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 the 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 the activation of AMPK is involved in 5-ASA-mediated anticolitic
effects at least partly via interference with pro-inflammatory NF-κB signaling.