Journal
MOLECULAR NEURODEGENERATION
Volume 7, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/1750-1326-7-21
Keywords
Embolic stroke; Focal ischemia; Gelatinase proteolysis; Intracerebral hemorrhage; Neuroprotection; Neurovascular unit; Pericytes
Categories
Funding
- American Heart Association [06BGIA0665051Y, 09NSDG2260983]
- Dana Foundation
- NIH grant [CA122417]
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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.
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