title: Peroxynitrite Decomposition Catalyst Reduces Delayed Thrombolysis-induced Hemorrhagic Transformation in Ischemia-reperfused Rat Brains.
abstract: OBJECTIVE
  Hemorrhagic transformation (HT) is a major complication of delayed tissue plasminogen activator (t-PA) treatment in ischemic stroke. We aimed to explore whether peroxynitrite decomposition catalyst (PDC) could prevent such complication.
  
  
  METHODS
  Male Sprague-Dawley (SD) rats were subjected to middle cerebral artery occlusion (MCAO) with t-PA (10 mg/kg) or t-PA plus FeTMPyP (3 mg/kg, a representative PDC) at MCAO for 2 or 5 h and reperfusion for 22 or 19 h, respectively. HT was assessed with hemoglobin assay. Neurological deficit was evaluated with Modified Neurological Severity Score (mNSS). Peroxynitrite formation was examined by detecting 3-nitrotyrosine (3-NT) formation. The expression and activity of MMP-9/MMP-2 were assessed by Western blotting and gelatin zymography.
  
  
  RESULTS
  t-PA treatment at 2 h of MCAO did not induce HT but attenuated neurological deficit, whereas treatment at 5 h significantly induced HT and worsened the neurological outcome. Such complications were prevented by FeTMPyP cotreatment. Early t-PA treatment inhibited 3-NT and MMP-9/MMP-2 expression, whereas delayed treatment induced 3-NT and MMP-9/MMP-2 expression and activity. FeTMPyP cotreatment downregulated 3-NT and inhibited MMP-9/MMP-2 in both time points.
  
  
  CONCLUSIONS
  Peroxynitrite decomposition catalyst could prevent hemorrhagic transformation and improve neurological outcome ischemic rat brains with delayed t-PA treatment via inhibiting peroxynitrite-mediated MMP activation.
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.
authors.forename: Han-Sen
authors.initials: HS
authors.lastname: Chen
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.
authors.forename: Xing-Miao
authors.initials: XM
authors.lastname: Chen
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.
authors.forename: Jing-Han
authors.initials: JH
authors.lastname: Feng
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Ke-Jian
authors.initials: KJ
authors.lastname: Liu
authors.affiliation: Research Center for Biochemistry and Molecular Biology and Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, China.
authors.forename: Su-Hua
authors.initials: SH
authors.lastname: Qi
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, Hong Kong, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.
authors.forename: Jian-Gang
authors.initials: JG
authors.lastname: Shen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D006470:Hemorrhage / Q000139:chemically induced* / Q000188:drug therapy*; D006490:Hemostatics / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009422:Nervous System Diseases / Q000209:etiology; D030421:Peroxynitrous Acid / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D012720:Severity of Illness Index; D010959:Tissue Plasminogen Activator / Q000009:adverse effects*
chemical_list: D005343:Fibrinolytic Agents; D006490:Hemostatics; D030421:Peroxynitrous Acid; D010959:Tissue Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Hemorrhage; Matrix metalloproteinases; Peroxynitrite; Tissue plasminogen activator