Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia

Molecular Neurodegeneration

Zezong Gu⁵  Grace Y Sun¹  Shahriar Mobashery³  Mayland Chang³  Mijoon Lee³  Gregory J Blair⁵  Tareq Lehmidi²  Or Hadass²  Rong Hu⁴  Wei Wu⁵  Fanjun Meng⁵  Chunyang Zhang⁵  Shanyan Chen⁴  Jiankun Cui⁵ 

[1] Department of Biochemistry, University of Missouri School of Medicine, Columbia, Missouri, 65212, USA;MS in Pathology Program, University of Missouri, Columbia, MO, 65212, USA;Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA;Interdisciplinary Neuroscience Program, University of Missouri, Columbia, Missouri, 65212, USA;Department of Pathology and Anatomical Sciences, Center for Translational Neuroscience, University of Missouri School of Medicine, Columbia, Missouri, 65212, USA

关键词: Pericytes;    Neurovascular unit;    Neuroprotection;    Intracerebral hemorrhage;    Gelatinase proteolysis;    Focal ischemia;    Embolic stroke;   

Others  :  863844
DOI  :  10.1186/1750-1326-7-21

 received in 2012-01-27, accepted in 2012-05-15,  发布年份 2012

【 摘 要 】

Background

Cerebral ischemia has been shown to induce activation of matrix metalloproteinases (MMPs), particularly MMP-9, which is associated with impairment of the neurovasculature, resulting in blood–brain barrier breakdown, hemorrhage and neurodegeneration. We previously reported that the thiirane inhibitor SB-3CT, which is selective for gelatinases (MMP-2 and −9), could antagonize neuronal apoptosis after transient focal cerebral ischemia.

Results

Here, we used a fibrin-rich clot to occlude the middle cerebral artery (MCA) and assessed the effects of SB-3CT on the neurovasculature. Results show that neurobehavioral deficits and infarct volumes induced by embolic ischemia are comparable to those induced by the filament-occluded transient MCA model. Confocal microscopy indicated embolus-blocked brain microvasculature and neuronal cell death. Post-ischemic SB-3CT treatment attenuated infarct volume, ameliorated neurobehavioral outcomes, and antagonized the increases in levels of proform and activated MMP-9. Embolic ischemia caused degradation of the neurovascular matrix component laminin and tight-junction protein ZO-1, contraction of pericytes, and loss of lectin-positive brain microvessels. Despite the presence of the embolus, SB-3CT mitigated these outcomes and reduced hemorrhagic volumes. Interestingly, SB-3CT treatment for seven days protected against neuronal laminin degradation and protected neurons from ischemic cell death.

Conclusion

These results demonstrate considerable promise for the thiirane class of selective gelatinase inhibitors as potential therapeutic agents in stroke therapy.

【 授权许可】

   
2012 Cui et al.; licensee BioMed Central Ltd.

【 图 表 】

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