Yonago Acta medica 2011;54:11–19

Protective Effects of Ginger against Aspirin-Induced
Gastric Ulcers in Rats
Zhongzhi Wang, Junichi Hasegawa, Xinhui Wang, Akiko Matsuda, Takahiro Tokuda,
Norimasa Miura and Tatsuo Watanabe*
Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science,and *Division of Integrative Physiology, Department of Functional, Morphological and Regulatory
Science, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan

We investigated the mechanism underlying the protective effects of ginger against gastricdamage induced by aspirin in rats. Gastric mucosal lesions were produced by orally administering 200 mg/kg aspirin suspended in 1% carboxymethylcellulose solution to pyloric-ligated male Wistar rats. Ginger powder (200 mg/kg) markedly reduced the aspirininduced gastric hemorrhagic ulcer area. The total acidity of gastric juice was not significantly influenced by aspirin or ginger. Ginger powder did not affect the aspirin-induced
reduction in mucosal prostaglandin E2 (PGE2) content; however, it did ameliorate theaspirin-induced increases in mucosal activity of the inducible form of NO synthase (iNOS)
and plasma tumor necrosis factor (TNF)- and interleukin (IL)-1 levels. In the next experiment, high and low doses of 6-gingerol and 6-shogaol were used instead of ginger powder in the same experimental model to examine their roles in the anti-ulcer mechanism ofginger. Both 6-gingerol and 6-shogaol reduced aspirin induced ulcer formation, mucosal
iNOS and plasma TNF- and IL-1 levels. In conclusion, ginger powder prevents the aspirin induced gastric ulcer formation by reducing mucosal iNOS activity and the plasma
levels of inflammatory cytokines but does not affect gastric juice or acid production or mucosal PGE2 content. This protective effect of ginger powder against gastric ulcers may be
attributable to both gingerol and shogaol.
Key words: aspirin; gastric damage; ginger powder; inflammatory cytokine; inducible form of NO
synthase activity
Aspirin is a potent nonsteroidal anti-inflammatory
drug (NSAID) that is used for the treatment ofrheumatoid arthritis and related diseases as well as
the prevention of cardiovascular thrombotic diseases. Gastric ulcer associated with the use of aspirin
is a major problem. Many factors such as gastricacid and pepsin secretion, gastric microcirculation, prostaglandin E2 (PGE2) content (Laine et al.,2008), and proinflammatory cytokines interleukin(IL)-1 and tumor necrosis factor (TNF)- (Santucci

et al., 1995; Appleyard et al., 1996) play importantroles in the genesis of gastric mucosal damage,and its subsequent development (Wang et al., 2007;
Wallace, 2008). It has been reported that increases
in NO synthase (NOS) activity is involved in thegastrointestinal mucosal defense and also in thepathogenesis of mucosal damage (Muskara et al.,
1999; Wallace et al., 2000).
Ginger (Zingiber officinale) has been used
as a spice and an ingredient of Chinese traditional

Abbreviations: IL, interleukin; iNOS, inducible form of NOS; LPS, lipopolysaccharide; NIH, National Institute of Health;
NOS, NO synthase; NSAID, nonsteroidal anti-inflammatory drug; PGE2, prostaglandin E2; TNF, tumor necrosis factor

