Gastro protecting influence of Topiramate in ethanol produced gastric ulcers in rats

Abstract

Background: Topiramate (TPM), an antiepileptic drug, is also effective against alcohol dependency, a crucial factor in forming gastric ulcers. There is an increased possibility of patients with compromised gastric conditions getting exposed to TPM, but its effect on gastric ulcers is unknown. This study investigates the implication of acute TPM in ethanol-produced gastric ulceration in rats.

Material and methods: The effect of TPM studied in male 200-225 g Sprague Dawley rats against ethanol-induced gastric ulcers and for gastric secretion and acidity. The factors assessed include gastric secretion and acidity, gastric ulcer score, biochemical and histological changes, NF-kB, and p53 expression. The analysis of data performed by using the Kruskal Wallis test and Dunnett's multiple comparison tests.

Results: TPM pretreatment showed gastroprotective effects. It significantly reduced ethanol-induced increased gastric secretion, acidity, and gastric ulcer index and prevented gastric mucus depletion. The ethanol-induced inflammation and apoptosis were also significantly decreased by reducing the increased gastric myeloperoxidase activity and the expression of NF-kB and p53. TPM pretreatment also reduced the ethanol-induced damage to the gastric histology in rats.

Conclusion: TPM exerted a gastro-protective effect against ethanol-induced gastric ulcers mediated by reducing the gastric ulcer index, preventing a decrease of the mucus levels, reduction in inflammation, damage to gastric histology, and a decrease in the enhanced expression of NF-kB and TPM. Further detailed investigations are essential to understand the chronic influence of TPM on gastric ulcers.

Keywords: Ethanol; Gastric ulcer; Myeloperoxidase; NF-kB; Rat; Topiramate; p5.

Graphical abstract

Fig. 1

Gross macroscopic appearance of the gastric mucosa of Control (A), Ethanol (B), Topiramate 50 mg/Kg (C), 100 mg/Kg (D), 200 mg/Kg (E), and Topiramate alone 200 mg/Kg (F) pretreated rats. Rats were pretreated with Topiramate 30 min earlier to ethanol exposure. Control, ethanol alone, and Topiramate alone grouped animals were given water instead of the drug.

Fig. 2

Topiramate pretreatment effects on gastric ulcer scores in ethanol-induced ulcers in rats. Groups compared by Kruskal Wallis test. F = 3 = 21.60. P < 0.0001. Topi – Topiramate 50, 100, and 200 mg/Kg. Animals in the ethanol alone group received water instead of the drug.

Fig. 3

Topiramate pretreatment effects on gastric secretion (A) and acidity (B) rats. # P < 0.05 and # # # P < 0.0001 as compared with control animals using ANOVA followed by post hoc comparison with Dunnett's test. Topi - Topiramate 50, 100 and 200 mg/Kg. Animals treated with only ethanol were given water instead of the drug.

Fig. 4

Topiramate pretreatment effects on ethanol-produced changes in the gastric mucous levels of rats. * * P < 0.001 when related to normal control animals and # # P < 0.001 when related to animals treated with ethanol by using Dunnett's multiple comparison test. Topi - Topiramate 50, 100 and 200 mg/Kg. Control, ethanol alone, and Topiramate alone grouped animals were given water instead of the drug.

Fig. 5

Topiramate pretreatment effects on ethanol-produced changes in the histology of the rat’s stomach. Figures A-E represent the light micrographs of the stomach of rats. A, - Normal rat Stomach. B, - Rat Stomach exposed to ethanol showing the damaged gastric mucosa and discontinuity in the mucosal lining (thick arrows). C – E, - Stomach of TPM pretreated rats (50 mg, 100 mg, and 200 mg/Kg of Topiramate + Ethanol, respectively). Animals in the control and the ethanol alone groups received water. Treatment with 100 mg/Kg and 200 mg/Kg of Topiramate showing almost complete normalcy in the histological architecture. Thick arrows show ethanol-induced gastric erosion, and the thin arrows show edema and hemorrhage.

Fig. 6

Topiramate pretreatment effects on ethanol-produced changes in the immunohistochemical localization and expression of p53 in rat's stomach. (A) Control animals show no p53 expression. (B) Ethanol-exposed rats are displaying a strong expression of p53. (C–E) Topiramate-pretreated animals show comparatively more minor staining and expression of p53. Animals in the control and ethanol alone groups received water.

Fig. 7

Topiramate pretreatment effects on ethanol-produced changes in the immunohistochemical localization and expression of NF-kB in rat's stomachs. Photomicrographs showing immunohistochemical activation of NF-kB. (A) Control animals show no NF-kB expression. (B) Ethanol-exposed rats are displaying a strong expression of NF-kB. (C–E). Topiramate pretreated animals are showing comparatively more minor staining and expression of NF-kB. Animals in the control and ethanol alone groups received water.

Fig. 8

Topiramate pretreatment effects on ethanol-produced changes in MPO activity of rats. * P < 0.01 related to control animals and # P < 0.05, # # P < 0.001 related with ethanol alone treated animals by using Dunnett's multiple comparison test. Topi - Topiramate 50, 100, and 200 mg/Kg Animals in the control, ethanol alone, and the Topiramate alone groups received water.