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

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.

Gaseous mediators (H2S, NO and CO) a new approach in gastrointestinal protection

“…19 Unlike the gastric mucosa, there is no proof that the reduction in mucus secretion and excess in HCl production contributes to the development of intestinal lesions associated with NSAID administration and interestingly drugs suppressing acid secretion have been shown to even aggravate small bowel injuries. 32,33 The mechanisms of intestinal injury have mostly been identified thanks to NSAIDs-induced intestinal damage models, suggesting that both COXs (COX-1 and COX-2) and PGs (PGE2 and PGI2) helps maintaining intestinal mucosal integrity, acting as potent vasodilators that neutralize back-diffusing acid, dilutes and removing any potentially toxic substances that have entered the subepithelial space when epithelial barrier function is compromised. 33,34,35 It is also of interest that NSAIDs are metabolized in the liver and conjugated with a glucuronic group for its excretion in bile, while the bacterial enzyme -Dglucuronidase enhances their resorption in the ileum leaving the NSAIDs in its free form, leading to the harmful re-exposure of the intestinal mucosa to these compounds.…”

“…8,49,50 Therefore, their use is limited to a certain group of patients with low risk of cardiovascular death. 32,51 Thus, until now there is not a fully effective therapeutic approach either in the prevention or in the treatment of gastroenteropathy.…”

Aspirin Derivatives Exploration: A Review on Comparison Study with Parent Drug

“…NO is needed to regulate the physiological pathways, particularly regarding the homeostasis of the GI tract. It is usually formed in esophageal, gastric, and intestinal mucosa via the enzymatic activity of NO synthases; neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) (24) .…”

Carbon Monoxide and Nitric Oxide as Examples of the Youngest Class of Transmitters

“…As discussed previously, NOS2 and NO are produced as a part of the immune response and have a regulatory role. In various pathological states, e.g., during infection, NO is released by macrophages and other immune cells at concentrations above 1 µM, where it serves as a broad-spectrum biocide [10,148,149]. To effectively exploit these properties of NO, a new class of nitric oxide donating nonsteroidal anti-inflammatory compounds (NO-NSAIDs) was developed (Figure 9).…”