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Mesalazine Activates Adenosine Monophosphate-activated Protein Kinase: Implication in the Anti-inflammatory Activity of This Anti-colitic Drug

Mesalazine Activates Adenosine Monophosphate-activated Protein Kinase: Implication in the Anti-inflammatory Activity of This Anti-colitic Drug

Heejung Park, Wooseong Kim, Dayoon Kim, Seongkeun Jeong, Yunjin Jung

Curr Mol Pharmacol. 2019;12(4):272-280.

PMID: 30848228

Abstract:

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.

Chemicals Related in the Paper:

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IAR42413073	Cytokine-Induced Neutrophil Chemoattractant-3 from rat			Price

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