Therapeutic effect of DA-9601 on chronic reflux gastritis induced by sodium taurocholate in rats

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• BASIC RESEARCH •

Key words: DA-9601; Refl ux gastritis; Erosive gastritis;

Atrophic gastritis; Sodium taurocholate

Oh TY, Shin CY, Sohn YS, Kim DH, Ahn BO, Lee EB, Park

CH. Therapeutic effect of DA-9601 on chronic reflux

gastritis induced by sodium taurocholate in rats. World J

Gastroenterol 2005; 11(47): 7430-7435

http://www.wjgnet.com/1007-9327/11/7430.asp

INTRODUCTION

Refl ux gastritis is a chronic disease in which the duodenal

contents, particularly bile acid, are flown back into the

stomach. It is associated with various symptoms, such

as epigastric pain, dyspepsia, loss of appetite, nausea

or vomiting1,2. While reflux gastritis is an occasional

occurrence, it is primarily found in patients with pyloric

insufficiency or delayed gastric emptying. It can also

be found in patients who have previously undergone

cholecystectomy or gastrectomy3. The refl ux of intestinal

fl uid containing bile juice to the residual stomach has been

considered as a primary pathogenic factor in this type of

gastritis4.

Although a number of treatments, such as improved

gastric emptying, reduction of hydrochloric acid secretion

and bile salt binding are available, a considerable portion

of patients do not achieve the complete mucosal healing

or suffer from sustained symptoms. Some studies have

suggested the possible participation of bile acid in the

development of erosive and atrophic gastritis1,2. Sodium

taurocholate (TCA), a component of bile acid, induces

erosive and atrophic gastritis, and is increasingly utilized in

animal models for the study of bile refl ux gastritis because

of its simplicity and reproducibility5. Chronic exposure of

the gastric mucosa of rats to TCA induces chronic erosive

gastritis characterized by mucosal erosions, infl ammatory

cell infi ltration, decreases in the number of parietal cells

and mucosal thickness, and interstitial fibrosis. These

characterizations are similar to those observed in human

chronic erosive and refl ux gastritis6.

DA-9601 was developed for the treatment of

gastritis7-9. DA-9601 was demonstrated to possess

cytoprotective actions in various experimental models,

including ethanol-induced gastric mucosal damage, and

trinitrobenzene sulfonic acid (TNBS)-induced colitis10.

Recently, DA-9601 has been reported to be effective

in reflux esophagitis11,12. Although the mechanism via

which DA-9601 exerts its mucosal protective effect has

Therapeutic effect of DA-9601 on chronic reflux gastritis

induced by sodium taurocholate in rats

Tae Young Oh, Chang Yell Shin, Yong Sung Sohn, Dong Hwan Kim, Byoung Ok Ahn, Eun Bang Lee,

Cho Hyun Park

Tae Young Oh, Chang Yell Shin, Yong Sung Sohn, Dong

Hwan Kim, Byoung Ok Ahn, Eun Bang Lee, Dong-A

Pharmaceutical Research Institute, Yongin, Korea

Cho Hyun Park, Department of General Surgery, Catholic

University of Medicine, Seoul, Korea

Supported by the grant from Korean Ministry of Health and

Welfare, HMP-98-D-1-0007

Correspondence to: Tae Young Oh, Dong-A Pharmaceutical

Research Institute, 47-5, Sanggal-ri, Kiheung-up, Yongin-shi,

Kyunggi-do 449-905, Korea. solemiooh@donga.co.kr

Telephone: +82-31-280-1389 Fax: +82-31-282-8564

Received: 2005-03-31 Accepted: 2005-08-09

Abstract

AIM: To investigate the therapeutic effects of DA-9601

on sodium taurocholate (TCA)-induced chronic reflux

gastritis in SD rats.

METHODS: In this study, we have investigated the

therapeutic effects of DA-9601 on chronic erosive and

atrophic gastritis induced by 6 mo of TCA administration

(5 mmol/L in drinking water) in SD rats.

RESULTS: Four weeks of DA-9601 administration

(0.065%, 0.216% in rat chow), following the withdrawal

of TCA treatment, resulted in a significant decrease

in total length of erosions in rats in a dose-dependent

manner. Furthermore, the indicators of atrophic gastritis,

such as reduced mucosal thickness and reduction in

the number of parietal cells, were improved by the

administration of DA-9601 in a dose-related manner.