11

Z. Wang et al.

received aspirin (200 mg/kg body weight) suspended in 3 mL of 1% carboxymethylcellulose in water.
Group 4 orally received aspirin together with ginger powder suspended in 3 mL of 1% carboxymethylcellulose in water. At 4 h after the test drug
administration, the animals were anesthetized, andthen blood was collected from the heart, and thestomach was removed after the esophageal end had
been tied (Jainu and Devi, 2006; Jainu et al., 2006).
The stomach was cut open along the greater curvature, and the contents were collected in tubes andcentrifuged at 200 × g for 10 min. The resultant
supernatant was used for the estimation of acid andgastric juice output. The stomach was then washedwith warm saline, and the inner surface was photographed to allow the measurement of the area covered by hemorrhagic ulceration. Next, the gastricmucosal tissues were removed, frozen in liquid nitrogen and stored at –80˚C. The total acid content
of the gastric juice was determined by titrating itwith 0.01 N NaOH, using phenolphthalein as indicator, and was expressed as mEq/4 h/100 g (Jainu
et al., 2006; Wang et al., 2007). The acidity of gastric juice was calculated as total acid content/gastricjuice volume in mEq/mL (Khushtar et al., 2009).
In animal experiments using 6-gingerol and6-shogaol, the same procedures as were used in
the first experiment to produce the pylorus ligatedrats were repeated using high dose (2 mg/kg) andlow dose (1 mg/kg) 6-gingerol, and high dose (1mg/kg) and low dose (0.5 mg/kg) 6-shogaol, instead of ginger powder suspended in 3 mL of 1%
carboxymethylcellulose in water. The doses of
6-gingerol and 6-shogaol used in the experimentwere determined by those found in normal ginger(Schwertner and Rios, 2007).

stomach medicine for thousands of years. In traditional medicine, ginger has been used to treat
many inflammatory conditions and associated pain
(Altman and Marcussen, 2001). The major pungent
constituents of ginger, 6-gingerol and 6-shogaol,
have been shown to have many interesting pharmacological effects, such as anti-oxidant, antitumor promoting and anti-inflammatory effects(Surh, 2002; Kim et al., 2005; Young et al., 2005).
However, the mechanism underlying the protective
effects of ginger against gastric damage is unclear.
Here, we investigated the antiulcer effects of ginger
in aspirin-induced gastric ulcer model rats.

Materials and Methods
Animal experiment using ginger powder
The experimental protocol was approved by the
ethics committee on animal experiments in Tottori
University, and the experiments were carried out inaccordance with the guidelines for animal experiments in the same facility.
Male Wistar rats at 8 weeks of age (weighing 300–350 g) were purchased from Shimizu
Laboratory Supplies (Kyoto, Japan). They wereacclimated in an air-conditioned room at 25˚C and
55% humidity and given standard chaw for a few
days. Before surgery, the rats were fasted for 24 h
and allowed free access to drinking water. Then,the animals were anesthetized using pentobarbital (30 mg/kg body weight, intraperitoneally), theabdomen was opened, and the pyloric end of stomach was ligated without causing any damage to its
blood supply. The stomach was then replaced, andthe abdominal wall was closed in two layers withsutures.
After they had fully recovered from the anesthesia, the animals were divided into 4 groups offive animals each. Group 1 orally received 3 mL
of 1% carboxymethylcellulose in water (vehicle)
by gavage. Group 2 orally received ginger powder(200 mg/kg body weight) suspended in 3 mL of 1%
carboxymethylcellulose in water. Group 3 orally

Quantification of the gastric hemorrhagic
ulcer area using NIH image
The photographs of the stomach were digitized andconverted to binary images through gray scale imaging (Khan, 2004). Using the National Instituteof Health (NIH) image-J software, the area of gastric hemorrhagic ulcers (mm2) was calculated.
12

Protection against gastric ulcers by ginger

Histological studies

Reagents

Gastric tissue samples from each group were fixedin 10% formalin for 24 h. The specimens werethen embedded in paraffin, sectioned and stainedwith hematoxylin and eosin, before being evaluatedby light microscopy.

Aspirin was purchased from Sigma Chemical (St.
Louis, MO). Carboxymethylcellulose sodium salt,
6-gingerol and 6-shogaol were purchased from
Wako Pure Chemical Industries (Osaka, Japan).
The ginger powder was a generous gift from Yawata Bussan (Yonago, Japan). It has been confirmed that 100 g of ginger powder contains 0.68 gof 6-gingerol (Japan Food Research Laboratories,
Tokyo, Japan).

