title: A New Chemical Compound, NecroX-7, Acts as a Necrosis Modulator by Inhibiting High-Mobility Group Box 1 Protein Release During Massive Ischemia-Reperfusion Injury.
abstract: BACKGROUND
  Necrotic cell death is common in a wide variety of pathologic conditions, including ischemia-reperfusion (IR) injury. The aim of this study was to develop an IR injury-induced hepatic necrosis model in dogs by means of selective left hepatic inflow occlusion and to test the efficacy of a new chemical compound, NecroX-7, against the IR injury-induced hepatic damage.
  
  
  METHODS
  A group of male Beagle dogs received intravenous infusions of either vehicle or different doses of NecroX-7 (1.5, 4.5, or 13 mg/kg) for a 20-minute period before a 90-minute left hepatic inflow occlusion followed by reperfusion.
  
  
  RESULTS
  The gross morphology in the NecroX-7-treated groups after occlusion appeared to be less congested and less swollen than that in vehicle-treated control group. Circulating alanine transaminase and aspartate transaminase levels in the control group were elevated during the course of IR, and were effectively blocked in the 4.5 and 13 mg/kg NecroX-7-treated groups. The serum levels of high-mobility group box 1 protein showed a peak at 8 hours after occlusion in control group, and this elevation was significantly blunted by 4.5 mg/kg NecroX-7 treatment. Histologic analysis showed a marked ischemia or IR injury-induced hepatocytic degenerations, sinusoidal and portal vein congestions, and inflammatory cell infiltrations in the control group, whereas the treatment groups showed significantly diminished histopathology in a dose-dependent manner.
  
  
  CONCLUSIONS
  These results demonstrated that NecroX-7 attenuated the hepatocyte lethality caused by hepatic IR injury in a large animal setting. We conclude that NecroX-7 may provide a wide variety of therapeutic options for IR injury in human patients.
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea. Electronic address: kmpark0909@gmail.com.
authors.forename: K M
authors.initials: KM
authors.lastname: Park
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: LG Life Sciences, Daejeon, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000097:blood; D008099:Liver / Q000098:blood supply / Q000293:injuries / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D009336:Necrosis; D009930:Organic Chemicals / Q000494:pharmacology*; D011169:Portal Vein / Q000503:physiopathology; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology
chemical_list: D024243:HMGB1 Protein; D009930:Organic Chemicals; C556282:necrox-7; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase