Abstract
This study aimed to investigate the possible gastroprotective effect of tocotrienol against water-immersion restraint stress (WIRS) induced gastric ulcers in rats by measuring its effect on gastric mucosal nitric oxide (NO), oxidative stress, and inflammatory biomarkers. Twenty-eight male Wistar rats were randomly assigned to four groups of seven rats. The two control groups were administered vitamin-free palm oil (vehicle) and the two treatment groups were given omeprazole (20 mg/kg) or tocotrienol (60 mg/kg) orally. After 28 days, rats from one control group and both treated groups were subjected to WIRS for 3.5 hours once. Malondialdehyde (MDA), NO content, and superoxide dismutase (SOD) activity were assayed in gastric tissue homogenates. Gastric tissue SOD, iNOS, TNF-α and IL1-β expression were measured. WIRS increased the gastric MDA, NO, and pro-inflammatory cytokines levels significantly when compared to the non-stressed control group. Administration of tocotrienol and omeprazole displayed significant protection against gastric ulcers induced by exposure to WIRS by correction of both ulcer score and MDA content. Tissue content of TNF-α and SOD activity were markedly reduced by the treatment with tocotrienol but not omeprazole. Tocotrienol significantly corrected nitrite to near normal levels and attenuated iNOS gene expression, which was upregulated in this ulcer model. In conclusion, oral supplementation with tocotrienol provides a gastroprotective effect in WIRS-induced ulcers. Gastroprotection is mediated through 1) free radical scavenging activity, 2) the increase in gastric mucosal antioxidant enzyme activity, 3) normalisation of gastric mucosal NO through reduction of iNOS expression, and 4) attenuation of inflammatory cytokines. In comparison to omeprazole, it exerts similar effectiveness but has a more diverse mechanism of protection, particularly through its effect on NO, SOD activity, and TNF-α.
Highlights
Stress is well known to be associated with the formation of gastric ulcers
Nitric oxide is a potent vasorelaxant involved in the control of the gastric blood flow and is a gaseous mediator contributing to the maintenance of gastric mucosal integrity [9]
Kwiecien et al [9] demonstrated that water-immersion restraint stress (WIRS) provokes acute inflammatory responses with interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF)-α acting as the major pro-inflammatory cytokines mediated by neutrophil infiltration in gastric mucosa
Summary
Stress is well known to be associated with the formation of gastric ulcers. The ulcers frequently emerge as a result of major stressful events including surgery, trauma, shock, sepsis, and burns. Inhibition of NOS causes a decrease in local NO production, impairs gastric microcirculation, and aggravates gastric lesions induced by noxious agents [10]. This is true, excessive NO production can create free radicals that have a negative effect on the gastric microenvironment. Kwiecien et al [9] demonstrated that water-immersion restraint stress (WIRS) provokes acute inflammatory responses with interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF)-α acting as the major pro-inflammatory cytokines mediated by neutrophil infiltration in gastric mucosa. Neutrophils produce superoxide radical anions (O2-), which react with cellular membrane lipids, leading to the formation of lipid peroxides that are metabolised to end products like malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) [11]
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