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Review
. 2021 Apr 29:12:657457.
doi: 10.3389/fphar.2021.657457. eCollection 2021.

Gaseous Mediators as a Key Molecular Targets for the Development of Gastrointestinal-Safe Anti-Inflammatory Pharmacology

Aleksandra Danielak  1 , John L Wallace  2 , Tomasz Brzozowski  1 , Marcin Magierowski  1
Affiliations
Review

Gaseous Mediators as a Key Molecular Targets for the Development of Gastrointestinal-Safe Anti-Inflammatory Pharmacology

Aleksandra Danielak et al. Front Pharmacol. .

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most widely used classes of drugs and play a pivotal role in the therapy of numerous inflammatory diseases. However, the adverse effects of these drugs, especially when applied chronically, frequently affect gastrointestinal (GI) tract, resulting in ulceration and bleeding, which constitutes a significant limitation in clinical practice. On the other hand, it has been recently discovered that gaseous mediators nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) contribute to many physiological processes in the GI tract, including the maintenance of GI mucosal barrier integrity. Therefore, based on the possible therapeutic properties of NO, H2S and CO, a novel NSAIDs with ability to release one or more of those gaseous messengers have been synthesized. Until now, both preclinical and clinical studies have shown promising effects with respect to the anti-inflammatory potency as well as GI-safety of these novel NSAIDs. This review provides an overview of the gaseous mediators-based NSAIDs along with their mechanisms of action, with special emphasis on possible implications for GI mucosal defense mechanisms.

Keywords: carbon monoxide; gastrointestinal safety; hydrogen sulfide; inflammation; nitric oxide; non-steroidal anti-inflammatory drugs.

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Conflict of interest statement

JW was employed by Antibe Therapeutics, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Pathomechanism of NSAIDs-induced gastrointestinal damage.
FIGURE 2
FIGURE 2
Possible mechanisms of action of NO-, H2S-releasing NSAIDs, NOSH-NSAIDs or NSAIDS applied with CO donors.
FIGURE 3
FIGURE 3
Chemical structures of selected NO-NSAIDs.
FIGURE 4
FIGURE 4
Chemical structures of selected H2S-NSAIDs.
FIGURE 5
FIGURE 5
Chemical structures of selected NOSH-NSAIDs.
FIGURE 6
FIGURE 6
Chemical structure of CO-ASS.
See this image and copyright information in PMC

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