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The Turkish Journal of Gastroenterology
2001, Volume 12, No 1, Page(s) 23-26
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Protective effects of vitamin E and Gingko biloba extract on stress induced gastric mucosal injury in rats
Çetin Mustafa1, Özbakır Ömer1, Kontaş Olgun2, Taşkapan Hülya1, Yücesoy Mehmet1
Erciyes University School of Medicine, Departments of Internal Medicine1 and Pathology2, Kayseri
Keywords: Stress ulcer, Vitamin E, Ginkgo biloba extract, Stres ülseri, E vitamini, Ginkgo biloba ekstresi.
Summary
Background/aims: The protective effect of vitamin E on stress or chemical induced gastric mucosal injury is well established. In this study, the protective effect of vitamin E and Ginkgo biloba extract, a free radical scavenger and PAF receptor antagonist, on experimentally induced gastric mucosal lesions in rats were compared. Methods: A total of 72 male and female Swiss albino rats, weighing between 180 g and 220 g, were divided equally into six groups:
Group I (Control Group): did not exposed to any stress.
Group II (Placebo Group): stress induced by fasting and immobilization and normal saline was given as a placebo.
Group III (Late Prophylaxis Group): put on 100 mg/kg/day of Vitamin E during stress test.
Group IV (Late Prophylaxis Group): put on 100 mg/kg/day of Ginkgo Biloba Extract during stress test.
Group V (Early Prophylaxis Group): given 100 mg/kg/day of Vitamin E for five days before and during stress test.
Group VI (Early Prophylaxis Group): given 100 mg/kg/day Ginkgo Biloba Extract for five days before and during stress test.
Results: No ulcer was observed in the control group. In the placebo group, mean ulcer area was 11.75 ± 4.33 mm2 while it was 4.10 ± 3.21 mm2, 2.06 ± 2.81 mm2, 6.84 ± 4.23 mm2 and 5.50 ± 3.40 mm2 in groups III, V, IV, and VI respectively. Mean ulcer areas were significantly smaller in rats given either vitamin E or Ginkgo biloba extract than that of the placebo group (p<0.05). This area in the group on early prophylactic vitamin E was smaller than both groups put on late prophylactic vitamin E or early prophylactic Ginkgo biloba extract (p<0.05). Such a difference did not exist between the groups receiving early or late prophylactic Ginkgo biloba extract, nor in the groups given either vitamin E or Ginkgo biloba extract as late prophylaxis (p>0.05). Conclusions: The protective effects of Vitamin E and Ginkgo biloba extract administration during stress were comparable. However, vitamin E given before stress was more protective than Ginkgo biloba extract. Though early administration of Vitamin E prior to stress was more effective than its late administration, such a difference was not observed with Ginkgo biloba extract.
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    • Introduction
    Cytoprotective drugs mechanism of action depends mainly on the free radical scavenger effect and/or membrane protection. Natural antioxidants such as vitamins A, C and E have been successfully employed in the treatment of gastric - duodenal ulcer and gastric malignancy and a synthetic antioxidant, 5-aminosalisilik acid, has also proved effective in the treatment of chronic inflammatory bowel disease (1). Free radicals may play a role in the pathogenesis of some stress ulcers and it has been demonstrated that vitamin E has a protective effect against gastric mucosal injury induced by ischemia, reperfusion, radiation, indomethacin, aspirin or ethanol and that stress might cause a decrease in vitamin E contents of some tissues (2-5). It has also been demonstrated that the infusion of a picomole platelet activating factor (PAF) facilitates ethanol induced gastric mucosal injury (6). CV - 6209 , a specific PAF receptor antagonist, has a protective effect against ischemia - reperfusion induced gastric mucosal lesions by decreasing the production of superoxide from neutrophils (7).

    In this study, the protective effects of vitamin E and Ginkgo Biloba Extract (GBE), a free radical scavenger and a PAF receptor antagonist, against experimentally induced gastric mucosal lesions were in rats was investigated.

    Figure 1: . Schematic apprearance of the study
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  • Materials And Methods
  • Results
  • Discussion
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    • Materials And Methods
    Seventy-two male and female Swiss - albino rats, weighing between 180 g and 220 g, provided by Erciyes University Experimental and Clinical Research Center for Health Sciences, were divided into six groups. There was no difference in sex and weight among groups. A standard fasting-immobilization stress test (8) was conducted on all groups, except for the control group for 24 hours. Stress was induced by immobilization (tied by four legs into supine position) and the rats were starved for 24 hours (and denied water for the last 12 hours (Figure 1) before being killed. Groups were then formed as follows:

    Group I (Control group): not exposed to any stress.