Measurement of mucosal PGE2
Frozen gastric mucosal tissue (1 g) was added to 5
mL homogenization buffer (0.1 M phosphate (pH7.4), containing 1 mM EDTA and 10 μM indomethacin) and homogenized. The lysate was thencentrifuged in a microcentrifuge at 16,000 × g for
15 min at 2˚C to 8˚C. The supernatant was transferred to a new tube, and its total protein content
was analyzed using the advanced protein assay.
PGE2 concentrations were investigated using the
PGE2 ELISA Kit (R&D Systems, Minneapolis,
MN).

Statistical analysis
All values are expressed as the mean ± SEM. All
results were analysed by one way analysis of variance followed by the proper post-hoc test by SPSS
11.0 J (SPSS Japan, Tokyo). P < 0.05 was considered statistically significant.
Results
Aspirin-induced gastric hemorrhagic ulcer
formation

Measurement of iNOS activity
Individual specimens of the gastric mucosa were
homogenized in sample buffer containing 10 mM
EDTA and centrifuged at 13,000 × g at 4˚C for 5
min. The supernatant was transferred to a newtube and had a total protein content of 10 μg/μL.
Gastric mucosal iNOS activity was measured with
the NOS-detect assay kit (Agilent Technologies,
Santa Clara, CA).

The macroscopic findings of the opened stomach
are shown in Fig. 1a. Hemorrhagic gastric ulcers
covered with coagulated blood were more apparent
in the aspirin administered group (Aspirin, Group3) than the control (Control, Group 1). Ginger
powder alone (Ginger, Group 2) had no effects on
the stomach, and the coadministration of ginger
powder with aspirin inhibited aspirin-induced ulcer
formation (Aspirin + Ginger, Group 4). Figure 1b
shows the mean area of gastric hemorrhagic ulcers
in each group. Even in the control conditions, pinpoint ulcers were sometimes seen. Aspirin-induced
ulcer formation was completely inhibited by the
coadministration of ginger powder (P < 0.01).

Determination of plasma TNF- and IL-1
levelsBlood samples in EDTA-containing vials were centrifuged at 1000 × g for 10 min at 4˚C. The levelsof IL-1 and TNF- were determined by ELISA
according to the manufacturer’s instructions (Assay
Designs, Ann Arbor, MI; Bender MedSystems, San
Diego, CA).

Histopathological findings of gastric mucosa
The histopathological findings of the gastric mucosa are shown in Fig. 2. The gastric mucosa
obtained from the control (Group 1) rats showed13

Z. Wang et al.

aControl

GingerAspirin

Aspirin + Ginger

Fig. 1. Effects of ginger powder against aspirin-induced
gastric ulcers in rats.
a: Photographs of the gastric mucosa in the control
group and the ginger, aspirin and aspirin with ginger
treatment groups are shown.
b: The hemorrhagic ulcer area (cm2) measured in eachcondition. In this and the following figures, values
are shown as the mean ± SEM. **P < 0.01 compared with the control rats. ##P < 0.01 comparedwith the aspirin-treated rats.

an intact cellular architecture (not shown). Ulcers
combined with distorted gastric glands, a damaged mucosal epithelium, inflammatory exudates
and cellular debris were found in the stomachsof the aspirin-treated rats (Fig. 2a, Aspirin). The
protection against these histopathological changes
induced by the coadministration of ginger powder

to rats resulted in the maintenance of glandularorganization and the structure of the muscularis
mucosa (Fig. 2b, Aspirin + Ginger). The histological examination of the ginger powder alone-treatedrats showed a normal cellular architecture in thegastric mucosa with no pathological changes (notshown).

ab

Aspirin

Aspirin + Ginger

Fig. 2. Histological examinations of gastric mucosal tissue. Ulcer formation with distorted gastric glands, a damaged
mucosal epithelium and cell debris are shown in a (Aspirin); however, the coadministration of ginger with aspirin protected against these changes, as shown in b (Aspirin + Ginger) (hematoxylin and eosin stain). Bar = 500 µm.

