Protective Effect of Excitatory Amino Acids on Cold-Restraint Stress-Induced Gastric Ulcers in Mice: Role of Cyclic Nucleotides

Previous studies have shown that excitatory amino acids (EAAs) and their receptors may play important roles in the mammalian enteric system. In this study, we investigated whether EEAs, including l-glutamate (l-Glu) and subtypes N-methyl-d-aspartate (NMDA), kainic acid (KA), and quisqualic acid (QA), reduce cyclic AMP (cAMP) levels and play a role in protecting gastric lesions in cold-restraint stress (CRS) mice. First, we found that dose-dependent administration of four selected EAAs significantly attenuated the increase of cAMP content and exhibited a protective effect on the development of gastric lesions induced by CRS. Second, CRS treatment exhibited a decrease of cGMP content and an increase of cAMP content with marked time-dependent changes, and a high cAMP/cGMP ratio in mice gastric mucosa. Third, pretreatment with 0.25 μg/kg or 0.5 μg/kg dibutyryl cGMP (db-cGMP) exhibited protective effects on CRS-induced gastric lesions, with preventive ratios of 24.61% and 35.32%, respectively. Moreover, db-cGMP at 0.5 μg/kg significantly attenuated the increase in both cAMP content and the cAMP/cGMP ratio in CRS-treated gastric mucosa. In contrast, db-cAMP exhibited no protective effect, and significantly decreased cGMP content and increased the cAMP/cGMP ratio. These results suggest that EAAs significantly reduce CRS-induced gastric ulcers in mice. The possible mechanism of the antiulcer activity of EAAs may be related to a decrease in the cAMP content in the gastric mucosa of mice. In addition, an increase of the cAMP/cGMP ratio significantly involved in CRS-induced gastric ulcer formation in mice.