| Resumo: |
(-)-Myrtenol is a bicyclic monoterpene alcohol structurally related to a-pinene found in diverse plant, such as herb Myrtus communis L. (Myrtaceae) used traditionally for the treatment of gastrointestinal disorders. This study was aimed to assess the potential gastroprotective and ulcer healing effects of (-)-myrtenol and the possible mechanisms involved, in vivo experimental models of gastric lesion and in vitro scratch assay. The results showed that (-)-myrtenol at the dose of 2000 mg/kg did not promote acute toxicity during the 14 days observation period in mice. Pretreatment with (-)-myrtenol (50 and 100 mg/kg, p.o.) significantly reduced (p<0.05) the area of gastric lesions induced by ethanol (83 and 83%, respectively) by indomethacin (89 and 87%, respectively), and by retention cold stress (79 and 73%, respectively), as compared to the respective vehicle groups. The mechanistic evaluation of (-)-myrtenol (50 mg/kg, p.o.) in ethanol-induced gastric ulcer involved antioxidant and anti-inflammatory activity, with increase in the activity of glutathione peroxidase, superoxide dismutase and catalase, a decrease in the activity of myeloperoxidase and malondialdehyde in gastric tissue and with increase in levels of nitrite/nitrate, gastric mucus and non-protein sulfhydryls. Pretreatment with GABA-A receptor antagonist flumazenil, the cyclooxygenase inhibitor indomethacin, and nitric oxid synthase inhibitor L-NAME significantly (p<0.05) blocked the (-)-myrtenol gastroprotection. The (-)-myrtenol (50 and 100 mg/kg) administered for seven days was also able to significantly reduced (p<0.05) acetic acid-induced gastric ulcer, increasing the rate of wound healing (47 and 32%, respectively) as compared to the vehicle group. Treatment with (-)-myrtenol (25, 50 and 100 mg/kg, v.o.) in acetic acid-induced gastric ulcer model did not changes significantly the body weight, absolute organ weight and biochemical parameters. The (-)-myrtenol also stimulated re-epithelialization in the ulcer area, reduced activity of N-acetylglicosaminidase and metalloproteinases (2 and 9) and proinflammatory cytokines expression (IL-1β and TNF-α), increased cyclooxygenase-2 expression, gastric mucus content and percentage of collagen fibers, as compared to the respective vehicle groups. In vitro scratch assay with AGS cells, (-)-myrtenol (0.1, 1, 10 and 100 nM) did not alter cell viability, stimulated cell migration in the presence and absence of hydroxyurea, with 6 and 24 hours of incubation, compared to the control group. In summary, these results provide, for the first time, evidence that (-)-myrtenol exert gastroprotective effect mainly due to inhibition of oxidative stress and peripheral GABA-A receptor modulation, regulating blood flow in the mucosa, probably by stimulate the production of nitric oxide and prostaglandins. The (-)-myrtenol shows a healing-promoting effect on acetic acid-induced gastric ulcers to modulate the proinflammatory cytokines expression (IL-1β and TNF-α) and COX-2 expression and to increase the mucus content of the stomach, reepithelialization and gastric cell matrix remodeling. |
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