title: Free-radical scavenger edaravone inhibits both formation and development of abdominal aortic aneurysm in rats.
abstract: OBJECTIVE
  An ideal pharmaceutical treatment for abdominal aortic aneurysm (AAA) is to prevent aneurysm formation and development (further dilatation of pre-existing aneurysm). Recent studies have reported that oxidative stress with reactive oxygen species (ROS) is crucial in aneurysm formation. We hypothesized that edaravone, a free-radical scavenger, would attenuate vascular oxidative stress and inhibit AAA formation and development.
  
  
  METHODS
  An AAA model induced with intraluminal elastase and extraluminal calcium chloride was created in 42 rats. Thirty-six rats were divided three groups: a low-dose (group LD; 1 mg/kg/d), high-dose (group HD; 5 mg/kg/d), and control (group C, saline). Edaravone or saline was intraperitoneally injected twice daily, starting 30 minutes before aneurysm preparation. The remaining six rats (group DA) received a delayed edaravone injection (5 mg/kg/d) intraperitoneally, starting 7 days after aneurysm preparation to 28 days. AAA dilatation ratio was calculated. Pathologic examination was performed. ROS expression was semi-quantified by dihydroethidium staining and the oxidative product of DNA induced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), by immunohistochemical staining.
  
  
  RESULTS
  At day 7, ROS expression and 8-OHdG-positive cells in aneurysm walls were decreased by edaravone treatment (ROS expression: 3.0 ± 0.5 in group LD, 1.7 ± 0.3 in group HD, and 4.8 ± 0.7 in group C; 8-OHdG-positive cells: 106.2 ± 7.8 cells in group LD, 64.5 ± 7.7 cells in group HD, and 136.6 ± 7.4 cells in group C; P < .0001), compared with group C. Edaravone treatment significantly reduced messenger RNA expressions of cytokines and matrix metalloproteinases (MMPs) in aneurysm walls (MMP-2: 1.1 ± 0.5 in group LD, 0.6 ± 0.1 in group HD, and 2.3 ± 0.4 in group C; P < .001; MMP-9: 1.2 ± 0.1 in group LD, 0.2 ± 0.6 in group HD, and 2.4 ± 0.2 in group C; P < .001). At day 28, aortic walls in groups LD and HD were less dilated, with increased wall thickness and elastin content than those in group C (dilatation ratio: 204.7% ± 16.0% in group C, 156.5% ± 6.6% in group LD, 136.7% ± 2.0% in group HD; P < .0001). Delayed edaravone administration significantly prevented further aneurysm dilatation, with increased elastin content (155.2% ± 2.9% at day 7, 153.1% ± 11.6% at day 28; not significant).
  
  
  CONCLUSIONS
  Edaravone inhibition of ROS can prevent aneurysm formation and expansion in the rat AAA model. Free-radical scavenger edaravone might be an effective pharmaceutical agent for AAA in clinical practice.
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Morimoto
authors.forename: Tomomi
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Bao
authors.initials: B
authors.lastname: Wulan
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Naoto
authors.initials: N
authors.lastname: Morimoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okita
authors.forename: Kenji
authors.initials: K
authors.lastname: Okada
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002122:Calcium Chloride; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D000077553:Edaravone; D004549:Elastin / Q000378:metabolism; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D010196:Pancreatic Elastase; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D015415:Biomarkers; D016166:Free Radical Scavengers; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004549:Elastin; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D003849:Deoxyguanosine; D002122:Calcium Chloride; D000077553:Edaravone; D000983:Antipyrine