Abstract
Gastric ulcers (GUs), a frequent gastrointestinal condition, cause mucosal injury and inflammation. We aimed to investigate the protective effects and underlying mechanisms of ezetimibe, statins, and their combination in indomethacin-induced GUs. Rats were assigned into six groups (n = 8, each): (I) normal (control), (II) gastric ulcer induced with a single oral dose of indomethacin (30 mg/kg body weight), (III) rats received oral simvastatin (40 mg/kg/day) for 14 days, (IV) rats received oral ezetimibe (10 mg/kg/day) for 14 days, (V) the combination group received both oral simvastatin and ezetimibe, and (VI) standard group received oral famotidine (20 mg/kg). On day 14, gastric ulcers were induced by a single oral dose of indomethacin (30 mg/kg), and the animals were sacrificed 6 h later for sample collection and tissue analysis. Tissue levels of malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), Kelch-like ECH-associated protein 1 (Keap1), superoxide dismutase (SOD), nuclear erythroid factor 2 (Nrf-2) and hem-oxygenase 1 (HO-1) were measured. Ezetimibe, simvastatin, and their combination prevented GU. The combination therapy significantly reduced MDA, TNF-α, Keap1, IL-1, and serum C-reactive protein (CRP). However, Nrf-2, HO-1, and SOD were significantly increased when compared to the GU group and monotherapy. Histological investigations demonstrated that the combination therapy reduced GU severity and preserved stomach tissue. Simvastatin plus ezetimibe exerted synergistic gastroprotective effects in rats, associated with Nrf2/HO-1 activation and suppression of Keap1, oxidative stress, and pro-inflammatory cytokines. This combination may represent a novel therapeutic approach for preventing NSAID-induced GUs, meriting further mechanistic and translational studies.