The hydrogen sulfide donor, Lawesson's reagent, prevents alendronate-induced gastric damage in rats

Abstract

Our objective was to investigate the protective effect of Lawesson's reagent, an H2S donor, against alendronate (ALD)-induced gastric damage in rats. Rats were pretreated with saline or Lawesson's reagent (3, 9, or 27 µmol/kg, po) once daily for 4 days. After 30 min, gastric damage was induced by ALD (30 mg/kg) administration by gavage. On the last day of treatment, the animals were killed 4 h after ALD administration. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), proinflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin (IL)-1β], and myeloperoxidase (MPO). Other groups were pretreated with glibenclamide (5 mg/kg, ip) or with glibenclamide (5 mg/kg, ip)+diazoxide (3 mg/kg, ip). After 1 h, 27 µmol/kg Lawesson's reagent was administered. After 30 min, 30 mg/kg ALD was administered. ALD caused gastric damage (63.35±9.8 mm2); increased levels of TNF-α, IL-1β, and MDA (2311±302.3 pg/mL, 901.9±106.2 pg/mL, 121.1±4.3 nmol/g, respectively); increased MPO activity (26.1±3.8 U/mg); and reduced GSH levels (180.3±21.9 µg/g). ALD also increased cystathionine-γ-lyase immunoreactivity in the gastric mucosa. Pretreatment with Lawesson's reagent (27 µmol/kg) attenuated ALD-mediated gastric damage (15.77±5.3 mm2); reduced TNF-α, IL-1β, and MDA formation (1502±150.2 pg/mL, 632.3±43.4 pg/mL, 78.4±7.6 nmol/g, respectively); lowered MPO activity (11.7±2.8 U/mg); and increased the level of GSH in the gastric tissue (397.9±40.2 µg/g). Glibenclamide alone reversed the gastric protective effect of Lawesson's reagent. However, glibenclamide plus diazoxide did not alter the effects of Lawesson's reagent. Our results suggest that Lawesson's reagent plays a protective role against ALD-induced gastric damage through mechanisms that depend at least in part on activation of ATP-sensitive potassium (KATP) channels.

Nitric oxide, afferent sensory nerves, and antioxidative enzymes in the mechanism of protection mediated by tricarbonyldichlororuthenium(II) dimer and sodium hydrosulfide against aspirin-induced gastric damage

“…It has previously been reported that differences in GPx-1 and SOD activities could serve as a marker of the pathological condition [41]. Our present observations support recent findings that H 2 S-releasing Lawesson's reagent or another CO donor, dimanganese decacarbonyl, protected gastric mucosa against alendronate-induced gastric damage via regulation of oxidative stress as manifested by an increase in reduced glutathione content and a decrease in MDA content in rat gastric mucosa injured by alendronate [42,43]. Thus, we conclude that the antioxidative properties of the gaseous mediators CO and H 2 S can contribute, at least in part, to the observed gastroprotective effect of these molecules against aspirininduced gastric damage.…”

Protective Effects of Simvastatin Against Alendronate-Induced Gastric Mucosal Injury in Rats

“…Chronic oral administration of ALD also caused hemorrhagic lesions in the mucosa of the glandular stomach, indicating true ulcer formation, and this was also supported by the histopathological findings of edema, increased inflammatory cells, and epithelial cell loss [15,16,26].…”

Toward Hydrogen Sulfide Based Therapeutics: Critical Drug Delivery and Developability Issues

“…In an effort to understand the mechanism through which H 2 S exerts its functions, animals were pretreated with glibenclamide, which binds and inhibits K ATP . It was found that glibenclamide ameliorated the protective effect of Lawesson's reagent, suggesting the involvement of K ATP channels in H 2 S's role in protection against ALD‐induced gastric damage . Even though Lawesson's reagent was found to release H 2 S, which shows pharmacological effects in various studies, there are certain properties that need improvement.…”

“…122 In more recent times, a study was carried out by Medeiros et al to understand the effect of Lawesson's reagent on gastric damage caused by alendronate (ALD)-a biphosphate drug used for osteoporosis and several other bone diseases. 123 ALD is responsible for mucosal damage, which could lead to hemorrhage, infiltration of inflammatory cells, and loss of epithelial cells. Rats were pretreated with saline or Lawesson's reagent (27 μmol/kg) once daily for 4 days.…”

“…It was found that glibenclamide ameliorated the protective effect of Lawesson's reagent, suggesting the involvement of K ATP channels in H 2 S's role in protection against ALD-induced gastric damage. 123 Even though Lawesson's reagent was found to release H 2 S, which shows pharmacological effects in various studies, there are certain properties that need improvement. For example, the H 2 S release rate cannot be controlled.…”