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

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.

• Authors: Jiankun Cui, Shanyan Chen, Chunyang Zhang, Fanjun Meng, Wei Wu, Rong Hu, Or Hadass, Tareq Lehmidi, Gregory J Blair, Mijoon Lee, Mayland Chang, Shahriar Mobashery, Grace Y Sun, Zezong Gu
• Journal: Molecular neurodegeneration (Mol Neurodegener) Vol. 7 Pg. 21 (May 15 2012) ISSN: 1750-1326 [Electronic] England
• PMID: 22587708 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Heterocyclic Compounds, 1-Ring
• Matrix Metalloproteinase Inhibitors
• SB 3CT compound
• Sulfones
• Matrix Metalloproteinase 9

Topics

• Animals
• Brain Ischemia (metabolism)
• Cerebrovascular Circulation (drug effects)
• Disease Models, Animal
• Heterocyclic Compounds, 1-Ring (pharmacology)
• Immunohistochemistry
• Intracranial Embolism (metabolism)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors (pharmacology)
• Mice
• Mice, Inbred C57BL
• Sulfones (pharmacology)