DA-9601 also attenuated inflammatory cell infiltration

and the proliferation of collagenous fi ber in the gastric

mucosa. The improvement in the reduction of the gastric

mucus was observed in the rats receiving a high dose of

DA-9601 (0.216%). The therapeutic effect of DA-9601

on experimental chronic erosive gastritis was superior

to that of rebamipide (1.08% in rat chow). Biochemical

analyses showed increased mucosal prostaglandin E2 and

reduced glutathione levels by DA-9601 treatment.

CONCLUSION: We suggest that DA-9601 is a promising

agent for the treatment of chronic erosive and atrophic

gastritis with an etiological factor of bile refl ux. Increased

mucosal prostaglandin E2 and reduced glutathione by

DA-9601 treatment may be therapeutic mechanisms for

chronic erosive and atrophic gastritis.

Oh TY et al. Therapeutic effect of DA-9601 on chronic refl ux gastritis 7431

not been fully elucidated, stimulation of the mucus,

mucosal prostaglandins (PG), and reduced glutathione

(GSH) are thought to play crucial roles in producing the

gastric mucosal protective effect. The present study was

undertaken to evaluate the effects of DA-9601 on TCAinduced

chronic and atrophic gastritis in rats.

MATERIALS AND METHODS

Animals

Male Sprague-Dawley rats (weighing 210-230 g, aged

7 wk) were purchased from Charles River Japan (Kanagawa,

Japan). Experimental procedures were performed in

conformity with the Institutional Standard Procedure for

Animal Care and Experiment (SOP-ANC) of Dong-A

Pharmaceutical Company. The animals were kept under

standard laboratory conditions and allowed free access to

rodent chow (Cheil, Korea) and UV-sterilized tap water

ad libitum in standard wire cage under a 12:12-h lightdark

(LD) cycle. After a 5 d acclimation period, rats were

treated according to the experimental protocols. Each

group contained 20 rats, of them 10 rats were used for

histological evaluation and the other rats were used for

molecular assay.

Materials

DA-9601 was produced by Dong-A Pharmaceutical Co.

Ltd. (Yongin, Korea). TCA was purchased from Sigma (St.

Louis, USA), and rebamipide was obtained from Korea

Otsuka (Seoul, Korea). DA-9601 (0.065% and 0.0216%)

and rebamipide (1.08%) were mixed with rodent chow and

then administered to the rats.

Sodium taurocholate (TCA)-induced gastritis and

administration of DA-9601

Chronic gastritis was induced in rats by the administration

of 5 mmol/L TCA dissolved in distilled water for

6 mo13,14. After discontinuation of TCA treatment, rats

were allowed to drink plain tap water. To investigate the

effects of the treatment, rats were divided into fi ve groups,

each consisting of 10 rats. In group 1, rats were fed a

standard pellet meal and tap water for 7 mo. In group 2,

rats were treated with TCA for 6 mo and then given the

same standard pellet meals as used in the previous 6 mo

and tap water alone for 1 mo. In groups 3, 4, and 5, rats

were treated with TCA for 6 mo and then fed a standard

pellet meal which was formulated to contain 0.065%,

0.216% of DA-9601 and 1.08% of rebamipide, respectively

for 1 mo. Group 3 (0.065% of DA-9601), group 4 (0.216%

of DA-9601), and group 5 (1.08% of rebamipide) all

received tap water, following discontinuation of TCA

treatment.

Histological evaluation

Rats were fasted for 24 h prior to the experiment and

killed by decapitation under light ether anesthesia. The

abdomen was opened and the stomach was then excised,

opened along the greater curvature, laid fl at so as not to

cause any damage, and examined carefully for any evidence

of macroscopic damage. The fl attened stomach was

divided into fi ve parts, and each part was rolled in a Swiss

manner for observation from the cardiac to the pyloric

region. The Swiss-rolled tissue specimens were fixed in

Bouin’s solution for 6 h at 4 °C, and paraffi n-embedded

blocks were prepared by the routine method. After sectioning,

each specimen was stained with H&E and Masson's

trichrome and examined under a light microscope

(BH-2, Olympus, Japan) by a pathologist who was blinded

to the study. The length of mucosal surface injury was

measured on the entire length of each tissue section in a

visual fi eld of 100-fold magnifi cation. The total length of

mucosal surface injury for the fi ve parts per stomach was

expressed as a measured length. The mucosal thickness

was measured in a visual fi eld of 100-fold magnifi cation.

