H(2)S-Releasing Aspirin Protects against Aspirin-Induced Gastric Injury via Reducing Oxidative Stress

Abstract

The aim of this study was to examine the effect of ACS14, a hydrogen sulfide (H2S)-releasing derivative of aspirin (Asp), on Asp-induced gastric injury. Gastric hemorrhagic lesions were induced by intragastric administration of Asp (200 mg/kg, suspended in 0.5% carboxymethyl cellulose solutions) in a volume of 1 ml/100 g body weight. ACS14 (1, 5 or 10 mg/kg) was given 30 min before the Asp administration. The total area of gastric erosions, H2S concentration and oxidative stress in gastric tissues were measured three hours after administration of Asp. Treatment with Asp (200 mg/kg), but not ACS14 (430 mg/kg, at equimolar doses to 200 mg/kg Asp), for 3 h significantly increased gastric mucosal injury. The damage caused by Asp was reversed by ACS14 at 1–10 mg/kg in a concentration-dependent manner. ACS14 abrogated Asp-induced upregulation of COX-2 expression, but had no effect on the reduced PGE2 level. ACS14 reversed the decreased H2S concentrations and blood flow in the gastric tissue in Asp-treated rats. Moreover, ACS14 attenuated Asp-suppressed superoxide dismutase-1 (SOD-1) expression and GSH activity, suggesting that ACS14 may stimulate antioxidants in the gastric tissue. ACS14 also obviously inhibited Asp-induced upregulation of protein expression of oxidases including XOD, p47phox and p67phox. In conclusion, ACS14 protects Asp induced gastric mucosal injury by inhibiting oxidative stress in the gastric tissue.

Hydrogen Sulfide in Renal Physiology and Disease

“…Intraperitoneal administration of 2-acetyloxybenzoic acid 4-(3-thioxo-3H-1, 2 dithiol-5-yl) phenyl ester (ACS14, Saspirin), a form of aspirin that releases H2S, prevented aspirin-induced gastric ulceration; this protective effect of Saspirin was reproduced by NaHS establishing that H2S was responsible for the ameliorative effect (54). The mechanism of H2S amelioration of aspirin-induced injury involved a decrease in the markers of oxidative stress and a reversal of aspirin-induced increased expression of xanthine oxidase in the gastric mucosa (54).…”

Anti-Cancer Activity of New Designer Hydrogen Sulfide-Donating Hybrids

“…Similarly, H 2 Sindomethacin (61), H 2 S-mesalamine (64), and H 2 S-naproxen (63) were also shown to cause significantly less damage to the stomach compared with their respective parent compound. In a recent study, H 2 S-donating ASA (ACS14) was shown to spare the stomach of rats from the harmful side effects of ASA when given 30 min before ASA administration (41). ACS14 also abrogated ASA-induced up-regulation of COX-2 expression, but it had no effect on the reduced PGE 2 levels; it also attenuated ASA-suppressed superoxide dismutase-1 expression and glutathione (GSH) activity (41).…”

“…In a recent study, H 2 S-donating ASA (ACS14) was shown to spare the stomach of rats from the harmful side effects of ASA when given 30 min before ASA administration (41). ACS14 also abrogated ASA-induced up-regulation of COX-2 expression, but it had no effect on the reduced PGE 2 levels; it also attenuated ASA-suppressed superoxide dismutase-1 expression and glutathione (GSH) activity (41). These data suggest that ACS14 enhances mucosal integrity by inhibiting oxidative stress in the gastric tissue.…”

Current Perspectives in NSAID-Induced Gastropathy

“…Derivatives of naproxen, diclofenac, and indomethacin which can release H2S have been reported [125–128]. Phosphatidylcholine-associated NSAIDs as well as NO- and H2S-releasing NSAIDs are under extensive preclinical testing for their influence on NSAID induced GI toxicity [129, 130].…”