    Group II (Placebo Group): stress induced by fasting and immobilization, as described above, and oral normal saline was given q.i.d. through an orogastric gavage needle as placebo. Orogastric administration was carried out according to the literature using a 15G curved and blunt-ended specific needle cannula (9)

    Group III (Late prophylaxis group): administered 100 mg/kg. vitamin E i.m (Euphynal‚ Amp. Roche) once, at the beginning of the stress test.

    Group IV (Late prophylaxis group): put on 100 mg/kg/day oral GBE (Tebokan‚ gutt. Abdi ibrahim) which was given q.i.d. through an orogastric gavage needle during the stress test.

    Group V (Early prophylaxis Group): administered 100 mg/kg/day. Vitamin E i.m for five days, before and during the stress test.

    Group VI (Early Prophylaxis Group): put on 100 mg/kg/day oral GBE which was given q.i.d. through an orogastric gavage needle for five days before and during the stress test.

    All rats were killed by decapitation after ether anesthesia. Their stomachs were dissected along the greater curvature and gastric mucosae were carefully examined macroscopically and microscopically. The total area of gross hemorrhagic necroses and/or erosions were measured planimetrically. The stomachs were resected and opened by the greater curvature. Eroded gastric mucosal areas were measured using a transparent sheet with one millimeter square scale and a stereo dissection microscope. All the stomachs were also examined histopathologically.

    Data were expressed as means ± SEM. Mann - Whitney U test was performed for statistical analyses. A p value < 0.05 was regarded as significant.

    Table 1: The effect of the late prophylactic and early prophylactic drug administration on total ulcer area.
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    • Results
    No gastric mucosal injury was observed in the control group. Severe gastric mucosal injury was detected in all rats of Group II, six of whom had macroscopical bleeding. In this group, mean ulcer area (MUA) was 11.75 ± 4.33 mm2. In groups III and V; MUAs were 4.10 ± 3.21 mm2 and 2.06 ± 2.81 mm2 respectively. In groups IV and VI; MUAs were 6.84 ± 4.23 mm2 and 5.50 ± 3.40 mm2 respectively.

    Mean ulcer areas measured in all groups given either vitamin E or GBE were significantly smaller than that of the placebo group (p < 0,05). In the group receiving early prophylactic vitamin E, this area was smaller than the group put on early prophylactic GBE (p < 0,05). Such a difference did not exist between the groups given either vitamin E or GBE for late prophylaxis (p > 0,05).

    Macroscopical bleeding was observed in none of the rats receiving vitamin E. Also, MUA was smaller in the group on early prophylactic vitamin E than the group on late prophylactic vitamin E (p < 0,05). Such a difference did not exist between the groups receiving early or late prophylactic GBE (p > 0,05). Macroscopical bleeding was found in two of the rats given early prophylactic GBE and in four of the rats given late prophylactic GBE (Table 1).

    Neutrophilic inflammatory infiltration,edema, congestion and hemorrhage were found on areas of mucosal erosion or ulceration by histopathological examination of samples from these areas.

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  • Summary
  • Introduction
  • Materials And Methods
  • Results
  • Discussion
  • References
    • Discussion
    It is thought that free oxygen radicals and lipid peroxidation play a role in the pathogenesis of gastric mucosal injury induced ischemia, by destruction of endothelial and epithelial cell components. Some investigators suggest that superoxide and active O2 particles lead to contractions in vascular smooth muscles by either a direct effect or interaction with nitric oxide. Ischemia, induced by these contractions, leads to gastroduodenal necrosis and injury. In severe ischemia, xanthine dehydrogenase turns into xanthine oxidase, which is the first documented biological source of superoxide radicals and is considered to be an important source of oxygen radicals (10).

    Free radical scavengers have a protective effect against gastroduodenal injury. Cochran et al. showed that as a potent scavenger, dimethyl sulphoxide has a strong protective effect on experimentally induced gastric mucosal injury in rats (11). It was demonstrated that, depending on their doses, administration of antioxidant enzymes such as catalase and superoxide dismutase to rats might produce a significant remission of ethanol induced gastric mucosal lesions (12). On the other hand, a decrease in tissue vitamin E content, resulting from consumption of vitamin E during the oxidative stress, may lead to mucosal lesions easily. It has been shown that vitamin E has an antioxidant protective effect on gastric mucosa (13).