14Protection against gastric ulcers by ginger

Table 1. Effects of ginger powder on gastricmucosal factors in experimental gastric ulcer
model rats

Gastric juice and acid production
Both ginger and aspirin reduced gastric juice production /100 g body weight. However this effects
disappeared by coadministration of ginger and aspirin. The total acidity showed no significant differences among these conditions (Table 1).

Group

Parameter
Volume of gastric juice
Acidity(mL/100 g)(mEq/mL)

Control
GingerAspirin
Aspirin + Ginger

Mucosal PGE2 levels

6.15 ± 1.3
3.03 ± 0.27*
3.80 ± 0.42*
6.20 ± 0.72#

52.54 ± 11.54
47.85 ± 12.40
46.71 ± 0.37
50.25 ± 7.02

Values are shown as the mean ± SEM.
* P < 0.05 compared with the control rats.
# P < 0.05 compared with the aspirin group.

The gastric mucosal PGE2 contents measured ineach condition are compared in Fig. 3. Aspirin
reduced the mucosal PGE2 content, and the coadministration of ginger powder failed to inhibit theaspirin-induced reduction of PGE2 content.

els between the ginger powder treated Group 2 andGroup 1 (control).

Mucosal iNOS expression

Expression of TNF- and IL-1 in plasma

Aspirin administration led to a significant increasein gastric mucosal iNOS activity in the ulcerated
rats as compared to that measured in the control orginger administered rats (Fig. 4). The coadministration of ginger powder resulted in a significant
decrease in gastric mucosal iNOS activity compared with that observed in the aspirin alone group(P < 0.05). No differences were seen in iNOS lev-

The plasma concentrations of TNF- and IL-1 inthe rats are shown in Fig. 5. The concentrationsof TNF- and IL-1 were significantly increased
after the administration of aspirin compared withthose seen in the control rats (Aspirin, Figs. 5a andb). Ginger powder attenuated these increases in theplasma levels of TNF- and IL-1 , even after thecoadministration of aspirin in rats (Ginger + Aspirin, Figs. 5a and b).

Fig. 3. Effects of ginger powder on the PGE2 level of thegastric mucosal tissue. Aspirin administration reduced
the PGE2 level, and the coadministration of ginger powder(200 mg/kg) for 4 h failed to inhibit the reduction in the
PEG2 level. **P < 0.01. NS, not significant; PGE2, prostaglandin E2 (pg/mL).

Fig. 4. Effects of ginger powder in iNOS activity in thegastric mucosa. The coadministration of ginger powder(200 mg/kg) inhibited the increase in iNOS activity induced by aspirin alone. **P < 0.01 compared with thecontrol rats. #P < 0.05 compared with the aspirin-treatedrats. iNOS, inducible form of NO synthase (dpm/10 mg).

15

Z. Wang et al.

Fig. 6. Effects of 6-gingerol and 6-shogaol on the gastricmucosal lesion formation induced by aspirin in rats. Both
6-gingerol and 6-shogaol inhibited the gastric ulcer formation induced by aspirin. The animals were treated alone with
2 mg/kg 6-gingerol (Gingerol), 1 mg/kg 6-shogaol (Shogaol),
200 mg/kg aspirin (Aspirin); and treated combinedly
with Aspirin and 1 mg/kg 6-gingerol ( lowG), 2 mg/kg
6-gingerol (highG), 0.5 mg/kg 6-shogaol (lowS), 1 mg/kg
6-shogaol (highS). **P < 0.01 compared with the control.
#P < 0.05 compared with the aspirin-induced rats.

Fig. 5. Effects of ginger powder on the plasma levels of
TNF- and IL-1 . The aspirin-administered rats showedmarked increases in their plasma TNF- and IL-1 levels.
The coadministration of ginger powder completely inhibited these marked increases in TNF- (a) and IL-1 (b)levels. *P < 0.05, **P < 0.01compared with the control
rats. #P < 0.05, ##P < 0.01 compared with the aspirin
administered rats. TNF- , tumor necrosis factor- ; IL-1 ,interleukin-1 .

