title: Matrix Metalloproteinase-12 Induces Blood-Brain Barrier Damage After Focal Cerebral Ischemia.
abstract: OBJECTIVE
  Matrix metalloproteinases (MMPs) have a central role in compromising the integrity of the blood-brain barrier (BBB). The role of MMP-12 in brain damage after ischemic stroke remains unknown. The main objective of the current study is to investigate the effect of MMP-12 suppression at an early time point before reperfusion on the BBB damage in rats.
  
  
  METHODS
  Sprague-Dawley rats were subjected to middle cerebral artery occlusion and reperfusion. MMP-12 shRNA-expressing plasmids formulated as nanoparticles were administered at a dose of 1 mg/kg body weight. The involvement of MMP-12 on BBB damage was assessed by performing various techniques, including Evans blue dye extravasation, 2,3,5-triphenyltetrazolium chloride staining, immunoblot, gelatin zymography, and immunofluorescence analysis.
  
  
  RESULTS
  MMP-12 is upregulated ≈31-, 47-, and 66-fold in rats subjected 1-, 2-, or 4-hour ischemia, respectively, followed by 1-day reperfusion. MMP-12 suppression protected the BBB integrity by inhibiting the degradation of tight-junction proteins. Either intravenous or intra-arterial delivery of MMP-12 shRNA-expressing plasmid significantly reduced the percent Evans blue dye extravasation and infarct size. Furthermore, MMP-12 suppression reduced the endogenous levels of other proteases, such as tissue-type plasminogen activator and MMP-9, which are also known to be the key players involved in BBB damage.
  
  
  CONCLUSIONS
  These results demonstrate the adverse role of MMP-12 in acute brain damage that occurs after ischemic stroke and, thereby, suggesting that MMP-12 suppression could be a promising therapeutic target for cerebral ischemia.
authors.affiliation: From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).
authors.forename: Bharath
authors.initials: B
authors.lastname: Chelluboina
authors.affiliation: From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Klopfenstein
authors.affiliation: From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).
authors.forename: David M
authors.initials: DM
authors.lastname: Pinson
authors.affiliation: From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).
authors.forename: David Z
authors.initials: DZ
authors.lastname: Wang
authors.affiliation: From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).
authors.forename: Raghu
authors.initials: R
authors.lastname: Vemuganti
authors.affiliation: From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.). krishnav@uic.edu.
authors.forename: Krishna Kumar
authors.initials: KK
authors.lastname: Veeravalli
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000473:pathology*; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology*; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D053508:Matrix Metalloproteinase 12; C000602030:matrix metallopeptidase 12, rat
keywords: blood–brain barrier; degradation; ischemia; matrix metalloproteinase; reperfusion; tight junction; tissue-type plasminogen activator