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

• Published in: Biochimica et biophysica acta Vol. 1830; no. 6; pp. 3776 - 3786
• Main Authors: Yadav, Sudhir K., Adhikary, Biplab, Bandyopadhyay, Sandip K., Chattopadhyay, Subrata
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2013
• Subjects: adhesion; adverse effects; Angiogenesis; Animals; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; anti-ulcer activity; Anti-Ulcer Agents - pharmacology; antioxidant activity; antioxidants; Catechols - chemistry; Catechols - pharmacology; Disease Models, Animal; enzyme-linked immunosorbent assay; Gastric ulcer; growth factors; histology; Indomethacin; Indomethacin - adverse effects; Indomethacin - pharmacology; Inflammatory modulator; Male; MAP Kinase Signaling System - drug effects; messenger RNA; Mice; Misoprostol - pharmacology; mitogen-activated protein kinase; nonsteroidal anti-inflammatory agents; NSAID; Omeprazole - pharmacology; oxidative stress; Oxidative Stress - drug effects; pharmacokinetics; Piper betle - chemistry; prostaglandins; receptors; Stomach Ulcer - chemically induced; Stomach Ulcer - drug therapy; Stomach Ulcer - metabolism; Stomach Ulcer - pathology; transcription factor NF-kappa B; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - metabolism; Angiogenesis; Inflammatory modulator; Indomethacin; Gastric ulcer; NSAID
• DOI: 10.1016/j.bbagen.2013.03.013
• ISSN: 0304-4165; 0006-3002

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. Mice were pre-treated with APC for 1h followed by IND (18mgkg−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-κB and MAPKs) were assessed by immunoblots/mRNA, and ELISA at the time points of their maximal changes due to IND administration. IND induced oxidative stress, triggering mucosal TNF-α that activated NF-κB 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 (5mgkg−1), trolox (50mgkg−1) and NAC (250mgkg−1) showed similar protection that was better than that by misoprostol (5μgkg−1) and omeprazole (3mgkg−1). The anti-ulcer effect of APC can be primarily attributed to its antioxidant action that helped in controlling various inflammatory parameters and augmenting angiogenesis. 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. •Rational formulation of allylpyrocatechol (APC) as a potential anti-ulcer agent.•Identification of TNF-α as the potential target of APC.•Establishment of molecular mechanism of action of APC.•Suggestion of different mechanisms of action of misoprostol and omeprazole.