Effects of 6-gingerol and 6-shogaol in thepresence of aspirin

ulcer model rats. Aspirin has been reported to reduce the gastric juice pH and increase the volume
of gastric juice (Wang et al., 2007), or decrease thevolume of gastric juice and its acid output (Jainu
et al., 2006). In the present study, the volume ofgastric juice and acid output/100 g body weight for
4 h reduced by aspirin and recovered by the coadministration of ginger with aspirin. The acidity ofgastric juice was not significantly changed by any
treatments. Our results suggest that the changes
in the volume of gastric juice and acid production
induced by aspirin are not a major factor in ulcer
formation or the protective effects of ginger powder
seen in these experimental ulcer model rats.
Prostaglandins have protective effects against
various gastric injury models (Wallace, 1992;
Brzozowski et al., 2005). Aspirin has been shown
to reduce the mucosal PGE2 content (Takeuchi etal., 1986; Lichtenberger et al., 2007; Wang et al.,2007). The lack of attenuation of the decrease ingastric mucosal PGE2 content after the coadministration of ginger powder also reveals that the restoration of the PGE2 level in the gastric mucosa is not

High and low doses of 6-gingerol and 6-shogaol,
the major constituents of ginger powder, had no adverse effects on the stomach and inhibited the ulcer
formation induced by aspirin (Fig. 6). 6-Gingerol
and 6-shogaol exerted inhibitory effects on the aspirin induced increases in mucosal iNOS activity(Fig. 7) and plasma TNF- and IL-1 levels (Fig. 8)
in the same manner as ginger powder.

Discussion
Ginger has been used as an ingredient of Chinese
traditional stomach medicines for thousands ofyears. The anti-ulcerative effects of ginger havepreviously been investigated in experimental gastric ulcer models (Yamaha et al., 1988; al-Yahva
et al., 1989; Khushtar et al., 2009). However, themechanism underlying the protective effects ofginger against gastric damage is unclear. In thepresent study, the anti-ulcerative effects of ginger
powder were investigated in aspirin-induced gastric16

Protection against gastric ulcers by ginger

Fig. 7. Effects of 6-gingerol and 6-shogaol on iNOS activity in the gastric mucosa. The effects of aspirin on theiNOS activity in the gastric mucosa were compared in theabsence and the presence of high and low doses of 6-gingerol or 6-shogaol. **P < 0.01, compared with the control
rats. #P < 0.05, ##P < 0.01 compared with the aspirintreated rats. iNOS, inducible form of NO synthase. The
definition of groups, refer to the legends for Fig. 6.

Fig. 8. Effects of 6-gingerol and 6-shogaol on the plasma
levels of TNF- and IL-1 . The effects of high and low
doses of 6-gingerol or 6-shogaol were examined during
their coadministration with aspirin. The increases inplasma TNF- (a) and IL-1 (b) levels induced by aspirin
were reduced by the coadministration of these constituents. **P < 0.01 compared with the control. #P < 0.05,##P < 0.01 compared with the aspirin-treated rats. The
definition of groups, refer to the legends for Fig. 6.

