title: Effects of edaravone, a free radical scavenger, on circulating levels of MMP-9 and hemorrhagic transformation in patients with intravenous thrombolysis using low-dose alteplase.
abstract: BACKGROUND
  Matrix metalloproteinase-9 (MMP-9) plays a key role for the blood-brain barrier disruption and intravenous tissue plasminogen activator (iv-tPA) therapy increases MMP-9. Edaravone, a free radical scavenger, reduces MMP-9-related blood-brain barrier disruption. We aimed to investigate whether edaravone would suppress the MMP-9 increase after iv-tPA using low-dose alteplase (0.6 mg/kg).
  
  
  METHODS
  Patients hospitalized within 12 hours after ischemic stroke onset between April 2008 and June 2013 were retrospectively examined. Patients with slight deficits (National Institutes of Health Stroke Scale score ≤ 4), stroke caused by arterial dissection, severe inflammatory disease or autoimmune disease, or regular use of steroid were excluded. Serum concentrations of high-sensitivity C-reactive protein, interleukin-6, MMP-2, and MMP-9 were serially measured at admission, after 24 hours, day 7, and day 14. General linear models were used to compare changes in concentrations of these biomarkers over time.
  
  
  RESULTS
  A total of 63 patients (38 men, aged 74.48 ± 13.8 years) were studied. Patients were divided into 2 groups according to the iv-tPA therapy, that is, tPA group (n = 32) and non-tPA group (n = 31). Edaravone was administered routinely except for contraindication (90.6% in the tPA group and 87.1% in the non-tPA group). Significant interaction of group × time factor was observed only in MMP-9 concentrations by repeated-measure analysis of variance (P = .004). Association between iv-tPA therapy and subsequent hemorrhagic transformation was highly significant, but MMP-9 concentrations at any point did not predictive of subsequent hemorrhagic transformation (area under the receiver operating characteristic curve, .681).
  
  
  CONCLUSIONS
  Low-dose iv-tPA increases MMP-9 concentration even in combination with Edaravone. The effect of higher dosage of Edaravone on circulating MMP-9 concentration and subsequent hemorrhagic transformation should be investigated.
authors.affiliation: Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan. Electronic address: shinnai@marianna-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tsuruoka
authors.affiliation: Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Atsumi
authors.affiliation: Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Heisuke
authors.initials: H
authors.lastname: Mizukami
authors.affiliation: Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imai
authors.affiliation: Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Hagiwara
authors.affiliation: Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D061605:Administration, Intravenous; D000368:Aged; D000369:Aged, 80 and over; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D002543:Cerebral Hemorrhage / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology; D000077553:Edaravone; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006801:Humans; D007564:Japan; D016014:Linear Models; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D011237:Predictive Value of Tests; D012372:ROC Curve; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D015912:Thrombolytic Therapy / Q000009:adverse effects*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D005343:Fibrinolytic Agents; D016166:Free Radical Scavengers; D010959:Tissue Plasminogen Activator; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D000077553:Edaravone; D000983:Antipyrine
keywords: Tissue plasminogen activator; hemorrhagic transformation; matrix metalloproteinase-9