NecroX-7 Ameliorate the Severity of Cerulein-Induced Acute Pancreatitis (CIP) Through Inhibition of Necroptosis/Necrosis via Reciprocal Regulation of Mitochondrial ROS and Proinflammatory Cytokines

Abstract

Background/Aims: Recently, NecroX series has been reported to be necroptosis inhibitor that shows scavenger activity against mitochondrial reactive oxygen species (ROS). The aim of our study was to evaluate the protective effect of the strong antioxidant and anti necroptosis agent, NecroX-7 (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1H-indole-7-yl]amine), on CIP in mice. Methods: C57BL/6 mice were randomly divided into 3 groups, control group (n = 15), cerulein treated (CIP) group (n = 15), and NecroX-7 with cerulein treated group (n = 15). NecroX-7 was administered intraperitoneal at a dose of 20 μg/kg per mice 30 min before the first cerulein injection. Each groups were compared with biochemistry, real time PCR, western blotting, and histological parameters. Results: The increase in amylase and lipase (8914.25 ± 741.83, 828.5 ± 252.75) were reduced after NecroX-7 administration (5632 ± 1231.33, 569.75 ± 215.04). The expression of TNF-α, IL-1β, IL-6, and MCP-1 were found to be substantially decreased in the NecroX-7 treated group, and NFκB was also suppressed by NecroX-7. As well as, the expression of necroptosis related genes were significantly enhanced and substantially reduced in NecroX-7 treated group. But, the expression of RIP3 was not changed. NecroX-7 also reduced level of HMGB1. There were also subtle decrease in procaspase 3 and caspase 8 and increase in Bcl-Xl and Bcl-2. Pancreas damage and lung injury substantially decreased in the NecroX-7 treated group. Conclusions: NecroX-7 ameliorates the severity of CIP, suggesting that NecroX-7 may be attenuated CIP by inhibition of inflammation and necroptosis.