(CANCER RESEARCH 50. 4931-4934. August 15. 1990)
Inhibition by 7-Amino-w-butyric Acid and Baclofen of Gastric Carcinogenesis
Induced by W-Methyl-yV'-nitro-W-nitrosoguanidine in Wistar Rats
Masaharu Tatsuta,1 Hiroyasu lishi, Miyako Baba, Akihiko Nakaizumi, Makoto Ichü,and Haruo Taniguchi
Departments of Gastrointestinal Oncology [M. T., H. !.. M. B., A. N., M. I.J and Pathology [H. T.], The Center for Adult Diseases, Osaka, 3-3, Nakamichi 1-chome,
Higashinari-ku, Osaka 53 7, Japan
suspended cages with a wire mesh bottom in a controlled room at 21
±1°Cand 40 ±10% humidity, with a 12-h light, 12-h darkness cycle.
ABSTRACT
The effect of -y-amino-n-butyric acid (GABA), the GABAA receptor
agonist muscimol (5-aminomethyl-3-hydroxyisoxazole), and the GABAB
receptor agonist baclofen [4-amino-3-(4-chlorophenyl)butanoic acid] on
the incidence and number of gastric cancers induced by /V-methyl-¿V'nitro-/V-nitrosoguanidine was investigated in Wistar rats. Rats received
alternate-day i.p. injections of 500 or 1000 mg/kg of body weight GABA,
0.25 or 0.5 mg/kg of body weight muscimol, or 4 or 8 mg/kg of body
weight baclofen after 25 wk of p.o. treatment with the carcinogen.
Prolonged administration of GABA at 1000 mg/kg of body weight, but
not at 500 mg/kg of body weight, and of baclofen at 4 and 8 mg/kg of
body weight significantly decreased the incidence and number of gastric
cancers of the glandular stomach in Wk 52, but long-term muscimol
administration had no influence. Histologically, GABA at the high dosage
and baclofen at both dosages significantly decreased the labeling index
of the antral mucosa and significantly increased the serum gastrin level.
Furthermore, baclofen at both dosages significantly decreased antral pH
and significantly increased gastric acid secretion. These findings indicate
that GABA inhibits gastric carcinogenesis via the GABAB receptor and
that this effect may be related to its effect in decreasing the proliferation
of antral mucosa.
INTRODUCTION
Much evidence has accumulated supporting the hypothesis
that most of the GABA2 related to mammalian brain function
acts as an inhibitory transmitter (1). The intracerebral admin
istration of GABA has been reported to inhibit gastric acid
secretion in rats (2). GABA is also present in various peripheral
tissues, including the gastrointestinal tract. There is now in
creasing evidence that GABA is a transmitter in the myenteric
plexus and also in other parasympathetic ganglia (1). Recently,
Jessen et al. (3) found that mucosal cells in the pyloric stomach
are strongly GABA immunoreactive, and they raised the pos
sibility that GABA acts as a gut hormone in the gastrointestinal
tract, in addition to its role as an enteric neurotransmitter. Gut
hormones have trophic effects on the gastrointestinal tract (4).
On the basis of recent studies, it appears that these hormones
also regulate development and growth of malignant gastroin
testinal tumors, including cancers of the stomach and pancreas
(5). Therefore, it seemed likely that GABA would affect the
development of gastric cancer. To test this idea, we examined
the effects of GABA, the GABAA receptor agonist muscimol,
and the GABAB receptor agonist baclofen on the incidence,
number, and histológica! types of adenocarcinomas induced by
MNNG in rats.
MATERIALS
AND METHODS
Animals. A total of 175 young (6-wk-old) male Wistar rats were
purchased from SLC (Shizuoka, Japan). The animals were housed in
Received 9/14/89; revised 2/26/90.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
' To whom requests for reprints should be addressed.
2The abbreviations and trivial names used are: GABA, ->-amino-n-butyric acid;
MNNG, yV-methyl-A"-nitro-A'-nitrosoguanidine: baclofen. 4-amino-3-(4-chlorophenyl)butanoic acid: muscimol. 5-aminomethyl-3-hydroxyisoxazole:
BrdUrd.
bromodeoxyuridine.
Regular chow pellets (Oriental Yeast, Tokyo, Japan) were available ad
libitum.
Experimental Design. The animals were given drinking water con
taining MNNG (50 /jg/ml; Aldrich, Milwaukee, WI) for 25 wk. From
Wk 26, the rats were given normal tap water ad libitum and were
randomly divided into seven groups. They were given injections i.p.
every other day, as follows, until the end of the experiment at Wk 52.