The number of parietal cells per unit area (mm2) in a visual

fi eld of 400-fold magnifi cation was counted. The extents

of infl ammatory cell infi ltration, the proliferation of collagenous

fi ber and stained gastric mucosa were evaluated

in a visual fi eld of 100-fold magnifi cation.

Tissue malondialdehyde (MDA) and reduced glutathione

(GSH)

The content of hepatic MDA was determined using the

method described by Ohkawa et al.15. In brief, after mincing

and trimming, the pieces of liver were homogenized

with four volumes of an ice-cold 0.1 mol/L potassium

phosphate buffer (pH 7.4) solution. Then, the reaction

mixture containing 0.2 mL of the homogenate, 81 g/L sodium

dodecyl sulfate, 200 g/L acetate buffer (pH 3.5), and

8 g/L thiobarbituric acid (TBA) solution was mixed well

for 3 min and incubated at 95 °C for 60 min. TBA reactive

substance, MDA, was extracted with a butanol-pyrimidine

mixture solution. The absorbance measured at 532 nm was

expressed as nmol/mg protein. The content of hepatic

glutathione (GSH) was determined by the spectrophotometric

method of Griffi th and expressed as nmol/mg

protein16. Protein content was determined by the method

described by Lowry et al.17 using BSA as the standard.

Level of prostaglandin E2

Using a commercially available EIA kits (Amersham, UK),

gastric mucosal PGE2 levels were measured. Immediately

after biopsy and gross observation, mucosal specimens

were frozen in liquid nitrogen and stored at -70 °C until

the measurement of PGE2. Tissue specimens were processed

for the assay according to the method described

previously by Lipscomb and Rees18. The fi nal PGE2 level

was expressed in pg/mg of wet biopsy weight.

Statistical analysis

All data were expressed as mean±SE. Scheffe’s t-test was

used for comparing body weight, tissue MDA, tissue GSH,

and endoscopic scores between the control group and

experimental groups. Rank transformation and Kruskal-

Wallis test were performed to determine the inter-group

difference of non-parametric data, and Bonferroni’s test

was used for multiple pair-wise comparison. A P<0.05 was

considered statistically signifi cant.

7432 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol December 21, 2005 Volume 11 Number 47

RESULTS

Inhibitory effect of DA-9601 on chronic gastritis

Macroscopic lesions were not observed on the surface of

mucosa in any of the groups, while marked changes were

observed microscopically in the gastric mucosa of the

rats treated with TCA for 6 mo (Figure 1). A signifi cant

increase in the length of erosion was observed in the

control animals as compared to normal level (Figure

2). However, the microscopic appearance of the gastric

mucosa taken from group 3 or 4, treated with 0.065%

and 0.216% DA-9601, respectively, showed a significant

decrease in the length of erosion. DA-9601 significantly

decreased the length of erosion in a dose-dependent

manner. Although treatment with rebamipide also caused

a significant decrease of erosive lesion, this protective

effect by rebamipide was not as prominent as observed

in group 4 (treated with 0.216% DA-9601). To explore

the mechanism underlying DA-9601-induced protection

against gastric lesions, the thickness of the gastric mucus

layer was measured (Figure 3). We observed that 0.065%

DA-9601 ameliorated the TCA-induced reduction of

mucosal thickness in the antrum, while 1.08% rebamipide

signifi cantly thickened the mucus layer in the fundus.

Effect of DA-9601 on parietal cells, infiltration of

infl ammatory cells and intestinal fi brosis

The number of parietal cells in the controls (99.1±2.2

cells/0.25 cm2) was significantly lower than that of the

normal level (107.5±2.8 cells/0.25 cm2). Furthermore,

0.065% DA-9601 (112.8±3.2 cells/0.25 cm2), 0.216%

DA-9601 (115.4±2.9 cm2) and 1.08% rebamipide (113.9

±2.9 cm2) significantly increased the number of parietal

cells in TCA-induced chronic gastritis as compared to the

control (Figure 4).

