title: 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.
  
  
  CONCLUSIONS
  These results demonstrate considerable promise for the thiirane class of selective gelatinase inhibitors as potential therapeutic agents in stroke therapy.
authors.affiliation: Department of Pathology and Anatomical Sciences, Center for Translational Neuroscience, University of Missouri School of Medicine, Columbia, Missouri 65212, USA.
authors.forename: Jiankun
authors.initials: J
authors.lastname: Cui
authors.forename: Shanyan
authors.initials: S
authors.lastname: Chen
authors.forename: Chunyang
authors.initials: C
authors.lastname: Zhang
authors.forename: Fanjun
authors.initials: F
authors.lastname: Meng
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Or
authors.initials: O
authors.lastname: Hadass
authors.forename: Tareq
authors.initials: T
authors.lastname: Lehmidi
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Blair
authors.forename: Mijoon
authors.initials: M
authors.lastname: Lee
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Sun
authors.forename: Zezong
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D007150:Immunohistochemistry; D020766:Intracranial Embolism / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D020780:Matrix Metalloproteinase 9