Abstract
Hydrogen sulfide (H2S) is an endogenously produced molecule with anti-inflammatory and cytoprotective properties. We aimed to investigate for the first time if a novel, esterase-sensitive H2S-prodrug, BW-HS-101 with the ability to release H2S in a controllable manner, prevents gastric mucosa against acetylsalicylic acid-induced gastropathy on microscopic and molecular levels. Wistar rats were pretreated intragastrically with vehicle, BW-HS-101 (0.5–50 μmol/kg) or its analogue without the ability to release H2S, BW-iHS-101 prior to ASA administration (125 mg/kg, intragastrically). BW-HS-101 was administered alone or in combination with nitroarginine (L-NNA, 20 mg/kg, intraperitoneally) or zinc protoporphyrin IX (10 mg/kg, intraperitoneally). Gastroprotective effects of BW-HS-101 were additionally evaluated against necrotic damage induced by intragastrical administration of 75% ethanol. Gastric mucosal damage was assessed microscopically, and gastric blood flow was determined by laser flowmetry. Gastric mucosal DNA oxidation and PGE2 concentration were assessed by ELISA. Serum and/or gastric protein concentrations of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, VEGF, GM-CSF, IFN-γ, TNF-α, and EGF were determined by a microbeads/fluorescent-based multiplex assay. Changes in gastric mucosal iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, and COX-2 mRNA were assessed by real-time PCR. BW-HS-101 or BW-iHS-101 applied at a dose of 50 μmol/kg protected gastric mucosa against ASA-induced gastric damage and prevented a decrease in the gastric blood flow level. H2S prodrug decreased DNA oxidation, systemic and gastric mucosal inflammation with accompanied upregulation of SOCS3, and EGF and HMOX-1 expression. Pharmacological inhibition of nitric oxide (NO) synthase but not carbon monoxide (CO)/heme oxygenase (HMOX) activity by L-NNA or ZnPP, respectively, reversed the gastroprotective effect of BW-HS-101. BW-HS-101 also protected against ethanol-induced gastric injury formation. We conclude that BW-HS-101, due to its ability to release H2S in a controllable manner, prevents gastric mucosa against drugs-induced gastropathy, inflammation and DNA oxidation, and upregulate gastric microcirculation. Gastroprotective effects of this H2S prodrug involves endogenous NO but not CO activity and could be mediated by cytoprotective and anti-inflammatory SOCS3 and EGF pathways.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA, the active ingredient of aspirin), exert analgesic, anti-pyretic, and anti-inflammatory effects
We aimed to investigate for the first time if pretreatment with a novel H2S prodrug, BW-HS-101 applied intragastrically (i.g.), protects gastric mucosa against ASA-induced injury and if this compound affects gastric blood flow (GBF)
We examined the possible involvement of endogenous carbon monoxide (CO) and nitric oxide (NO) produced by heme oxygenase (HMOX) or NO synthase (NOS) activities, respectively, in gastric mucosal integrity maintenance by BW-HS-101
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA, the active ingredient of aspirin), exert analgesic, anti-pyretic, and anti-inflammatory effects. The mechanism of action of ASA is through the inhibition of cyclooxygenases (COX-1, COX-2), enzymes involved in the synthesis of pro-inflammatory and cytoprotective prostaglandins (PGs) such as PGE2. Despite the beneficial effects of ASA on the cardiovascular system, the adverse effects of this drug within the gastrointestinal (GI) tract, such as gastric mucosal injuries, remain a major limitation of its therapeutic effectiveness in humans [2]. The pathogenesis of this ASAinduced gastrotoxicity is attributed to its topical and systemic effects [3,4] since this drug irreversibly inhibits COX-1 and COX-2. ASA itself is chemically irritating and cytotoxic for gastric epithelial cells [5]
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