The number of infiltrating inflammatory cells in the

gastric mucosa of animals in the control group (4.7±0.86)

was compared to the normal level (0.9±0.11). We observed

signifi cantly decreased number of infi ltrating infl ammatory

cells in the gastric mucosa of the animals treated with

0.065% DA-9601 (1.4±0.27), 0.216% DA-9601 (2.0±

0.35) and 1.08% rebamipide (3.0±0.37) as compared to the

controls (P<0.05) (Figure 5).

In addition, 0.065% DA-9601 (0.4±0.1) significantly

A B

C D

Figure 1 Microscopic appearance of gastric mucosa showing the effect of

DA-9601 and rebamipide on sodium taurocholate (TCA)-induced erosive and

atrophic gastritis in rats (×100). Rats were administered with 5 mmol/L TCA for

6 mo (given along with drinking water). A: Normal; B: control; C: 0.216% DA-9601;

D: 1.08% rebamipide.

Figure 2 Inhibitory effects of DA-9601 and rebamipide on the length of mucosal

lesion of TCA-induced erosive and atrophic gastritis in rats. DA-9601 (0.065%

and 0.0.216%) and rebamipide (1.08%) were mixed with rodent chow and then

administered to the rats. N: Normal; C: control; DL: 0.065% DA-9601; DH: 0.216%

DA-9601; R: 1.08% rebamipide. Data are expressed as mean±SE. aP<0.05 vs

controls.

16

14

12

10

8

6

4

2

0

N C DL DH R

Lesion length (mm)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Mucosal thickness (mm)

N C DL DH R

Figure 3 Effects of DA-9601 and rebamipide on the mucosal thickness of TCAinduced

erosive and atrophic gastritis in rats. N: Normal; C: control; DL: 0.065%

DA-9601; DH: 0.216% DA-9601; R: 1.08% rebamipide. Data are expressed as

mean±SE. aP<0.05 vs controls.

a

Figure 4 Effects of DA-9601 and rebamipide on the number of parietal cells

in TCA-induced erosive and atrophic gastritis in rats. N: Normal; C: control;

DL: 0.065% DA-9601; DH: 0.216% DA-9601; R: 1.08% rebamipide. Data are

expressed as mean±SE. aP<0.05 vs controls.

120

100

80

60

40

20

0

Parietal cells (count/0.25 cm2)

N C DL DH R

a

a a a

Oh TY et al. Therapeutic effect of DA-9601 on chronic refl ux gastritis 7433

reduced TCA-induced intestinal fibrosis (Figure 6). We

found an obvious increase in the score of intestinal

fi brosis in controls (1.1±0.2) as compared to normal level

(0.3±0.2). On contrary, 0.216% DA-9601 (0.6±0.1) and

1.08% rebamipide (0.6±0.1) showed a decreasing tendency

in the score of intestinal fi brosis (Figure 6).

Effects of DA-9601 on gastric mucosal MDA, PGE2, and

GSH

Lipid peroxidation is a well-established mechanism of

cellular injury, and the accumulation of MDA is used as

an indicator of oxidative stress in cells and tissues. The

mean level of MDA in animals treated with DA-9601 and

rebamipide was not significantly different from that of

controls (Figure 7).

PGE2 plays an important role in the regulation

of gastric mucus secretion. As shown in Figure 8, we

detected a significant decrease in PGE2 contents in the

controls (215.2±84.4 pg/mg of protein) as compared

to the normal level (374.0±64.9 pg/mg of protein). The

treatment with 0.065% DA-9601 (440.3±93.0 pg/mg of

protein) and 0.216% DA-9601 (538.7±78.5 pg/mg of

protein) could significantly increase the PGE2 contents

in a dose-dependent manner, and 1.08% rebamipide

(421.6±88.4 pg/mg of protein) could significantly

ameliorate the PGE2 production (Figure 8).

As shown in Figure 9, we found a significant

decrease in the GSH contents in the controls (23.5±

4.3 nmol/mg of protein) as compared to normal level

(37.0±4.6 nmol/mg of protein). We observed that the

treatment with 0.065% DA-9601 (42.7±6.1 nmol/mg

of protein) and 0.216% DA-9601 (48.5±4.5 nmol/mg

of protein) significantly increased the GSH contents

in a dose-dependent manner, and 1.08% rebamipide

(43.2±5.3 nmol/mg of protein) signifi cantly ameliorated

the GSH production.