    In this study, the total area of mucosal lesions was significantly lower in the groups put on both early or late vitamin E prophylaxis compared with placebo group (p < 0.05). The total ulcer area was smaller in rats receiving early prophylactic vitamin E compared to that of rats receiving late prophylactic vitamin E (p<0.05). Zaror-Behrens et al. found that vitamin E contents of gastroduodenal mucosae and liver decreased significantly in rats put on a vitamin E restricted diet for 10 months, whereas vitamin E levels in liver, gastric fundus, antrum and duodenal mucosa increased in the rats put on a vitamin E rich diet for same period (14); this better gastroprotective effect in the early prophylactic group may therefore be due to the accumulation of vitamin E in gastric tissue.

    In recent years, it has been shown that platelet - activating factor (PAF) levels increase during ischemia-reperfusion, and that induction of superoxide generation by neutrophils is one of the important effects of PAF (15). CV-6209, a specific PAF receptor antagonist, significantly attenuates gastric mucosal injury and inhibits both the increase of thiobarbituric acid reactive substances and the decrease of alpha tocopherol in gastric mucosal blood flow during ischemia - reperfusion (6,7). In our study, the total ulcer area was smaller in both groups receiving early or late prophylactic GBE, another PAF receptor antagonist, than that of the placebo group. However, there was no significant difference in total ulcer areas between these groups. This observation suggests that the effect of GBE on PAF inhibition is temporary and that it is not accumulated in gastric mucosa, as with vitamin E.

    In conclusion, our findings suggest that both vitamin E and GBE, given before or during stress, have a protective effect against stress induced gastric mucosal injury. Vitamin E given prior to stress induction leads to a more significant level of protection than GBE.

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  • Summary
  • Introduction
  • Materials And Methods
  • Results
  • Discussion
  • References
    • References

    1) Feher J, Pronai L. The role of free radical scavengers in gastrointestinal diseases (abstract). Orv Hetil 1993; 134: 693-6.

    2) Yoshiwa A, Yasuda K, Veda S, et al. Vitamin E in gastric mucosal injury induced by ischemia - reperfusion. Am J Clin Nutr 1991; 53: 2105 - 45.

    3) Zaror-Behrens G, Greselin E, Madere R, Behrens WA. Vitamin E levels in gastric mucosa and indomethacin - induced gastric lesions in rats. Res Commun Chem Pathol Pharmacol 1992; 75: 185 - 92.

    4) Empey LR, Papp JD, Jewell LD. Mucosal protective effects of vitamin E and misoprostal during acute radiation - induced enteritis in rats. Dig Dis Sci 1992; 37: 205-14.

    5) Hollander D, Tarnawskı A, Krause WJ, Gergely H. Protective effect of sucralfate against alcohol-induced gastric mucosal injury in the rat. Gastroenterology 1985; 88: 366-74.

    6) Wallace JL, Whittle BJR. Picomole doses of platelet activating factor predispose gastric mucosa to damage by topical irritants. Prostaglandins 1986; 31: 989.

    7) Yoshikawa T, Takahashi S, Naito Y, et al. Effects of platelet-activating factor antagonist, CV-6209, on gastric mucosal lesions induced by ischemia-reperfusion. Lipids 1992; 27: 1058 - 60.

    8) Yücesoy M, Patıroğlu TE, Özesmi Ç, Gönen Ö. Testosteron propionat ve ketotifenin stres ülseri oluşumuna ve gastrik mukozal mast hücresi degranülasyonuna etkileri. Erciyes Tıp Dergisi 1986; 8: 161-9.

    9) Waynforth HB, Flecknel PA. Administration of substances. in Experimental and Surgical Technique In The Rat. (2.nd ed.) Harcourt Brace Company, London 1992 A pp: 27-32.

    10) Salim AS, Sulphydryl - containing agents: a new approach to the problem of refractory peptic ulceration. Pharmacology 1992; 45: 301-6.

    11) Cochran TA, Stefanko J, Moore C, Saik RP. Cytotoxic free radicals in stress ulceration. Surg Forum 1983; 33: 159-61.

    12) Szabo S. Gastroduodenal mucosal injury - acute and chronic; pathways, mediators and mechanisms. J Clin Gastro-enterol 1931; 13: 1-8.

    13) Kurose I, Fukumura D, Miura S. Fluorographic study on the oxidative stress in the process of gastric mucosal injury attenuating effect of vitamin E. J Gastroenterol Hepatol 1993; 8: 254-8.

    14) Zaror - Behrens G, Behrens WA. Repletion and depletion of vitamin E in gastroduodenal mucosa. Scand J Gastroenterol 1991; 26: 839-42.

    15) Chatterjee SS, Gabard B. Protection of doxorubicin toxicity by an extract of ginkgo biloba. Pharmacol 1982; 319:12-15.

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  • Introduction
  • Materials And Methods
  • Results
  • Discussion
  • References
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