Role of soluble guanylate cyclase activation in the gastroprotective effect of the HO-1/CO pathway against alendronate-induced gastric damage in rats

Abstract

Our objective was to evaluate the role of soluble guanylate cyclase (sGC) activation in the gastroprotective effect of the HO-1/CO pathway against alendronate-induced gastric damage in rats. Rats were pretreated, once daily for 4 days, with saline, hemin (HO-1 inducer), or dimanganese decacarbonyl (DMDC, CO donor). Another group received zinc protoporphyrin IX (ZnPP IX, HO-1 antagonist) 1 h before hemin treatment or sGC inhibitor (ODQ) 30 min before hemin and DMDC treatment. After 30 min, gastric damage was induced by alendronate (30 mg/kg) by gavage. On the last day of treatment, 4 h after alendronate administration, the animals were killed. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1β), myeloperoxidase (MPO), or bilirubin. Another group was used to measure gastric mucus. HO-1 expression was determined after saline or alendronate administration by immunohistochemistry. Alendronate induced gastric damage, produced neutrophil accumulation, increased MDA levels and MPO activity, and reduced GSH and mucus in the gastric tissue. Alendronate also increased HO-1 immunoreactivity and the level of bilirubin in gastric mucosa. Pretreatment with hemin or DMDC reduced neutrophil infiltration and TNF-α, IL-1β, and MDA formation, and increased the levels of GSH and mucus in the gastric tissue. ODQ completely abolished the gastroprotective effect of hemin and DMDC and increased alendronate gastric damage. Our results suggest that the HO-1/CO pathway plays a protective role against alendronate-induced gastric damage through mechanisms that can be dependent on sGC activation.

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].…”

“…However, chronic use of ALD, a frequently used biphosphonate, also is associated with gastric ulcers via mechanisms differing from those of NSAIDs and ethanol. Adverse effects of ALD in the upper gastrointestinal tract have been attributed, in many cases, to adherence of the drug to the mucosal surface, causing lesions in the antrum that subsequently develop into ulcers (with white cap) [15,16]. However, the effect of SIM on gastric mucosal injury induced by ALD has remained unexplored.…”

Assessment of Gastroprotective Potential of <i>Delonix regia</i> (Boj Ex Hook) Raf against Ethanol and Cold Restrain Stress-Induced Ulcer in Rats

“…Myeloperoxidase, an enzyme found primarily in neutrophil azurophilic granules, has been used extensively as a biochemical marker for granulocyte infiltration into various tissues, including the gastrointestinal tract [18,19]. MPO activity was determined using an MPO activity measurement kit by adding 0.2 ml of odianisidine hydrochloride and 0.0005 % hydrogen peroxide to 4 ml buffer containing 0.2 ml homogenates.…”