Ulinastatin protects brain against cerebral ischemia/reperfusion injury through inhibiting MMP-9 and alleviating loss of ZO-1 and occludin proteins in mice

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Background:The effects of Ulinastatin (UTI) on the blood-brain barrier (BBB) in the acute phase of cerebral ischemia/reperfusion (I/R) are not clear. This study was to investigate the potential protective effects of UTI on the BBB and the underlying mechanisms.Methods:Male CD-1 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly assigned to four groups: Sham (sham-operated), tMCAO (tMCAO + 0.9% saline), UTI-L (tMCAO + UTI 1500 U/100 g) and UTI-H (tMCAO + UTI 3000 U/100 g) group. UTI was administered immediately after reperfusion in the UTI-L and UTI-H groups. At 24 h after reperfusion, the neurological deficit, brain water content, and infarct volume were determined. Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to examine the expression of matrix metalloproteinase (MMP)-9, Zonula occludens-1 (ZO-1) and occludin in ischemic cerebral cortex. The integrity of the BBB was assessed by the leakage of Evans blue.Results:Compared with tMCAO group, both UTI-L and UTI-H groups showed significantly (P < 0.001) ameliorated the neurological deficit (2.00 ± 0.71 and 1.60 ± 0.55 vs. 4.60 ± 0.55), lessened brain water content (82.99% ± 0.21% and 82.05% ± 0.59% vs. 84.28% ± 0.0.57%) and decreased the infarct volume (38.52% ± 1.72% and 24.78% ± 1.20% vs. 49.48% ± 1.93%). In addition, significantly (P < 0.001) decreased expression of MMP-9 (0.48 ± 0.06 and 0.37 ± 0.05 vs.0.76 ± 0.10 for protein and 2.88 ± 0.23 and 2.17 ± 0.16 vs. 3.90 ± 0.24 for mRNA) and alleviated loss of ZO-1 (0.19 ± 0.04 and 0.24 ± 0.05 vs. 0.25 ± 0.03) and occludin (0.74 ± 0.08 and 0.87 ± 0.07 vs. 0.94 ± 0.06) proteins were observed in both UTI-L and UTI-H groups.Conclusion:UTI protects the brain against ischemic injury potentially via down-regulating the expression of MMP-9 and alleviating loss of ZO-1 and occludin proteins to restore the BBB permeability.HIGHLIGHTSUlinastatin treatment exerts protective effects against cerebral ischemia/reperfusion injury in mice.Ulinastatin ameliorates the blood-brain barrier permeability in mice with transient middle cerebral artery occlusion.Ulinastatin down-regulates MMP-9 while up-regulates ZO-1 and occludin expression.

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