Omega‐3 polyunsaturated fatty acids rescued from indomethacin‐induced gut damages via GI mucosal membrane stabilization of lipid raft organization

Abstract

Non‐steroidal anti‐inflammatory drugs (NSAIDs) damage GI epithelial cell membranes by inducing several signals through lipid raft organization after membrane incorporation, whereas ω‐3 polyunsaturated fatty acids (PUFAs) can relieve inflammation, reduce oxidative stress, and provide cytoprotection, consequent to lipid raft disorganization. Therefore, we hypothesized that ω‐3 PUFAs can protect the GI from NSAID‐induced damages by initiating the gatekeeper action of cell membranes, subsequent to anti‐inflammatory and anti‐oxidative actions. Administration of indomethacin (IND) leads to the formation of lipid rafts and activation of caveolin‐1; however, no such observations were made upon co‐administration of eicosapentaenoic acid (EPA) and IND. In addition, the EPA‐induced lipid raft disorganization, caveolin‐1 inactivation, and cellular cytotoxicity were inhibited when target cells were knocked‐out using GPR120. EPA significantly attenuated IND‐induced oxidative damage and apoptosis. IND administration induced significant ulceration, bleeding, and oedema in the stomach or small intestine of wild‐type (WT) mice; whereas GI mucosal damages significantly decreased in fat‐1 transgenic (TG) mice (p < 0.001), accompanied with significantly decreased cyclooxygenase‐2 expression and apoptosis, decreased interleukin‐1b and FAS concentrations, and increased HO‐1 concentration. Among common sources of plant oils containing the ω‐3 PUFAs ALA fatty acid include walnut which also showed that walnut‐phenolic‐extract had similar effects in IND‐induced gastrointestinal damage via anti‐oxidant and anti‐inflammatory actions. Our study indicates that the gatekeeper function of ω‐3 PUFAs improves GI safety when administered with NSAID.