Group 1 (25 rats) was given only the vehicle (0.9% NaCl solution).
Groups 2 and 3 (25 rats each) were given GABA at dosages of 500 and
1000 mg/kg of body weight per day, respectively. Groups 4 and 5 (25
rats each) were given baclofen at dosages of 4 and 8 mg/kg of body
weight per day, respectively. Groups 6 and 7 (25 rats each) were given
muscimol at dosages of 0.25 and 0.5 mg/kg, respectively.
The doses and injection intervals were based on the results of our
previous experiment1 and that of Minano el al. (6). Minano et al.
reported that 1000 mg/kg of GABA significantly decreased the inci
dence, number, and ulcer index of gastric ulcers in pylorus-ligated rats.
We previously found that, after i.p. administration of 1000 mg/kg of
GABA, elevated levels in the blood were apparent within 30 min,
peaked at 4 h, and declined to zero by 24 h. ' and that rats became
moribund when GABA was injected every day. Therefore, we injected
1000 and 500 mg/kg of GABA every' other day.
GABA (Sigma, St. Louis, MO), baclofen (kindly provided by CibaGeigy, Japan, Takarazuka, Japan), and muscimol (Sigma) were pre
pared as a solution in 0.9% NaCl solution. Injections were given i.p.
every other day in a volume of 2 ml/mg, between 2 and 3 p.m. each
day.
Histológica! Observations. All rats that survived for more than 50
wk were included in the effective numbers, because the first tumor of
the glandular stomach was found in a rat from Group 1 that died in
Wk 50. All rats were killed at the end of the experiment in Wk 52.
Specimens were embedded in paraffin, and serial sections 5 ¿imthick
were cut and stained with hematoxylin and eosin. Sections were ex
amined without knowledge of which group they were from.
Definition and Classification of Gastric Cancers. Histologically, we
defined adenocarcinomas as lesions in which neoplastic glandular tissue
had penetrated the muscularis mucosae to involve the submucosa or
deeper layers. As previously reported (7), the adenocarcinomas were
classified as very well differentiated, well differentiated, or poorlydifferentiated.
Measurement of Gastric Mucosal Labeling Index. The labeling index
of gastric mucosa was measured in Wk 30 and 52 with an ¡mmunohistochemical analysis kit for assaying BrdUrd incorporation (BectonDickinson, Mountain View, CA) (8, 9), by the modified method de
scribed by Tada et al. (10). In Wk 30, the rats were fasted for 12 h and
then received their usual treatment. One h later, the animals were given
an i.p. injection of BrdUrd (20 mg/kg), and after another hour they
were killed by ether. In Wk 52, the labeling index was measured 2 and
24 h after their last usual injection. For this, the rats were fasted for 12
h, divided into two groups of five rats each, and received their usual
treatment. One or 23 h later, the animals were given an i.p. injection
of BrdUrd (20 mg/kg), and after another hour they were killed by ether.
To analyze the BrdUrd labeling index of the gastric mucosa, the
numbers of BrdUrd-labeled and unlabeled cells in the zone of prolifer
ating cells (11) were counted without knowing which treatment group
the sample was from. From these measurements we derived the BrdUrdlabeling index (number of BrdUrd-labeled cells per total number of
3 M. Tatsuta, H. lishi, and M. Baba, unpublished data.
4931
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GABAERGIC CONTROL OF GASTRIC CARCINOGENESIS
cells within the zone of proliferation).
Measurement of Serum Gastrin Levels, Antral Miu-osul pH, and
Gastric Acid Secretion. Serum gastrin level, annal mucosa! pH, and
gastric acid secretion were examined in Wk 52. To measure serum
gastrin and mitral pH, rats were starved for 12 h and then given their
usual treatment. One h later, the rats were anesthetized, and blood was
obtained by cardiac puncture. We previously found that an elevated
serum gastrin level was apparent within 30 min, peaked at 1 h, and
declined to basal level by 3 h. The stomach was opened, and antral pH
was measured with a fine electrode. Within 1 wk of obtaining the
samples, the gastrin content of the serum was assayed with a radio
immunoassay kit from Dainabot Radioisotope Laboratories (Tokyo,
Japan) (12).