the mechanism underlying the protective effects ofginger powder in this aspirin induced ulcer model.
This is not unexpected because the reduction of thegastric mucosal PGE2 concentration induced by aspirin does not necessarily participate in gastric ulcer generation (Takeuchi et al., 1986; Lichtenberger
et al., 2007).
One of the mechanisms by which aspirin
damages the gastric mucosa is the increased production of NO due to the overexpression of iNOS(Kontureck et al., 2006). NO is a mediator not
only of gastrointestinal mucosal defense (Calatayud
et al., 2001), but also of its damage (Muscara andWallace, 1999). It has been shown that different
concentrations of NO have completely opposite effects in the same tissue (Wallace and Millor, 2000).
In general, the mucosal and endothelial NOS isoforms produce low amounts of NO. However, thehigh quantity of NO produced by iNOS damages
the epithelium (Piotrowski et al., 1999; Wallace
and Miller, 2000). The excessive release of NO
from gastric epithelial cells induced by aspirin has
been reported to exert detrimental effects (Whittle,
2003; Hsu and Liu, 2004). Inhibiting aspirininduced increases in iNOS expression in the gastricmucosa leads to a reduction in gastric mucosal
damage (Konturec et al., 2006). In the present
study, ginger powder reduced iNOS activity and inhibited the production of gastric ulcers, even in thepresence of aspirin.
Inflammation and neutrophil infiltration are
also important in the pathogenesis of the gastricdamage induced by NSAIDs (Wallace et al., 1990;
Lee et al., 1992; Trevethick et al., 1993; Souza etal., 2004). The inflammation induced in the gastricmucosa by aspirin is accompanied by increased
TNF- production (Naito et al., 2001; Jainu andDevi, 2006), which augments neutrophil-derived
superoxide generation (Kwiecieñ et al., 2002) andstimulates IL-1 production, leading to neutrophil
accumulation (Kokura et al., 2000; Odashima etal., 2006). In the present study, the levels of TNFand IL-1 were increased by aspirin administration, and the coadministration of ginger powder
inhibited the increases in TNF- and IL-1 without
ulcer formation progressing. These effects re17

Z. Wang et al.

induced by aspirin by reducing iNOS activity in thegastric mucosa and inflammatory cytokine (TNFand IL-1 ) expression. These effects of ginger
powder seem to be derived from the actions of gingerol and shogaol, the main ingredients of ginger.

sembled those induced by pretreatment with Cissus
quadrangularis extract for 7 days (Jainu and Devi,
2006).
Then, the anti-inflammatory effects of themain constituents of ginger were examined using
the same experimental protocol. In the previous study, 6-gingerol, 6-shogaol, 8-gingerol and
10-gingerol have been identified as the principal
components of ginger powder (Chen et al., 1986).
6-Shogaol, a dehydration product of 6-gingerol,
is found in ginger powder but not in fresh ginger
powder. 6-Shogaol appears to be formed from
6-gingerol during thermal processing and longterm storage (Chen et al., 1986). In general, theability of compounds was related to both the lengthof the side chain and to the parent compound (gingerol versus shogaol). According to the relatively
similar potency for several effects, their contribution on the effects of ginger may depends on theiramounts. Therefore, several studies have focusedon the effects of major components, 6-gingerol
and 6-shogaol. The anti-inflammatory effects of
6-gingerol have been examined in the acetic acidinduced writhing response in mice and carrageenan-induced rat paw edema model (Young et al.,2005). Lipopolysaccharide (LPS) induced PGE2
production was inhibited by treatment with either
gingerol or shogaol (Lantz et al., 2007). Shogaol
has been reported to markedly inhibit the LPSinduced expression of iNOS and COX-2 (Pan et al.,2008) and to have no effect on COX-2 expression(Lantz et al., 2007), whereas gingerol was foundto inhibit LPS-induced COX-2 expression (Lantz
et al., 2007). Both gingerol and shogaol have beenshown to inhibit TNF- mediated actions at thecellular level (Lantz et al., 2007; Isa et al., 2008).
In the present study, both constituents of ginger
showed protective effects against aspirin-induced
gastric ulcers together with anti-inflammatory effects. We failed to show the dose dependency on
the anti-inflammatory effects of these constituents;
however, the rather high concentrations of thesecompounds used may explain this result.
From these results, ginger powder is suggested
to protect the stomach against the ulcer formation

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Received December 20, 2010; accepted December 28, 2010
Corresponding author: Junichi Hasegawa, MD, PhD

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