Involvement of nitric oxide pathway in the anti-inflammatory effect of modafinil on indomethacin-, stress-, and ethanol -induced gastric mucosal injury in rat

Abstract

Gastric ulcer is a prevalent disease with various etiologies, including non-steroidal anti-inflammatory drugs (NSAIDs), stress conditions, and alcohol, resulting in an inflammatory condition in the gastric mucosa. The aim of this study was to explore the protective effects of modafinil on gastric erosions induced by indomethacin, water-immersion stress, and alcohol in rats and to evaluate the role of nitric oxide (NO) pathway. Animals were allocated to the three experimental models of gastric ulcer - indomethacin (30 mg/kg PO), water-immersion stress, and ethanol (5 ml/kg PO). Induction of gastric ulcer in all models caused an increase in J-score (macroscopic assessment), biochemical markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and myeloperoxidase (MPO), and microscopic destructions. Administration of modafinil (50 and 100 mg/kg i. p) significantly improved J-score in the indomethacin (P < 0.05) and stress models (P < 0.001). Moreover, the level of TNF-α IL-1β, and MPO was deceased after modafinil administration (P < 0.001). However, modafinil did not have any effects on gastric injury induced by ethanol. In addition, co-administration of L-NAME (a non-specific NO synthase inhibitor) and aminoguanidine (an inducible NO synthase inhibitor) with modafinil significantly neutralized the gastroprotective effect of modafinil in the indomethacin and water-immersion stress groups (P < 0.05, and P < 0.01; respectively), while 7-nitroindazole (a neuronal NO synthase inhibitor) did not show such reversing effects. In conclusion, modafinil possesses gastroprotective effects on the gastric lesions induced by indomethacin and stress, which are probably mediated via the inflammation inhibition and NO pathway modulation.

Keywords: Gastric mucosal injury; Inflammation; Modafinil; Nitric oxide; Rat.

Fig. 1

Effects of oral administration of indomethacin on J-score. Data were analyzed by Mann–Whitney test and the Kruskal Wallis Test. Bars represent mean ± S.E.M (8 rats per group). ^@@@ p < 0.001 significantly different from untreated control group p < 0.05 and ***p < 0.001 significantly different from gastric injury control group. ^#p < 0.001 and ^##p < 0.01 significantly different from modafinil 100 mg/kg group.

Fig. 2

Effects of water-immersion stress on J-score. Data were analyzed by Mann–Whitney test and the Kruskal Wallis Test. Bars represent mean ± S.E.M (8 rats per group).^@@@ p < 0.001 significantly different from untreated control group * p < 0.05, **p < 0.01, and ***P < 0.001 significantly different from gastric injury control group^# p < 0.001 and ^##p < 0.01 significantly different from modafinil 100 mg/kg group.

Fig. 3

Effects of the oral administration of ethanol on J-score. Data were analyzed by Mann–Whitney test and the Kruskal Wallis Test. Bars represent mean ± S.E.M (8 rats per group).^@@@ p < 0.001 significantly different from untreated control group.

Fig. 4

Histopathologic feature of gastric mucosa of rat (8 rat per group). I: indomethacin, S: (Water-immersion) stress, E: ethanol. a: gastric injury control group, b: peptic ulcer + modafinil 20 mg/kg, c: peptic ulcer + modafinil 50 mg/kg, d: peptic ulcer + modafinil 100 m/kg, e: peptic ulcer + modafinil 100 mg/kg and L-NAME 10 mg/kg, g: peptic ulcer + modafinil 100 mg/kg and 7-nitroindazole 40 mg/kg, f: peptic ulcer + modafinil 100 mg/kg and aminoguanidine 50 mg/kg. Black flash: destroyed gastric epithelium, White flash: destroyed gastric gland, Black star: normal gastric epithelium and gastric pit. Scale bar: 100 μm.