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. 2022 Aug 31;27(17):5598.
doi: 10.3390/molecules27175598.

Therapeutic Versus Preventative Use of Ginkgo biloba Extract (EGb 761) against Indomethacin-Induced Gastric Ulcer in Mice

Ahmed M Abd-Eldayem  1 , Sulaiman Mohammed Alnasser  2 , Hanan H Abd-Elhafeez  3 , Soha A Soliman  4 , Rania A Abdel-Emam  1
Affiliations

Therapeutic Versus Preventative Use of Ginkgo biloba Extract (EGb 761) against Indomethacin-Induced Gastric Ulcer in Mice

Ahmed M Abd-Eldayem et al. Molecules. .

Abstract

The main bioactive constituents in the standardized Ginkgo biloba leaf extract (EGb 761) are the terpene lactones and flavonoid glycosides. EGb 761's antioxidant and anti-inflammatory properties have previously been demonstrated. Indomethacin-induced gastric ulcers have a multifactorial etiology and represent a major restriction to its therapeutic utility. The underlying ulcerogenic process involves oxidative and inflammatory biomolecular insults. This study was performed to explore the curative and preventative benefits of EGb 761 in experimentally-induced ulcers. To develop gastric ulcers in mice, indomethacin (40 mg/kg) was administered orally. EGb 761 (200 mg/kg) was given by gavage for 7 days before (preventative) and after (therapeutic) indomethacin administration. The histological alterations and macroscopic mucosal lesions were assessed. In gastric tissue homogenates, malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), and inflammatory cytokines were measured. The expressions of cyclooxygenase-2 (COX-2), cytokines, and proliferating cell nuclear antigen (PCNA) in the stomach mucosa were also investigated. The ulcer index, histological alterations, gastric oxidants, and inflammatory biomarkers were all significantly increased by indomethacin. In stomach specimens, it increased COX-2 and PCNA expression. EGb 761 treatments, both prophylactic and therapeutic, resulted in significant reductions in ulcer lesions, nitrosative and oxidative damage, and inflammatory markers, along with the lowering of COX-2 and PCNA expressions. Furthermore, in the fight against stomach ulcers, EGb 761 treatment was found to be more efficient than prevention.

