Journal
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
Volume 48, Issue 3, Pages 401-411Publisher
WILEY
DOI: 10.1111/1440-1681.13414
Keywords
cGMP; gastric mucosa; gastric ROS production; NO; NSAIDS; PDE5 inhibitor
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Funding
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior [001]
- Fundacao Estadual de Amparo a Pesquisa do Estado do Espirito Santo [18/2018-552/2018, 21/2018-120/2019]
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The study demonstrates that different doses of Sildenafil exhibit a dose-dependent gastroprotective effect against NSAID-induced gastric ulcers, by reducing oxidative damage through modulation of oxidative stress. Additionally, Sildenafil increases the bioavailability of nitric oxide, enhances antioxidant enzyme levels, and restores gastric mucosa damage through various antioxidant, antigenotoxic, and antiapoptotic mechanisms.
Sildenafil (SIL) has potential as an interesting gastroprotective drug. However, the pathways of its protective effect still needs to be clarified, and its use as a potential gastroprotective agent validated. This study aims to evaluate the effects of SIL via modulation of oxidative stress in a NSAID-induced gastric lesion model. Male Swiss mice were divided into six groups: control (CON, water), nonsteroidal anti-inflammatory drug (NSAID, water), proton pump inhibitor (PPI, 30 mg/kg of lansoprazole), SIL 5 (5 mg/kg), SIL 25 (25 mg/kg) and SIL 50 (50 mg/kg). The animals were treated by gavage (a single dose) after 24 hours of fasting, and gastric lesions were performed after 30 minutes, with indomethacin (40 mg/kg, by gavage). After 6h, the animals were killed and the stomach was removed to evaluate reactive oxygen species (ROS) production, oxidation of macromolecules, quantification of antioxidant enzymes, DNA fragmentation, apoptosis and macroscopic and histologic analysis of gastric lesions. SIL exerts a dose-dependent gastroprotective effect against NSAID-induced mucosal injury, also reducing cytoplasmic levels of ROS and consequent oxidative damage to macromolecules. In addition, SIL increases nitric oxide bioavailability, antioxidant enzymes and gastric cellular viability, as well as restoring important factors involved in gastroprotection. Our results demonstrate that different doses of SIL prevent indomethacin-induced gastric ulcer in mice via different, but complementary antioxidant, antigenotoxic and antiapoptotic mechanisms.
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