Effect of PJ-34 PARP-Inhibitor on Rat Liver Microcirculation and Antioxidant Status

Attila Szijártó, Enkhjargal Batmunkh, Oszkár Hahn, Zoltán Mihály, Adám Kreiss, András Kiss, Gábor Lotz, Zsuzsa Schaff, László Váli, Anna Blázovics, Domokos Geró, Csaba Szabo, Péter Kupcsulik

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 (PMPJ-34: 58%, PMcontrol: 37%; RAPJ-34.: 48%, RAcontrol: 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. Conclusion: PARP plays a pathogenetic role in the deterioration of the hepatic microcirculation and promotes hepatocellular necrosis in liver reperfusion injury.

Original languageEnglish (US)
Pages (from-to)72-80
Number of pages9
JournalJournal of Surgical Research
Volume142
Issue number1
DOIs
StatePublished - Sep 2007
Externally publishedYes

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Microcirculation
Antioxidants
Liver
Reperfusion
Poly(ADP-ribose) Polymerases
Transferases
Reperfusion Injury
Free Radicals
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Poly(ADP-ribose) Polymerase Inhibitors
Ischemia
Serum
Single-Stranded DNA Breaks
Flowmeters
DNA Nucleotidylexotransferase
Poisons
Oxidants
DNA Damage
Wistar Rats
Lasers

Keywords

  • apoptosis
  • ischemia
  • laser Doppler flowmeter
  • liver
  • PARP
  • PJ-34
  • reperfusion

ASJC Scopus subject areas

  • Surgery

Cite this

Szijártó, A., Batmunkh, E., Hahn, O., Mihály, Z., Kreiss, A., Kiss, A., ... Kupcsulik, P. (2007). Effect of PJ-34 PARP-Inhibitor on Rat Liver Microcirculation and Antioxidant Status. Journal of Surgical Research, 142(1), 72-80. https://doi.org/10.1016/j.jss.2006.08.003

Effect of PJ-34 PARP-Inhibitor on Rat Liver Microcirculation and Antioxidant Status. / Szijártó, Attila; Batmunkh, Enkhjargal; Hahn, Oszkár; Mihály, Zoltán; Kreiss, Adám; Kiss, András; Lotz, Gábor; Schaff, Zsuzsa; Váli, László; Blázovics, Anna; Geró, Domokos; Szabo, Csaba; Kupcsulik, Péter.

In: Journal of Surgical Research, Vol. 142, No. 1, 09.2007, p. 72-80.

Research output: Contribution to journalArticle

Szijártó, A, Batmunkh, E, Hahn, O, Mihály, Z, Kreiss, A, Kiss, A, Lotz, G, Schaff, Z, Váli, L, Blázovics, A, Geró, D, Szabo, C & Kupcsulik, P 2007, 'Effect of PJ-34 PARP-Inhibitor on Rat Liver Microcirculation and Antioxidant Status', Journal of Surgical Research, vol. 142, no. 1, pp. 72-80. https://doi.org/10.1016/j.jss.2006.08.003
Szijártó, Attila ; Batmunkh, Enkhjargal ; Hahn, Oszkár ; Mihály, Zoltán ; Kreiss, Adám ; Kiss, András ; Lotz, Gábor ; Schaff, Zsuzsa ; Váli, László ; Blázovics, Anna ; Geró, Domokos ; Szabo, Csaba ; Kupcsulik, Péter. / Effect of PJ-34 PARP-Inhibitor on Rat Liver Microcirculation and Antioxidant Status. In: Journal of Surgical Research. 2007 ; Vol. 142, No. 1. pp. 72-80.
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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 (PMPJ-34: 58{\%}, PMcontrol: 37{\%}; RAPJ-34.: 48{\%}, RAcontrol: 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. Conclusion: PARP plays a pathogenetic role in the deterioration of the hepatic microcirculation and promotes hepatocellular necrosis in liver reperfusion injury.",
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T1 - Effect of PJ-34 PARP-Inhibitor on Rat Liver Microcirculation and Antioxidant Status

AU - Szijártó, Attila

AU - Batmunkh, Enkhjargal

AU - Hahn, Oszkár

AU - Mihály, Zoltán

AU - Kreiss, Adám

AU - Kiss, András

AU - Lotz, Gábor

AU - Schaff, Zsuzsa

AU - Váli, László

AU - Blázovics, Anna

AU - Geró, Domokos

AU - Szabo, Csaba

AU - Kupcsulik, Péter

PY - 2007/9

Y1 - 2007/9

N2 - 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 (PMPJ-34: 58%, PMcontrol: 37%; RAPJ-34.: 48%, RAcontrol: 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. Conclusion: PARP plays a pathogenetic role in the deterioration of the hepatic microcirculation and promotes hepatocellular necrosis in liver reperfusion injury.

AB - 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 (PMPJ-34: 58%, PMcontrol: 37%; RAPJ-34.: 48%, RAcontrol: 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. Conclusion: PARP plays a pathogenetic role in the deterioration of the hepatic microcirculation and promotes hepatocellular necrosis in liver reperfusion injury.

KW - apoptosis

KW - ischemia

KW - laser Doppler flowmeter

KW - liver

KW - PARP

KW - PJ-34

KW - reperfusion

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