To measure gastric acid secretion, gastric secretions were collected
for 3 h by the method of Shay et al. (13). Briefly, the animals were
starved for 12 h and anesthetized with ether, and the gastric pylorus
was ligated. The animals then received their usual treatment. Three h
later, the fluid in the gastric cavity was collected. Its volume was
measured, and its acid concentration was determined by titration of a
2-ml portion with a 0.1 N NaOH to pH 7.0 with a glass electrode. Then
the acid output was calculated.
Statistical Analysis. Data were analyzed by the x2 test or Fisher's
exact probability test or by one-way analysis of variance with Dunn's
multiple comparison (14-16). Data are given as the mean ±SE. Results
are reported as significant if the calculated P value was less than 0.05.
RESULTS
Incidence, Number, Histológica! Type, and Depth of Involve
ment of Gastric Cancers. Five rats in each group were killed in
Wk 30 for determination of the labeling index of the gastric
mucosa. One rat each in Groups 1 and 3 and two rats each in
Groups 2, 5, and 7 were killed before Wk 50 because they
became moribund. No tumors were found in any of these
animals, and they were excluded from the effective numbers.
The incidence, number, histológica! type, and depth of in
volvement of gastric cancers are summarized in Table 1. In
Group 1 (NaCl solution only), gastric cancers were found in 13
(68%) of 19 rats examined, and the average number of gastric
cancers per rat was 1.2 ±0.2. In Group 3 (GABA at 1000 mg/
kg), but not in Group 2 (GABA at 500 mg/kg), the incidence
and the average number of gastric cancers per rat were signifi
cantly lower than in Group 1. In Groups 4 (baclofen at 4 mg/
kg) and 5 (baclofen at 8 mg/kg), the incidence and the average
number of gastric cancers were significantly lower than in
Group 1. However, in Groups 6 (muscimol at 0.25 mg/kg) and
7 (muscimol at 0.5 mg/kg), the incidence and the average
number of gastric cancers per rat were similar to those in Group
1.
All tumors induced in the glandular stomach were histologically identified as adenocarcinomas. In Group 1, all cancers
were very well differentiated. Well-differentiated adenocarci
nomas were found in Groups 1, 5, 6, and 7, and poorly differ
entiated adenocarcinoma only in one rat from Group 7. There
were no significant differences in the histológica! types of
adenocarcinomas among the several groups. Table 1 also shows
that there were no significant differences in the depth of involve
ment of gastric cancers among the seven groups. All cancers
were found in the antral mucosa, and no métastaseswere seen
in any rat.
Labeling Index of Gastric Mucosa. Table 2 summarizes the
data on the labeling index of gastric mucosae 2 h and/or 24 h
after the last injection in Wk 30 and 52. At both times, 2 h
and/or 24 h after the last injection, administration of 1000 mg/
kg of GABA or of 4 or 8 mg/kg of baclofen caused a significant
decrease in the labeling index of the antral mucosa, but not of
the fundic mucosa, as compared with untreated Group 1. How
ever, muscimol had no influence on the labeling indices of the
antral and fundic mucosa.
Serum Gastrin Level, Antral pH, and Gastric Acid Secretion.
Table 3 summarizes the data on serum gastrin levels, antral
pH, and gastric acid secretion in Wk 52. Serum gastrin levels
were significantly higher for Groups 2 and 3 (GABA at 500 or
1000 mg/kg, respectively) and Groups 4 and 5 (baclofen at 4
or 8 mg/kg, respectively) than for Group 1 (NaCl solution
only). However, values for Groups 6 and 7 (muscimol at 0.25
or 0.5 mg/kg) were not significantly different from those for
Group 1.
Antral mucosal pH and gastric acid secretion were signifi
cantly lower and higher, respectively, for baclofen-treated
Groups 4 and 5 than for Group 1. However, values for GABAtreated Groups 2 and 3 and for muscimol-treated Groups 6 and
7 were not significantly different from those for Group 1.
DISCUSSION
Recent studies on GABA in the enteric nervous system sug
gest that GABAergic neurons occur in the peripheral autonomie
Table 1 Incidence, number, histológica!type, and depth of involvement of gastric cancers in MNNG-treated rats
Group
Treatment"
Wk 26
Wk 52
Depth of
involvement
Histology
Body wt (g)
Effective
no.
