title: Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator.
abstract: OBJECTIVE
  Intracerebral hemorrhage, induced by recombinant tissue plasminogen activator (rtPA) in ischemic stroke, is attributable to the increased activity of matrix metalloproteinase-9 (MMP-9). Patients with acute infarct benefit from the neuroprotective drug edaravone, a free radical scavenger. We examined the mechanisms by which edaravone may help to suppress rtPA-induced brain hemorrhage.
  
  
  METHODS
  Male Wistar rats weighing 250 to 280 g were subjected to 3-hour transient middle cerebral artery occlusion (MCAO) and divided randomly into 3 groups. Immediately after reperfusion, 1 group was intravenously injected with 10 mg/kg rtPA, another with rtPA plus 3 mg/kg edaravone, and the 3rd group received no treatment. We assessed the hemorrhage volume and the activity of MMP-9 in the brain 24 hours postischemia. We also studied the activity of MMP-9, its mRNA expression, and nuclear factor-kappa B (NF-kappaB) activity in rtPA-stimulated human microvascular endothelial cells (HBECs).
  
  
  RESULTS
  The degree of hemorrhage and the level of endothelial cell-derived MMP-9 were elevated in rats treated with rtPA alone and attenuated in rats treated with rtPA plus edaravone. In rtPA-stimulated HBECs, edaravone suppressed the activity and mRNA expression of MMP-9 in a dose-dependent manner. Edaravone also inhibited NF-kappaB activation.
  
  
  CONCLUSIONS
  We demonstrate that edaravone inhibits rtPA-induced cerebral hemorrhage in the ischemic brain of rats via the inhibition of MMP-9 expression in vivo, which is substantiated by inhibition of MMP-9 expression and NF-kappaB activation in HBECs. Edaravone may render thrombolytic therapy safer for the administration of rtPA in patients with ischemic stroke.
authors.affiliation: Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. kenji-yagi@mail.goo.ne.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Yagi
authors.forename: Keiko T
authors.initials: KT
authors.lastname: Kitazato
authors.forename: Masaaki
authors.initials: M
authors.lastname: Uno
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Tada
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kinouchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimada
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020768:Middle Cerebral Artery / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D016166:Free Radical Scavengers; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator; D000077553:Edaravone; D000983:Antipyrine