Efeito gastroprotetor da amifostina (ETHYOL®) na lesão gástrica induzida por etanol em ratos: papel dos grupos sulfidrílicos não-protéicos e neurônios sensoriais aferentes

Abstract

Amifostine (WR-2721) has been widely tested as a cytoprotective agent against a number of aggressors in different organs. Recently, a gastroprotective effect was observed for this drug in a model of indomethacin-induced gastric injury (MOTA et al., 2007). OBJECTIVES: We investigated the effect of amifostine on ethanol-induced gastric injury and the role played by afferent sensory nerves, non-protein sulfhydryl groups, nitric oxide, ATP-sensitive potassium channels and cyclooxygenase-2 in the mechanism. METHODS: Wistar rats were treated with amifostine (22.5, 45, 90 or 180 mg/kg, p.o. or s.c.). Thirty minutes after amifostine administration, the animals were given 100% ethanol (5 ml/kg p.o.). Sixty minutes after ethanol administration the animals were euthanized. Macroscopic and histological studies were carried out and stomach fragments were retrieved and submitted to analysis for non-protein sulfhydryl groups and hemoglobin. Some animals were pretreated with L-NAME (10 mg/kg i.p.), glibenclamide (10 mg/kg p.o.), celecoxib (10 mg/kg p.o.) or saline solution. Thirty minutes after pretreatment the animals were given amifostine (90 mg/kg p.o. or s.c.) and, after another 30 minutes, 100% ethanol (5 ml/kg). The animals were euthanized 60 minutes later. Other rats were desensitized with capsaicin (125 mg/kg s.c.) 10-14 days before amifostine treatment. RESULTS: Amifostine treatment significantly reduced ethanol-induced macroscopic stomach injury at 45, 90 and 180 mg/kg p.o. and at 90 and 180 mg/kg s.c. The histological parameters (edema, hemorrhage and epithelial cell loss) were also reduced (p<0.05) when the animals were treated with amifostine. Animals receiving ethanol only presented reduced GSH levels in the stomach. Amifostine reverted this effect either by stimulating de novo GSH production or by preventing the consumption of GSH. Amifostine-promoted gastroprotection against ethanol-induced stomach injury was reversed by pretreatment with neurotoxic doses of capsaicin, but not by L-NAME, glibenclamide or celecoxib. CONCLUSIONS: Amifostine protects against ethanol-induced gastric injury by increasing GSH levels and stimulating the afferent sensory nerves in the stomach independently of ATP-sensitive potassium channels activation, nitric oxide synthase and cyclooxygenase-2 activity.