title: Effect of PJ-34 PARP-inhibitor on rat liver microcirculation and antioxidant status.
abstract: BACKGROUND
  Ischemia-reperfusion (I-R) injury during liver resection leads to the production of toxic free radicals and oxidants that influence the microcirculation. DNA single-strand breaks can be induced by these reactive species. In response to excessive DNA damage, PARP [poly(ADP-ribose) polymerase] becomes overactivated, which can lead to cellular ATP depletion and cell death. The aim of our study was to evaluate whether PARP is expressed in post-ischemic liver, and to examine the effect of the administration of PJ-34 PARP inhibitor on liver function, histopathology, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) reaction, and the oxidative state of the liver after injury.
  
  
  METHODS
  Male Wistar rats (weighing 250 g) underwent 60 min of normothermic, segmental liver ischemia followed by 30 min of reperfusion. The animals (n = 45) were divided into three groups: sham operated; I-R (control) treated with saline; and PJ-34 pre-treated (10 mg/kg i.v.). Hepatic microcirculation was monitored by a laser Doppler flowmeter. The reperfusion was characterized as the integral of the reperfusion area (RA) and the maximal plateau (PM). Histological alterations, TUNEL-reaction, serum, and liver tissue antioxidant levels, as well as serum ALT and AST levels were measured.
  
  
  RESULTS
  Upon reperfusion, the PJ-34 group had significantly (P < 0.05) higher flow rates than control groups (PM(PJ-34): 58%, PM(control): 37%; RA(PJ-34.): 48%, RA(control): 25%). At the end of the 30 min reperfusion, PJ-34 resulted in significantly (P < 0.05) lower serum ALT and AST levels and chemiluminescent intensity (free radicals) of the liver. The liver's free SH-group concentration and H-donor ability of the plasma was elevated in the PARP-inhibitor treated group. Positive staining for TUNEL, after PJ-34 pre-treatment was significantly increased (P < 0.05); in contrast, the control tissues were less positively stained for TUNEL but necrotic tissue was abundant.
  
  
  CONCLUSIONS
  PARP plays a pathogenetic role in the deterioration of the hepatic microcirculation and promotes hepatocellular necrosis in liver reperfusion injury.
authors.affiliation: Department of Surgery, Semmelweis University, Budapest, Hungary. szijartoattila@freemail.hu
authors.forename: Attila
authors.initials: A
authors.lastname: Szijártó
authors.forename: Enkhjargal
authors.initials: E
authors.lastname: Batmunkh
authors.forename: Oszkár
authors.initials: O
authors.lastname: Hahn
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Mihály
authors.forename: Adám
authors.initials: A
authors.lastname: Kreiss
authors.forename: András
authors.initials: A
authors.lastname: Kiss
authors.forename: Gábor
authors.initials: G
authors.lastname: Lotz
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Schaff
authors.forename: László
authors.initials: L
authors.lastname: Váli
authors.forename: Anna
authors.initials: A
authors.lastname: Blázovics
authors.forename: Domokos
authors.initials: D
authors.lastname: Geró
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.forename: Péter
authors.initials: P
authors.lastname: Kupcsulik
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D043384:Glutamyl Aminopeptidase / Q000097:blood; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D023421:Models, Animal; D009336:Necrosis / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology
chemical_list: D000975:Antioxidants; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D011065:Poly(ADP-ribose) Polymerases; D000410:Alanine Transaminase; D043384:Glutamyl Aminopeptidase