title: Effects of U-74389G (21-Lazaroid) and Ascorbic Acid on Liver Recovery After Acute Ischemia and Reperfusion in Rats.
abstract: OBJECTIVE
  The free radical-scavenging effects of the lazaroid U-74389G have been shown in several experimental models to protect the liver from ischemia/reperfusion (I/R), however, the mechanism of cytoprotection is not fully understood. Similar findings were observed when ascorbic acid was administered. This study investigates the effects of infusion of lazaroid U-74389G and ascorbic acid on cytokines and liver structure in a liver I/R rat model.
  
  
  METHODS
  Sixty male Wistars rats, weighting 220-290 g, were used in the study. Six experimental groups were formed: Group 1 (control group): ischemia for 30 min and reperfusion for 60 min; group 2 (control group): ischemia for 30 min and reperfusion for 120 min; group 3: ischemia for 30 min, intraportal injection of ascorbic acid, and reperfusion for 60 min; group 4: ischemia for 30 min, ascorbic acid administration, and reperfusion for 120 min; group 5: ischemia for 30 min, U-74389G administration, and reperfusion for 60 min; and group 6: ischemia for 30 min, U-74389G administration, and reperfusion for 120 min. Tissue and blood sampling took place upon completion of each model's reperfusion. U-74389G was administered at 10 mg/kg animal body weight and ascorbic acid at 100 mg/kg. Anesthesia was induced with ketamine and xylazine. Surgery was performed through a midline laparotomy. The portal vein and the common hepatic artery were isolated and prepared for occlusion. Blood samples and wedge liver biopsies were taken to measure levels of liver enzymes, cytokines and for microscopic analysis upon completion of reperfusion once for each model.
  
  
  RESULTS
  Histopathological evaluation revealed a statistically significant reduction in the degree of necrosis of liver tissue in the treated groups compared to the control groups 1 and 2 [groups 3, 5 (p=0.010) and 4, 6 (p<0.0005)]. On the other hand, tissue malondialdehyde levels (MDA) were statistically significantly increased only between control group 2 and groups 4, 6 (p<0.0005). There was no statistically significant difference in tumor necrosis factor-α between groups. As for liver enzymes, only alkaline phosphatase (ALP) and gamma-glutamyl transferase (gGT) were statistically significantly reduced in treated groups 3 and 5 (ALP: p=0.027, and gGT: p=0.002) and 4 and 6 (ALP: p=0.004, and gGT: p=0.015) compared to control groups 1 and 2.
  
  
  CONCLUSIONS
  Based on histological data and the reduction of some of the liver enzymes, in spite of a rise of malondialdehyde, in this rat model, administration of U-74389G in liver ischemia/reperfusion (I/R) injury has potential in attenuating liver damage.
authors.affiliation: The Hillingdon Hospital NHS Trust, Imperial Lead Provider, London Deanery, London, U.K.
authors.forename: Vasileios
authors.initials: V
authors.lastname: Bonatsos
authors.affiliation: Department of Surgery, Nursing School, University of Athens, Athens, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kappas
authors.affiliation: Department of Surgery, Nursing School, University of Athens, Athens, Greece.
authors.forename: Konstantine
authors.initials: K
authors.lastname: Birbas
authors.affiliation: Department of Forensic Medicine, University of Athens, School of Medicine, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Vlachodimitropoulos
authors.affiliation: First Department of Propaedeutic Surgery, University of Athens, School of Medicine, Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Toutouzas
authors.affiliation: Experimental Research Center ELPEN, Athens, Greece.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Karampela
authors.affiliation: Experimental Research Center ELPEN, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Syrmos
authors.affiliation: Department of Surgery, Nursing School, University of Athens, Athens, Greece.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Bonatsos
authors.affiliation: Experimental Research Center ELPEN, Athens, Greece apapalois@elpen.gr.
authors.forename: Apostolos E
authors.initials: AE
authors.lastname: Papalois
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood / Q000378:metabolism; D015415:Biomarkers; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009336:Necrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011281:Pregnatrienes / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D016207:Cytokines; D011281:Pregnatrienes; D017382:Reactive Oxygen Species; C074965:U 74389F; D008315:Malondialdehyde; D001219:Aspartate Aminotransferases; D001205:Ascorbic Acid
keywords: Reactive oxygen species (ROS); antioxidants; inflammation; lazaroids; liver ischemia-reperfusion; oxidant stress; rats