Effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase, in a mouse model of acute pancreatitis induced by cerulein Emanuela Mazzon a,b , Tiziana Genovese a,b , Rosanna Di Paola a , Carmelo Muià a , Concetta Crisafulli a , Giuseppe Malleo a , Emanuela Esposito c , Rosaria Meli c , Edoardo Sessa a , Salvatore Cuzzocrea a,b, ⁎ a Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di Messina, Italy b IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy c Department of Experimental Pharmacology, University of Naples “Federico II”, Via D. Montesano 49, 80131 Napoli, Italy Received 23 March 2006; received in revised form 25 July 2006; accepted 2 August 2006 Available online 15 August 2006 Abstract 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-β (TGF-β) 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-β 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. © 2006 Published by Elsevier B.V. Keywords: PARP [Poly (ADP-ribose) polymerase]; Pancreatitis; Adhesion molecules; Inflammation; Neutrophil infiltration 1. Introduction Acute pancreatitis is a common disease with great variability in severity. Whereas it runs a fairly benign course in most patients, in others it can take a severe form, characterized by pancreatic glandular necrosis and significant mortality (Bradley, 1993). The mortality rate for severe pancreatitis is about 29.8% whereas that for moderate pancreatitis is about 2.3%. The main causes of death included circulatory shock, cardiac insufficiency, renal, respiratory and hepatic failure. Therefore, it has been demonstrated that many patients with pancreatitis developed dysfunction of a mean of two organs indicating that multiple organ failure (MOF) occurred (Ogawa, 1998). Acute pancreatitis is caused by various factors, but once proteolytic enzymes become activated and pancreatic tissues digested, patients show a similar pattern of aggravation and MOF follows. Thus, the prog- nosis of severe acute pancreatitis is highly dependent on pre- vention and on appropriate measures to prevent MOF (Powell et al., 1998; Lowham et al., 1999; Gloor et al., 2001). Much effort has resulted in an improved understanding of the mechanism of disease progression from acinar cell injury to an overwhelming life-threatening illness (Powell et al., 2000). Factors involved in European Journal of Pharmacology 549 (2006) 149 – 156 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica – Policlinico Universitario Via C. Valeria – Gazzi – 98100 Messina Italy. Tel.: +39 090 2213644; fax: +39 090 2213300. E-mail address: salvator@unime.it (S. Cuzzocrea). 0014-2999/$ - see front matter © 2006 Published by Elsevier B.V. doi:10.1016/j.ejphar.2006.08.008