No. of rats
with gastric
cancer
No. of
gastric
cancers
No. of gastric
cancers/rat
Very well
differentiated
Well differentiated
Poorly differentiated
Submucosai
layer
Deeper
layer
5*364
±
1234567NaClGABA.500
±8324
±0.20.6
±6352
0.20.3
±
(100)6(100)7
±9325
mg/kgGABA,1000
(a)'5
(26)
(bf0.4
±0.1
±4367 ±9332
mg/kgBaclofen.4
(a)0.4
+ 0.1
(100)18(100)17
±6365
±9328
(a)5
(25)
mg/kgBaclofen,8
(a)1.0
±0.2
±5370 ±9349
(a)12(60)12(67)221167819161.2
(28)
mg/kgMuscimol,0.25
±
±0.30.9
(89)15(94)3(14)0(0)0(0)0(0)0(0)2(11)1
±6363 12358
mg/kgMuscimol,0.5
±0.222(100)10(91)6(100)7(100)6(75)15(79)13(81)0(0)1(9)0(0)0(0)2(25)4(21)2(13)0(0)0(0)0(0)0(0)
±6359 ±1019181920182018I3(68)c9(50)5
mg/kg362
°Treatment regimens: NaCl. 2 ml/kg of 0.9% NaCl solution given i.p. every other day after MNNG treatment for 25 wk; GABA, 500 or 1000 mg/kg of GABA
given i.p. every other day after MNNG treatment for 25 wk; baclofen. 4 or 8 mg/kg of baclofen given i.p. every other day after MNNG treatment for 25 wk; muscimol,
0.25 mg/kg of muscimol given i.p. every other day after MNNG treatment for 25 wk.
* Mean ±SE.
' Numbers in parentheses, percentage.
' Significantly different from the values for Group 1: P< 0.05 (a); />< 0.01 (b).
4932
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GABAERGIC CONTROL OF GASTRIC CARCINOGENESIS
Table 2 Labeling
indices of gastric mucosae in MNNG-lreated
injectionExperimental
rats
2 h after
wk3052Group1
GABA, 500 mg/kg
2
GABA, 1000 mg/kg
3
4
Baclofen, 4 mg/kg
Baclofen, 8 mg/kg
5
671234567Treatment"Nad
Muscimol,
mg/kgMuscimol,
0.25
mg/kgNaCIGABA,
0.5
mg/kgGABA,
500
mg/kgBaclofen,
1000
mg/kgBaclofen.
4
mg/kgMuscimol,
8
mg/kgMuscimol,
0.25
0.5 mg/kgFundic
°For explanation of treatments, see Table 1.
* Mean ±SE.
' Significantly different from the value for Group 1: P < 0.001 (a); P <
mucosa0.21
±0.01*
0.22 ±0.02
0.20 ±0.01
0.21 ±0.01
0.21 ±0.01
±0.010.21
0.21
±0.010.21
±0.010.21
±0.020.19
±0.010.20
0.010.21
±
±0.020.19
±0.000.20
±0.01Antral
injectionFundic
h after
mucosa0.17
mucosa0.20
mucosa0.18
0.010.21
0.010.19
0.010.20
0.020.20
0.020.19
±0.010.21
±0.02Antral
±0.010.18
0.010.12
±
(b)0.13
±0.01
(b)0.12
±0.00
(b)0.19
±0.01
±0.010.19
±0.01
±0.01
0.16 ±0.00
0.09 ±0.00 (a)r
0.09 ±0.01 (a)
0.08 ±0.01 (a)
±0.010.16
0.17
±0.010.18
±0.010.18
±0.010.1
(b)f0.12
2 ±0.01
(a)0. ±0.00
(a)0.18
11 ±0.00
±0.010.18
±0.0124
0.01 (b).
Table 3 Serum gaslrin, antral pH, and gastric acid secretion in MNNG-treated
rats
Serum gasGastric acid secre
Treatment"
Antral pH
tion (mEq/h)
Group
trin (pg/ml)
171 ±20"
3.6 ±0.1
0.038 ±0.001
1 NaCI
327 ±30 (a)' 3.5 ±0.2
2
GABA, 500 mg/kg
0.050 ±0.001
3
GABA, 100 mg/kg
325 ±31 (a) 3.1 ±0.1
0.056 ±0.000
328 ±19 (a) 2.6 ±0.2 (b)' 0.151 ±0.001 (a)
4
Baclofen, 4 mg/kg
5
Baclofen, 8 mg/kg
323 ±44 (a) 2.6 ±0.2 (b) 0.257 ±0.001 (b)
6
Muscimol, 0.25 mg/kg 217 ±37
3.3 ±0.1
0.053 ±0.001
0.026 ±0.001
7
Muscimol, 0.5 mg/kg 205 ±38
3.1 ±0.1
" For explanation of treatments, see Table 1.
