title: Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion.
abstract: OBJECTIVE
  Intravenous recombinant tissue plasminogen activator (rtPA) can be beneficial in ischemic stroke despite an increased risk of hemorrhage and potential neurotoxic effects. We hypothesized that rtPA-mediated adverse effects depend on the timing of reperfusion and injury to the blood-brain barrier (BBB).
  
  
  METHODS
  Male Wistar rats had middle cerebral artery occlusion (MCAO) by intraluminal thread placement. Intervals of ischemia/reperfusion, respectively, in hours were 0/18, 1.5/16.5, 3/15, 6/12, 18/0, and 6/1. Animals received either rtPA or saline for 1 hour at the time of reperfusion or, for the 18/0 trial, starting 1 hour after MCAO. Outcome parameters were mortality, matrix metalloproteinase-2 and -9 (MMP-2 and -9) concentrations, tissue hemoglobin, and brain water content. We analyzed the permeability of the BBB by using the brain 14C[sucrose] uptake method. Effects of the MMP inhibitor BB-94 on the BBB without rtPA treatment and on mortality with rtPA were tested in animals with 6/1 and 6/12, respectively.
  
  
  RESULTS
  In delayed reperfusion (6/12), rtPA increased mortality from 17% to 83% (P<0.01) without significantly affecting other outcome parameters. In 6/1, sucrose uptake in the ischemic hemisphere was markedly increased (8.80+/-1.14% vs 2.15+/-0.26%; P<0.01). This uptake was reduced by treatment with BB-94 (3.95+/-1.48%, P<0.01). Furthermore, BB-94 reduced rtPA-mediated mortality in 6/12 to 33% (P<0.05).
  
  
  CONCLUSIONS
  rtPA-mediated mortality in delayed reperfusion is associated with early opening of the BBB. Closure of the BBB with BB-94 given before rtPA treatment reduced mortality, suggesting that treatment with MMP inhibitors might reduce the risk associated with thrombolysis.
authors.affiliation: Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA. thomaspfefferkorn@hotmail.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfefferkorn
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D015424:Reperfusion / Q000379:methods; D013395:Sucrose / Q000493:pharmacokinetics; D015996:Survival Rate; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome; D014867:Water / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D013876:Thiophenes; D014867:Water; D010649:Phenylalanine; D013395:Sucrose; C080985:batimastat; D010959:Tissue Plasminogen Activator; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9