Inhibition of TNF-α, and NF-κB and JNK pathways accounts for the prophylactic action of the natural phenolic, allylpyrocatechol against indomethacin gastropathy

Background: The gastro-intestinal disorders, induced by the NSAIDs including indomethacin (IND) remain unresolved medical problems. Herein, we disclose allylpyrocatechol (APC) as a potential agent against IND-gastropathy and rationalize its action mechanistically. Methods: Mice were pre-treated with APC for 1 h followed by IND (18 mg kg(-1)) administration, and the ulcer-prevention capacity of APC was evaluated on the 3rd day by histology. Its effect on the inflammatory (MPO, cytokines, adhesion molecules), ulcer-healing (COX, prostaglandins, growth factors and their receptors) and signaling parameters (NF-kappa B and MAPKs) were assessed by immunoblots/mRNA, and ELISA at the time points of their maximal changes due to IND administration. Results: IND induced oxidative stress, triggering mucosal TNF-alpha that activated NF-kappa B and JNK MAPK signaling in mice. These increased the pro-inflammatory biochemical parameters, but reduced the healing factors. APC reversed all the adverse effects to prevent gastric ulceration. APC (5 mg kg(-1)), trolox (50 mg kg(-1)) and NAC (250 mg kg(-1)) showed similar protection that was better than that by misoprostol (5 mu g kg(-1)) and omeprazole (3 mg kg(-1)). Conclusions: The anti-ulcer effect of APC can be primarily attributed to its antioxidant action that helped in controlling various inflammatory parameters and augmenting angiogenesis. General significance: Given that APC is an effective, non-toxic antioxidant with appreciable natural abundance, further evaluation of its pharmacokinetics and dynamics would help in promoting it as a new anti-inflammatory agent (C) 2013 Elsevier B.V. All rights reserved.