The H2S-Releasing Naproxen Derivative ATB-346 and the Slow-Release H2S Donor GYY4137 Reduce Intestinal Inflammation and Restore Transit in Postoperative Ileus

Abstract

Objective: Intestinal inflammation triggers postoperative ileus (POI), commonly seen after abdominal surgery and characterized by impaired gastrointestinal transit; when prolonged, this leads to increased morbidity. Hydrogen sulfide (H 2 S) is recognized as an important mediator of many (patho)physiological processes, including inflammation, and is now investigated for anti-inflammatory application. Therefore, the aim of this study was to investigate the effect of the H 2 S-releasing naproxen derivative ATB-346, developed to reduce gastrointestinal injury by naproxen, and the slow-release H 2 S donor GYY4137 on intestinal inflammation and delayed gastrointestinal transit in murine POI. Methods: C57Bl6J mice were fasted for 6 h, anesthetized and after laparotomy, POI was induced by compressing the small intestine with two cotton applicators for 5 min (intestinal manipulation; IM). GYY4137 (50 mg/kg, intraperitoneally), ATB-346 (16 mg/kg, intragastrically) or naproxen (10 mg/kg, intragastrically) were administered 1 h before IM. At 24 h postoperatively, gastrointestinal transit was assessed via fluorescent imaging, and mucosa-free muscularis segments were prepared for later analysis. Inflammatory parameters and activity of inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2 were measured. Histological examination of whole tissue sections was done on hematoxylin-eosin stained slides. Results: Pre-treatment with GYY4137 (geometric center; GC: 7.6 ± 0.5) and ATB-346 (GC: 8.4 ± 0.3) prevented the delayed transit induced by IM (GC: 3.6 ± 0.5 vs. 9.0 ± 0.4 in non-operated controls) while naproxen only partially did (GC: 5.9 ± 0.5; n = 8 for all groups). GYY4137 and ATB-346 significantly reduced the IM-induced increase in muscular myeloperoxidase (MPO) activity and protein levels of interleukin (IL)-6, IL-1β and monocyte chemotactic protein 1; the reduction by naproxen was less pronounced and only reached significance for MPO activity and IL-6 levels. All treatments significantly reduced the increase in COX-2 activity caused by IM, whereas only GYY4137 significantly reduced the increase in iNOS activity. Naproxen treatment caused significant histological damage of intestinal villi. Conclusion: The study shows that naproxen partially prevents POI, probably through its inhibitory effect on COX-2 activity. Both ATB-346 and GYY4137 were more effective, the result with GYY4137 showing that H 2 S per se can prevent POI.

Basic Pharmacological Characterization of EV-34, a New H2S-Releasing Ibuprofen Derivative

“…H 2 S-releasing NSAIDs have been shown to exhibit a better GI side effect profile. Furthermore, for example, H 2 S-releasing naproxen exhibit better anti-inflammatory property than naproxen [ 36 ]. Thus, EV-34 could be a useful tool in the treatment of patients with high cardiovascular risk and long-term ibuprofen treatment, since our newly synthetized molecule has NSAID properties and also H 2 S-releasing ability.…”

Novel approach for discrimination of eosinophilic granulocytes and evaluation of their surface receptors in a multicolor fluorescent histological assessment

“…These findings mean that HFD causes modification of AM and can serve as a trigger for formation of self-destructive mitochondria and mitochondrial dysfunction which are signs of early stages of oxidative stress that could be a target for therapy. In this regard, potent anti-oxidative substances, such as exogenous H 2 S compounds have potent cytoprotective properties [16,32,33]. To demonstrate the action of exogenous H 2 S compounds on AM upon HFD and WIS exposure, we used administration of NaHS, a novel H 2 S-releasing derivate of ASA (H 2 S-ASA [ATB-340]), or a combination of ASA and NaHS.…”

H2S Donors Reverse Age-Related Gastric Malfunction Impaired Due to Fructose-Induced Injury via CBS, CSE, and TST Expression

“…The control samples were treated similarly, except the studied material was added to the medium after incubation and cooling. The amount of H 2 S was estimated with the methylene blue production by a standard method ( Van Dingenen et al., 2019 ). There were added 0.5 ml 20 mM N,N-dimethyl-p-phenylenediamine in 7.2 M HCl, 0.4 ml 30 mM FeCl3 in 1.2 М HCl to the samples and incubated for 20 min at 18‑22° С, then added 1 ml 20% TCA and centrifuged for 10 min at 3000 rpm.…”

“…Recently, it has been found that the synthesis of H 2 S from cysteine and cysteine with homocysteine affects glucose regulation and provides protection of vascular endothelium against oxidative stress and correction of hyperhomocysteinemia, which may be a predictor of accelerated aging and H 2 S signaling network is the source for reversion of vascular aging ( Das et al., 2018 ; De Cabo and Diaz-Ruiz, 2020 ). Interestingly, H 2 S mediates the activity of arachidonic cycle and production of prostaglandins and recent advances in the creation of the latest hybrid H 2 S-releasing drugs, analogs of nonsteroidal anti-inflammatory drugs (NSAIDs, H 2 S-NSAIDs) or organic Lawesson’s reagent derivative, have shown ability to reverse decrementing side effects that arise from the digestive system, cardiovascular system and systemic reactions ( Wallace et al., 2007 ; Guo et al., 2012 ; Kang et al., 2017 ; Zhang et al., 2018 ; Van Dingenen et al., 2019 ). Among NSAIDs aspirin is the most widely used drug in the aged population for different reasons.…”