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.
BackgroundWe examined whether metoclopramide (MCP), a modulator of dopamine and serotonin receptors, alleviated colitis and had synergistic effects when coadministered with 5-aminosalicylic acid (5-ASA) in an experimental model of colitis.MethodsMCP azo-linked to 5-ASA (5-[4-chloro-2-{2-(diethylamino)ethylcarbamoyl}– 1-methoxyphenyl]azosalicylic acid, MCP-azo-ASA) was synthesized, where 5-ASA was used as a colon-targeting carrier and an anti-colitic agent, and the ability of MCP-azo-ASA to target the colon in vitro and in vivo was evaluated.ResultsOur results indicate that MCP-azo-ASA was cleaved to MCP and 5-ASA in the cecal contents, but not in the contents of the small intestine. Oral gavage with equimolar concentrations of MCP-azo-ASA and sulfasalazine (SSZ, a colon-specific prodrug of 5-ASA widely used clinically) demonstrated that the two prodrugs delivered comparable amounts of 5-ASA to the cecum. MCP was barely detected in the blood after oral gavage with MCP-azo-ASA. In a rat model of 2,4-dinitrobenzene sulfonic acid hydrate (DNBS)-induced colitis, MCP-azo-ASA alleviated colonic damage in a dose-dependent manner. Moreover, MCP-azo-ASA reduced the concentrations of inflammatory mediators in the inflamed colon. At low equimolar doses, MCP-azo-ASA, but not SSZ, resulted in significant anti-colitic effects, which indicates that MCP has anti-colitic activity. MCP-azo-ASA had anti-colitic effects equal to those of SSZ at high equimolar doses.ConclusionThus, our results indicate that MCP-azo-ASA is a colon-specific prodrug of MCP. Targeted delivery of MCP to the colon ameliorated DNBS-induced colitis in rats, and we did not observe any synergistic effects of MCP after co-delivery with 5-ASA.
Amisulpride (ASP), an anti-psychotic agent, is a pharmacologically equivalent to sulpiride (SP). Because SP demonstrates anti-ulcer and anti-colitic activities, ASP with an aniline moiety was azo-coupled to salicylic acid to generate 5-(aminoethanoylsulfamoyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxybenzamide (ASP-azo-ASA), with the expectation that it would act as a colon-specific mutual prodrug against colitis. Following a 24 h incubation, approximately 80% of ASP-azo-ASA was cleaved to form ASP and 5-aminosalicylic acid (5-ASA) in the cecal contents, whereas it remained stable in the small intestinal contents. Oral gavage of ASP-azo-ASA (oral ASP-azo-ASA) delivered 5-ASA to the cecum to levels comparable with those observed for sulfasalazine (SSZ; clinical colon-specific prodrug of 5-ASA) and without detectable concentrations of ASP in the blood, indicating efficient colonic delivery. Oral ASP-azo-ASA ameliorated 2, 4-dinitrobenzenesulfonic acid hydrate (DNBS)-induced colitis in rats more effectively than oral SSZ. Additionally, oral ASP-azo-ASA lowered the levels of inflammatory mediators in the inflamed distal colon more effectively than oral SSZ. Combined treatment with 5-ASA and ASP via the rectal route more effectively reversed colonic damage and inflammation than treatment with 5-ASA or ASP alone, confirming the mutual anti-colitic actions of 5-ASA and ASP. In conclusion, ASP-azo-ASA is an orally active mutual prodrug against rat colitis with limited systemic absorption of ASP.
Localization of the Sustainable Development Goals (SDGs) refers to the process of defining, implementing, and monitoring strategies at the local level to achieve global, national, and subnational sustainable development goals and targets. The key question addressed by this baseline document is how SDG localization can be practically, efficiently, and effectively implemented in what remains of the Decade of Action.
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