Objective: Mesalazine, 5-aminosalicylic acid (5-ASA), is an anti-inflammatory drug that is most widely used for the treatment of inflammatory bowel disease (IBD). Despite extensive clinical use, the exact pharmacological mechanism underlying the anti-colitic effects of 5-ASA has not yet been elucidated. A potential molecular mechanism underlying 5-ASA-mediated anti-colitic activity was investigated.
Methods: An anti-inflammatory pharmacology of 5-ASA was scrutinized in human colon carcinoma cells and murine macrophages and in a TNBS-induced rat colitis model.
Results: 5-ASA induced phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrate acetyl-CoA carboxylase in cells. 5-ASA activation of AMPK occurred regardless of the presence of the pro-inflammatory mediators tumor necrosis factor alpha (TNF-α) and lipopolysaccharide. 5-ASA inhibits TNF-α-dependent nuclear factor-kappa B (NF-κB) activation, which was dampened by AMPK inhibition. Oral gavage of sulfasalazine (a colon-specific prodrug of 5-ASA) or rectal administration of 5-ASA ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rat colitis and activated AMPK in the inflamed colonic tissues while markedly diminishing the levels of NF-κB-regulated pro-inflammatory mediators cyclooxygenase-2, inducible nitric oxide synthase, and cytokine-induced neutrophil chemoattractant-3, elevated by induction of inflammation. Rectal co-administration of 5-ASA and an AMPK inhibitor undermined 5-ASA-mediated activation of AMPK and its anti-colitic effects.
Conclusion: These findings suggest that activation of AMPK is involved in 5-ASA-mediated anti-colitic effects at least partly via interference with pro-inflammatory NF-κB signaling.