Chondroitin-4-Sulphate Reduced Oxidative Injury in Caerulein-Induced Pancreatitis in Mice: The Involvement of NF-κB Translocation and Apoptosis Activation

Abstract

Activation of nuclear factor κB (NF-κB) and caspases may greatly amplify inflammation and cell damage in addition to that directly exerted by free radicals. Since reactive oxygen species (ROS) are involved in acute pancreatitis, we studied whether the administration of chondroitin-4-sulphate (C4S), in addition to its antioxidant activity, was able to modulate NF-κB and caspase activation in an experimental model of caerulein-induced acute pancreatitis in mice. Hyperstimulating doses of caerulein (50 μg/ kg), five injections per mouse given at hourly intervals produced the following: high serum lipase and amylase activity; lipid peroxidation, evaluated by 8-isoprostane concentrations; loss of antioxidant defenses such as glutathione reductase (GR) activity; NF-κB activation and loss of cytoplasmic IκBα protein; increases in tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), caspase-3, and caspase-7 gene expression and their related protein; accumulation and activation of neutrophils in the damaged tissue, evaluated by elastase (ELA) determination; and pancreatic injury, evaluated by histologic analysis. Pretreatment of mice with different doses of C4S, given 1 hr before caerulein injections and 1 and 2 hrs after the last caerulein injection, reduced lipid peroxidation, inhibited NF-κB translocation and cytoplasmic IκBα protein loss, decreased TNF-α, IL-6, and caspase gene expression and their related protein levels, limited endogenous antioxidant depletion, and reduced tissue neutrophils accumulation and tissue damage. Since molecules with antioxidant activity can block NF-κB and apoptosis activation, we suggest that C4S administration is able to block NF-κB and caspase activation by reducing the oxidative burst.