* Mean ±SE.
c Significantly different from the value for Group 1: P < 0.05 (a); P < 0.01 (b).
nervous system as well as in the central nervous system (1, 17).
Furthermore, it has been shown that there are at least two types
of GABA receptor: GABAA and GABAB receptors. The former
is bicuculline sensitive and has a high affinity for muscimol; the
latter is not blocked by bicuculline and has a high affinity for
baclofen (18-20). In the present work, we found that prolonged
alternate-day injections of GABA after MNNG treatment sig
nificantly reduced the incidence and the average number of
gastric cancers in the glandular stomach in Wistar rats. We
also found that long-term administration of baclofen but not of
muscimol significantly reduced the incidence and number of
gastric cancers. These findings indicate that GABA inhibits the
development of gastric cancers, and that this effect of GABA
may be mediated via GABAB receptors.
Stimulation of these two subtypes of GABA receptor may
affect gastric function differently. Although the exact mecha
nism is still unclear, at least two possible explanations can be
considered. The first is the effect of GABA and GABA agonists
on the secretion of various hormones. Anderson and Mitchell
(21) reported that muscimol affects secretion of growth hor
mones, luteinizing hormone, and adrenocorticotropic hormone,
but that baclofen has no effect on the basal secretion of these
hormones. Furthermore, Harty and Franklin (22) found that
GABA is a potent stimulant of antral gastrin release. In the
present work, we found that administration of GABA and of
baclofen significantly increased the serum level of gastrin, but
that muscimol had no influence on gastrin secretion. Some of
these hormones are closely related to gastric carcinogenesis.
We already found that prolonged administration of tetragastrin
in depot form after MNNG treatment significantly reduced the
incidence of gastric cancers (23, 24), and that this effect of
tetragastrin may be closely related to decreased cell prolifera
tion of antral mucosa. In the present work, we found that
administration of GABA at a high dose and of baclofen signif
icantly reduced the labeling index of the antral mucosa. How
ever, these treatments did not influence the labeling index of
the fundic mucosa. We previously found that the elevated serum
gastrin level after injection of GABA or baclofen declined to
basal level by 3 h. These findings suggest that hypergastrinemia
induced by GABA and baclofen may have little or no influence
on inhibition of gastrin carcinogenesis. Harty and Franklin (22)
found that GABA is capable of inhibiting basal somatostatin
release from antral mucosa. Recently, we found that alternateday injection of somatostatin significantly increased the inci
dence and number of gastric cancers induced by MNNG (25).
The second possible explanation is the effect of GABA and
GABA agonists on gastric acid secretion. The role of the central
nervous system in the regulation of gastric acid secretion has
been recognized for many years (26). Evidence for the potential
physiological significance of GABA in the regulation of gastric
acid secretion comes from the observation that the highest
concentration of GABA is in the lateral hypothalamus and that
GABA concentrations increase during hypoglycemia, which
induces gastric acid secretion (27). Administration of baclofen
i.v. or s.c. stimulates gastric acid secretion (28-30). However,
reports of the effect of muscimol on gastric acid secretion are
conflicting. Tsai et al. (31) and Blandizzi et al. (32) reported
that s.c. administration of muscimol increased gastric acid
secretion. Levine et al. (33), however, found that i.v. adminis
tration of muscimol did not alter basal gastric acid secretion.
In the present work, we found that i.p. administration of
baclofen, but not of muscimol, significantly increased gastric
acid secretion. Although the relationship between gastric acid
hypersécrétion
and the development of gastric cancers is still
unclear, cancerous foci might be digested as a result of increased
gastric acid secretion. Mallory (34) and Palmer and Humphreys
(35) reported that cancerous lesions are easily ulcerated by
gastric acid.
In the present work, we found that alternate-day injections
of GABA and baclofen significantly decreased the incidence
and number of gastric cancers and the labeling index of the
antral mucosa. These findings indicate that GABA inhibits
gastric carcinogenesis and that its effect may be mediated via
the GABAB receptor but not the GABAA receptor.
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Inhibition by γ-Amino-n-butyric Acid and Baclofen of Gastric
Carcinogenesis Induced by N-Methyl-N′-nitro-N
-nitrosoguanidine in Wistar Rats
Masaharu Tatsuta, Hiroyasu Ishi, Miyako Baba, et al.
Cancer Res 1990;50:4931-4934.
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