6

5

4

3

2

1

0

N C DL DH R

Infl ammatory cell infi ltration (count)

a

Figure 5 Effects of DA-9601 and rebamipide on the infiltration of inflammatory

cells induced by TCA. N: Normal; C: control; DL: 0.065% DA-9601; DH: 0.216%

DA-9601; R: 1.08% rebamipide. Data are expressed as mean±SE. aP<0.05 vs

controls.

Figure 6 Effects of DA-9601 and rebamipide on the proliferation of collagenous

fi ber induced by TCA in rats. N: Normal; C: control; DL: 0.065% DA-9601; DH:

0.216% DA-9601; R: 1.08% rebamipide. Data are expressed as mean±SE.

aP<0.05 vs controls.

Figure 7 Effects of DA-9601 and rebamipide on malondialdehyde (MDA) induced

by TCA in rat gastric mucosa. N: Normal; C: control; DL: 0.065% DA-9601; DH:

0.216% DA-9601; R: 1.08% rebamipide. Data are expressed as mean±SE.

aP<0.05 vs controls.

Figure 8 Effects of DA-9601 and rebamipide on PGE2 induced by TCA in rat

gastric mucosa. N: normal; C: control; DL: 0.065% DA-9601; DH: 0.216%

DA-9601; R: 1.08% rebamipide. Data are expressed as mean±SE. aP<0.05 vs

controls.

Figure 9 Effects of DA-9601 and rebamipide on glutathione (GSH) induced by

TCA in rat gastric mucosa. N: Normal; C: control; DL: 0.065% DA-9601; DH: 0.216%

DA-9601; R: 1.08% rebamipide. Data are expressed as mean±SE. aP<0.05 vs

controls.

N C DL DH R

2

1

0

Intestinal fi brosis (score)

a

a a

N C DL DH R

2

1

0

MDA (nmol/L/mg of protein)

700

600

500

400

300

200

100

0

PGE2 (pg/mg of protein)

N C DL DH R

a

60

50

40

30

20

10

0

GSH (nmol/L/mg of protein)

N C DL DH R

a

7434 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol December 21, 2005 Volume 11 Number 47

DISCUSSION

In the present study, 6 mo of DA-9601 administration

resulted in a signifi cant improvement of the experimental

chronic erosive and atrophic gastritis induced by 6 mo

of TCA treatment. The therapeutic effects of DA-9601

on experimental gastritis were superior to those of

rebamipide observed in clinical practice for the treatment

of gastritis. Six months of oral administration of TCA

solution as drinking water induced the mucosal surface

erosions and gastric mucosal thinning, and decreased

parietal cell numbers, infl ammatory cell infi ltration in the

lamina propria of the mucosa and mucosal fi brosis in rats.

These characterizations were similar to those observed in

chronic gastritis caused by bile refl ux in human beings19,20.

DA-9601 ameliorated the reduction in mucosal thickness

and the decrease in the number of parietal cells induced

by TCA treatment. Furthermore, DA-9601 increased the

stimulation of PGE2 and GSH in the gastric mucosa.

These results suggest that DA-9601 promotes the healing

of TCA-induced chronic erosive and atrophic gastritis

with an etiological factor of the bile refl ux.

The TCA-induced infi ltration of infl ammatory cells in

the gastric mucosa was ameliorated by the administration

of DA-9601. Tissue damage causes the infiltration of

infl ammatory cells that have migrated from the capillary

vessels. Therefore, this amelioration of inflammatory

cell infiltration by DA-9601 may be due to a decreased

infl ammatory response against damaging tissues through

the healing of gastric surface injury. The interstitial space

in the gastric mucosa may play an important role as a

regulative factor in local microcirculation, and changes

in this area may influence the gastric gland, particularly

the glandular portion and the cell proliferative zone.

Mizumachi et al. 21 reported that interstitial fibrosis was

associated with decreased gastric mucosal blood flow.

In this study, DA-9601 markedly ameliorated the TCAinduced

proliferation of collagenous fiber. This change

appears to be associated with the improvements in

microcirculation via DA-9601-induced increased PGE2

level.

