Page
- 2577
- End Page
- 2590
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/45312
- DOI
- 10.1007/s12035-017-0509-3
- ISSN
- 0893-7648
1559-1182
- 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-alpha 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-alpha-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-alpha 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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