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Mol Neurobiol. 2018 Mar;55(3):2577-2590. doi: 10.1007/s12035-017-0509-3. Epub 2017 Apr 18.

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

Author information

1
Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea.
2
Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
3
School of Integrative Engineering, Chung-Ang University, Seoul, 06911, Republic of Korea.
4
Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea. soohong@cha.ac.kr.
5
Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea. hanib@cha.ac.kr.

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.

KEYWORDS:

Blood–spinal cord barrier; MMP-8; Neuroinflammation; Occludin; Spinal cord injury; Tight junctions

PMID:
28421532
DOI:
10.1007/s12035-017-0509-3
[Indexed for MEDLINE]

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