In fact, reactive oxygen species has been suggested to

be involved in the pathogenesis of gastric lesion caused

by indomethacin22,23. In addition, previous studies have

reported that the levels of scavengers and mucosal

SOD activity were decreased and the lipid peroxide

concentration was increased in the gastric mucosa before

the sign of tissue injury appeared24,25. Some drugs that

are capable of scavenging or inhibiting the generation of

ROS have been introduced as effective agents to prevent

the gastric mucosal injuries induced by various agents26,27.

Recently, DA-9601 has been demonstrated to inhibit

xanthine oxidase, a major source of ROS generation28.

One of the causes of TCA-induced gastric lesions

is that taurocholate selectively inhibits the synthesis of

the vasodilator, PGI2, an endogenous gastroprotector29.

The suppression of PGI2 production decreases the

PGI2/TXA2 ratio, suggesting that the action of TXA2

overcomes the action of PGI2. This decreased ratio

may reflect the pathogenesis of gastric ischemia due to

vasoconstriction30,31.

The mechanism by which DA-9601 produces such

a therapeutic effect is possibly through its actions that

elevate mucosal concentrations of PGE2, increase the

gastric mucosal blood fl ow, and stimulate re-epithelization

and the formation of glandular tissue. PGE2 has been

reported to exert its cytoprotective effect on gastric

mucosal epithelial cells by increasing gastric mucus

secretion and stimulating cell proliferation in pyloric glands

in rats32. It has been suggested that DA-9601 promotes

the compensatory elevation in proliferative activity of

generative cells through the possible increase in PG, which

would be available to repair the gastric mucosa in erosive

and atrophic gastritis. Gastric mucosal blood flow is

essential for the homeostasis of the mucosal structure and

functionWhittle et al.[30 reported that the administration

of (15s)-15-methyl PGE2 decreased acid back diffusion,

increased mucosal blood fl ow, and signifi cantly reduced the

lesions formed by topical TCA plus HCl and indomethacin

administration. Kishimoto et al.5 reported that mucosal

blood fl ow was decreased by the administration of TCA.

DA-9601 may improve the decreased mucosal blood fl ow

induced by TCA administration although the mucosal

blood fl ow was not measured in this study.

Another possible mechanism is that DA-9601, an

antioxidant, neutralizes reactive free oxygen metabolites in

the mucosa and attenuates the infl ammation. Our results

demonstrated that gastric mucosal GSH concentrations

were depleted in TCA-induced chronic erosive and

atrophic gastritis. The depletion of gastric mucosal GSH

in rats with chronic gastritis is likely to render the gastric

mucosa more susceptible to oxidative damages and the

injurious effects of reactive oxygen species. GSH acts as

a scavenger of free radicals and toxic substances ingested

with foods or produced directly in the gastrointestinal

tract34.

Reflux gastritis, which occasionally occurs after

gastrectomy, is associated with various symptoms, such

as abdominal pain, nausea, emesis, and loss of appetite.

However, the pathogenic mechanism responsible for the

development of gastritis due to bile regurgitation in the

stomach has not been fully elucidated. Treating patients

exhibiting alkaline refl ux symptoms with bile acid binding

agents, such as cholestyramine or sucralfate, has been

reported to be successful in some cases, but not uniformly

successful. It is possible that the presence of lysolecithin,

pancreatic enzymes, and cholic acids is responsible for

causing erosive changes in the stomach wall11. A study has

suggested that these factors destroy the mucosal barrier

and increase its permeability to hydrogen ions, which can

initiate infl ammation through a mechanism similar to the

one attributed to the erosive effects of salicylates12.

In conclusion, DA-9601 is a promising agent for the

treatment of chronic erosive and atrophic gastritis with an

etiological factor of bile refl ux. Increased mucosal PGE2

and reduced glutathione levels by DA-9601 may be its

therapeutic mechanisms for chronic erosive and atrophic

gastritis.

Oh TY et al. Therapeutic effect of DA-9601 on chronic refl ux gastritis 7435

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Science Editor Kumar M and Guo SY Language Editor Elsevier HK

Therapeutic effect of DA-9601 on chronic reflux gastritis induced by sodium taurocholate in rats

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