Effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase, in a mouse model of acute pancreatitis induced by cerulein.
Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the colon injury associated with experimental colitis. The aim of the present study was to examine the effects of 3-aminobenzamide (3-AB), an inhibitor of PARP activity, in the development of acute pancreatitis caused by cerulein in mice. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced expression of the intercellular adhesion molecule-1 (ICAM-1) and P-selectin. Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) in the pancreas of cerulein-treated mice in comparison to sham-treated mice. Acute pancreatitis in vehicle-treated mice was also associated with a significant mortality (40% survival at 5 days after cerulein administration). In contrast, (1) the degree of pancreatic inflammation and tissue injury (histological score), (2) upregulation/formation of ICAM-1 and P-selectin, (4) neutrophils infiltration and (5) the expression of TGF-beta and VEGF was markedly reduced in pancreatic tissue obtained from cerulein-treated mice which have been treated with 3-AB. These findings provide the evidence that PARP inhibition reduce the degree of pancreas injury caused by acute pancreatitis induced by cerulein administration.
Mazzon
Emanuela
E
Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di Messina, Italy.
Genovese
Tiziana
T
Di Paola
Rosanna
R
Muià
Carmelo
C
Crisafulli
Concetta
C
Malleo
Giuseppe
G
Esposito
Emanuela
E
Meli
Rosaria
R
Sessa
Edoardo
E
Cuzzocrea
Salvatore
S
D000208:Acute Disease; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002108:Ceruletide / Q000633:toxicity*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D019007:P-Selectin / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D001549:Benzamides; D004791:Enzyme Inhibitors; D019007:P-Selectin; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D002108:Ceruletide; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases