Role of glutathione status and nitric-oxide synthase activity in protection against ethanol-induced gastric mucosal injury in rats

ABSTRACT

The present study was devoted to investigate the effect of selenium chloride, N-ethyl maleimide [NEM] and N-nitro-L-arginine methylester [NAME] on ethanol-induced gastric lesions in rats. The ultimate aim was to explore further the possible role of endogenously formed glutathione and nitric oxide [NO] in the protection against ethanol-induced gastric mucosal injury in rats. All rats treated with 80 percent ethanol developed hemorrhagic ulceration. This was associated with a significant increase in lipid degradation products represented by increased levels of malondialdehyde; the degradation product of lipid peroxides, together with a significant decrease in gastric mucosal glutathione peroxidase [GSHPx] activity and mucosal glutathione [GSH]. Orally administered selenium chloride exerted significant protection against gastric mucosal injury induced by ethanol, possibly via increasing endogenous antioxidant reserve represented by increased GSHPx activity. This acts to scavenge oxygen free radicals produced during mucosal ischemia induced by ethanol with resultant decrease in rate of lipid peroxidation. Depletion of endogenous GSH by NEM had no potentially ulcerogenic effect in the control rats. However, when given before ethanol treatment, the ulcer index significantly increased. Lipid peroxides were not significantly affected in the control rats in spite of the significant depletion of GSH. However, when the mucosa was challenged during ethanol treatment in the presence of depleted GSH and decreased GSHPx activity, oxygen free radicals failed to be buffered and lipid peroxides increased more significantly. Blocking NO synthase activity by NAME during alcohol treatment exaggerated the mucosal lesions as revealed by a decrease of the preventive index. This supports the protective role of endogenous NO on the gastric mucosal injury induced by ethanol. The aggressive effect of NAME was accompanied with a significant decrease of GSHPx activity as well as of endogenous GSH. The lipid peroxides, however, were found to be reduced despite the decreased antioxidant activity. In conclusion, repletion of gastric GSHPx system by selenium chloride exerts cytoprotective effect while blockade of endogenous GSH via NEM or blockade of NO synthesis with NAME aggravated the alcohol-induced gastric lesions