ORIGINAL PAPER Alteration in inflammatory/apoptotic pathway and histone modifications by nordihydroguaiaretic acid prevents acute pancreatitis in swiss albino mice Ujwal Mukund Mahajan • Chanchal Gupta • Preshit Ravindra Wagh • Pinakin Arun Karpe • Kulbhushan Tikoo Published online: 27 August 2011 Ó Springer Science+Business Media, LLC 2011 Abstract Reactive oxygen radicals, pro-inflammatory mediators and cytokines have been implicated in caerulein induced acute pancreatitis. Nordihydroguaiaretic acid (NDGA), a plant lignin, has marked anti-inflammatory properties. The present study aimed to investigate the possible protective effect of NDGA against caerulein induced pancreatitis. Acute pancreatitis was induced by intraperitoneal administration of eight doses of caerulein in male swiss albino mice. NDGA was administered after 9 h of acute pancreatitis induction. Pancreatic damage and the protective effect of NDGA were assessed by oxidative stress parameters and histopathology of pancreas. The mRNA expression of heat shock proteins (DNAJ C15 and HSPD1) was examined by real-time RT-PCR analysis. Expression of HSP 27, NF-jB, TNF-a, p-p38, Bcl-2, p-PP2A, procaspase-3, caspase-3 and histone modifications were examined by western blotting. NDGA attenuated the oxidative stress, led to increased plasma a-amylase and decreased IGF-1 in AP mice. It modulated the mRNA and protein levels of heat shock proteins and reduced the expression of NF-jB, TNF-a and p-p38. It increased the number of TUNEL positive apoptotic cells in the pancreas of AP mice. In addition, NDGA prevented the changes in modifications of histone H3 in acute pancreatitis. To best of our knowledge, this is the first report which suggests that NDGA prevents the progression of acute pancreatitis by involving alteration of histone H3 modifications and modulating the expression of genes involved in inflam- matory/apoptotic cascade, which may be responsible for decreased necrosis and increased apoptosis in this model of acute pancreatitis. Keywords Acute pancreatitis Á Oxidative stress Á Histone H3 modifications Á Inflammation Á Apoptosis Á Necrosis Abbreviations AP Acute pancreatitis NDGA Nordihydroguaiaretic acid ROS Reactive oxygen species NF-jB Nuclear factor-jB TNF-a Tumour necrosis factor-a SOD Superoxide dismutase GSH Reduced glutathione TBARS Thiobarbituric acid reactive substrate PP2A Protein phosphatase 2A IGF-1 Insulin-like growth factor 1 Introduction Acute pancreatitis (AP) is characterized by high serum a-amylase level, leukocyte infiltration and vacuolation of acinar cells [1]. Increased vascular permeability leads to increased edema and ischemia of the pancreas [2]. The pathogenesis of AP involves the interplay of local and systemic immune responses. Pancreatic injury seems to trigger two different pathways, viz. pro-inflammatory cytokines [2] and oxidative stress [3]. Primary cellular Electronic supplementary material The online version of this article (doi:10.1007/s10495-011-0643-8) contains supplementary material, which is available to authorized users. U. M. Mahajan Á C. Gupta Á P. R. Wagh Á P. A. Karpe Á K. Tikoo (&) Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab 160 062, India e-mail: tikoo.k@gmail.com 123 Apoptosis (2011) 16:1138–1149 DOI 10.1007/s10495-011-0643-8