title: Reperfusion activates metalloproteinases that contribute to neurovascular injury.
abstract: In this study, we examine the effects of reperfusion on the activation of matrix metalloproteinase (MMP) and assess the relationship between MMP activation during reperfusion and neurovascular injury. Ischemia was produced using suture-induced middle cerebral artery occlusion in rats. The MMP activation was examined with in situ and gel zymography. Injury to cerebral endothelial cells and basal lamina was assessed using endothelial barrier antigen (EBA) and collagen IV immunohistochemistry. Injury to neurons and glial cells was assessed using Cresyl violet staining. These were examined at 3 h after reperfusion (8 h after initiation of ischemia) and compared with permanent ischemia at the same time points to assess the effects of reperfusion. A broad-spectrum MMP inhibitor, AHA (p-aminobenzoyl-Gly-Pro-D-Leu-D-Ala-hydroxamate, 50 mg/kg intravenously) was administered 30 min before reperfusion to assess the roles of MMPs in activating gelatinolytic enzymes and in reperfusion-induced injury. We found that reperfusion accelerated and potentiated MMP-9 and MMP-2 activation and injury to EBA and collagen IV immunopositive microvasculature and to neurons and glial cells in ischemic cortex and striatum relative to permanent ischemia. Administering AHA 30 min before reperfusion decreased MMP-9 activation and neurovascular injury in ischemic cerebral cortex.
authors.affiliation: Department of Neurology, University of Cincinnati, Cincinnati, OH 45267-0532, USA.lua@ucmail.uc.edu
authors.forename: Aigang
authors.initials: A
authors.lastname: Lu
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Clark
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Broderick
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Pyne-Geithman
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Wagner
authors.forename: Ruiqiong
authors.initials: R
authors.lastname: Ran
authors.forename: Pooja
authors.initials: P
authors.lastname: Khatri
authors.forename: Thomas
authors.initials: T
authors.lastname: Tomsick
authors.forename: Frank R
authors.initials: FR
authors.lastname: Sharp
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D001485:Basement Membrane / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020214:Cerebrovascular Trauma / Q000209:etiology*; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion / Q000009:adverse effects*; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C044589:epidermolysis bullosa acquisita antigen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9