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- Title
Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia.
- Authors
Jiankun Cui; Shanyan Chen; Chunyang Zhang; Fanjun Meng; Wei Wu; Rong Hu; Hadass, Or; Lehmidi, Tareq; Blair, Gregory J; Mijon Lee; Chang, Mayland; Mobashery, Shariar; Sun, Grace Y; Zezong Gu
- Abstract
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.
- Subjects
ISCHEMIA; GELATINASES; BLOOD-brain barrier; HEMORRHAGE; NEURODEGENERATION
- Publication
Molecular Neurodegeneration, 2012, Vol 7, Issue 1, p21
- ISSN
1750-1326
- Publication type
Article
- DOI
10.1186/1750-1326-7-21