Keywords: EGb 761; indomethacin; mice; preventative; therapeutic; ulcer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The effects of IND and EGb 761 on the gastric mucosa (macroscopic pictures and damage score). Results are represented as mean ± SEM (n = 6). (A) Control, (B) IND-induced ulcer, (C) EGb 761 pre-treatment, (D) EGb 761 treatment, (E) ulcer index scores. **** (p < 0.0001) significantly different from control. ϕϕϕϕ (p < 0.0001) significantly different from the ulcer group. ΔΔ (p < 0.01) significantly different from EGb 761+IND (Prophylactic EGb 761) group. IND: Indomethacin; EGb 761: Standardized G. biloba extract.
Figure 2
Figure 2
Changes were obtained by the administration of IND and EGb 761 on the gastric MDA tissue levels (A), GSH (B), and NO (C). Data are presented as mean ± SEM (n = 6). *** (p < 0.001) and **** (p < 0.0001) significantly different from control. ϕ (p < 0.05), ϕϕ (p < 0.01), ϕϕϕ (p < 0.001), and ϕϕϕϕ (p < 0.0001) significantly different from IND group. Δ (p < 0.05) and ΔΔ (p < 0.01) significantly different from EGb 761+ IND (Prophylactic EGb 761) group. IND: Indomethacin; EGb 761: Standardized G. biloba extract.
Figure 3
Figure 3
The effects of administration of indomethacin and EGb 761 on the gastric tissue levels of TNF-α (A) and IL-6 (B). Data are presented as mean ± SEM (n = 6). **** (p < 0.0001) significantly different from control. ϕϕ (p < 0.01) and ϕϕϕ (p < 0.001) significantly different from the IND group. Δ (p < 0.05) and ΔΔ (p < 0.01) significantly different from EGb 761 + IND (Prophylactic EGb 761) group. IND: Indomethacin; EGb 761: Standardized G. biloba extract.
Figure 4
Figure 4
Gastric mucosal representative micrographs stained by hematoxylin and eosin. Effect of EGb 761 administration on the indomethacin-induced gastric ulcer. (A,B): Normal gastric mucosa in control mice. (C,D): Indomethacin-induced gastric ulceration (m) (IND). (E,F): EGb 761-pre-treated mice (Prophylactic EGb 761). (G,H): EGb 761 treatment after indomethacin (Therapeutic EGb 761). IND: Indomethacin; EGb 761: Standardized G. biloba extract.
Figure 5
Figure 5
Photomicrograph immunohistochemistry of gastric mucosal expression of COX-2. (A–D): Control mice. (E–H): Indomethacin-induced ulcer (IND). (I-L): EGb 761 +IND (Prophylactic EGb 761). (M–P): IND+EGb 761 (Therapeutic EGb 761). Negative marker control is shown in the inset of Figure 5A. IND: Indomethacin; EGb 761: Standardized G. biloba extract; COX-2: Cyclooxygenase-2.
Figure 6
Figure 6
Photomicrograph immunohistochemistry of gastric mucosal samples shows the effects of indomethacin and EGb761 on gastric IL-1β expression. (A–D): Control mice. (E–H): Indomethacin-induced ulcer (IND). (I–L): EGb 761 +IND (Prophylactic EGb 761). (M–P): IND+EGb 761 (Therapeutic EGb 761). Negative marker control is shown in the inset of Figure 6M. IND: Indomethacin; EGb 761: Standardized G. biloba extract; IL-1β: Interleukin-1β.
Figure 7
Figure 7
The changes in gastric TNF-α expression during indomethacin and EGb 761 administration were illustrated in photomicrograph immunohistochemistry of gastric mucosal samples. (A): Control mice. (B): Indomethacin-induced ulcer (IND). (C): EGb 761 +IND (Prophylactic EGb 761). (D): IND+EGb 761 (Therapeutic EGb 761). Negative marker control is shown in the inset of Figure 7A. IND: Indomethacin; EGb 761: Standardized G. biloba extract; TNF-α: Tumor necrosis factor-alpha.
Figure 8
Figure 8
Immunohistochemical presentation of gastric tissue samples illustrating the effect of administration of indomethacin and EGb 761 on the expression levels of IL-6. (A–D): Control mice. (E-H): Indomethacin-induced ulcer (IND). (I–L): EGb 761 +IND (Prophylactic EGb 761). (M–P): IND+EGb 761 (Therapeutic EGb 761). Negative marker control is shown in the inset of Figure 8A. IND: Indomethacin; EGb 761: Standardized G. biloba extract; IL-6: Interleukin-6.
Figure 9
Figure 9
Photomicrograph immunohistochemistry of PCNA in the gastric mucosa. (A,B): Control mice. (C,D): Indomethacin-induced ulcer (IND). (E,F): EGb 761 +IND (Prophylactic EGb 761). (G,H): IND+EGb 761 (Therapeutic EGb 761). Negative marker control is shown in the inset of Figure 9G. IND: Indomethacin; EGb 761: Standardized G. biloba extract; PCNA: Proliferating Cell Nuclear Antigen.
Figure 10
Figure 10
Area percentage values with statistical analysis regarding the expression of COX-2 (A), IL-1β (B), TNF-α (C), IL-6 (D), and PCNA (E) on immunohistochemical investigations of gastric mucosa in different groups. COX-2: Cyclooxygenase-2; IL-1β: Interleukin-1beta; TNF-α: Tumor necrosis factor-alpha; IL-6: Interleukin-6; PCNA: Proliferating Cell Nuclear Antigen. A high area percentage of expression values is noticed in the IND group (ulcer group). Prophylactic (EGb 761+IND) and therapeutic EGb 761 (IND+EGb 761) were associated with a dramatically low area percentage of expression. IL-1β, IL-6, and PCNA expressions were lower in therapeutic EGb 761 group when compared to prophylactic EGb 761. a: significant difference from control animals; b: significant difference from ulcer group; c: significant difference from prophylactic EGb 761 group.
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