Influence of fluoxetine on the gastric healing process: experimental evidence of sexual dimorphism

Previous studies have demonstrated that fluoxetine, a selective serotonin reuptake inhibitor, exerts gastroprotective effects in models of acute gastric ulceration. However, its ability to promote the healing of established gastric ulcers remains unclear. This study investigated the effects of fluoxetine on gastric ulcer healing and potential sex-related differences in this response in rats. Gastric ulcers were induced in male and female rats by acetic acid instillation. Two days after ulcer induction, animals received vehicle (water, 1 mL/kg), omeprazole (20 mg/kg), or fluoxetine (0.17 or 1.7 mg/kg) orally once daily for seven days. Biochemical, histological, and histochemical analyses were performed. In addition, the antisecretory activity of fluoxetine was measured in another cohort of rats of both sexes using the pylorus-ligation method. Treatment with fluoxetine (0.17 and 1.7 mg/kg) significantly reduced ulcer area in male rats but not in females compared with the vehicle-treated group. In females, acetic acid instillation decreased glutathione (GSH) levels and increased malondialdehyde (MDA) levels and myeloperoxidase (MPO) activity, regardless of treatment. In contrast, ulcerated male rats treated with vehicle showed increased MPO and N-acetyl-β-D-glucosaminidase (NAG) activities, whereas fluoxetine reduced both parameters. Fluoxetine also reduced mast cell density and increased mucin content in the gastric mucosa of male rats. Furthermore, the tested doses did not affect gastric acidity, volume, or peptic activity in pylorus-ligated rats. These findings demonstrate that fluoxetine promotes gastric ulcer healing in male rats, possibly by enhancing mucosal barrier defenses and attenuating inflammation, while no healing effect was observed in females, suggesting a sex-dependent response.