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Anti-Ulcerogenic Efficacy of Leaf Fractions of Argemone mexicana Against Indomethacin Induced-Ulceration in Rats

Authors:
  • Federal University of Health Sciences, Otukpo, Benue State
  • @osaliu@noun.edu.ng

Abstract

Background and Objective: Peptic ulcer disease still remains a burden in under-developed and developing countries. Argemone mexicana is a plant locally used in folk medicine of Nigeria to treat peptic ulcer disease. Therefore this study aimed to investigate the anti-ulcer activity of solvent-partitioned fractions of Argemone mexicana leaves in indomethacin ulcerated rats. Materials and Methods: Dried leaves of A. mexicana were extracted with ethanol and the crude extract was subjected to solvent-partitioning using n-hexane, ethylacetate and butanol. Phytochemical screening of the partitioned fractions was carried out using standard methods. A total of 36 rats were randomized into six groups of six rats each. Group 1 serve as the control and received distilled water only, Group 2 serve as ulcerated group, Groups 3 serve as ulcerated group treated with 20 mg kg-1 b.wt., Omeprazole while Groups 4-6 were ulcerated rats treated with 200 mg kg-1 b.wt., of ethylacetate, butanol and n-hexane fractions respectively. The rats were ulcerated by single dose of indomethacin (25 mg kg-1 b.wt.,) administered orally followed by treatment with the fractions. Ulcer indices, antioxidant enzymes status, levels of glutathione and lipid peroxidation were assessed. Results: The results revealed the presence of alkaloids and flavonoids only in ethylacteate and butanol fractions. A significant increase (p<0.05) in gastric acid, volume, malondialdehyde concentration, pepsin and H+/K+ ATPase activities was observed in the ulcerated rats. Significant decrease (p<0.05) was observed in gastric mucus content, glycoprotein concentration and antioxidant activities in ulcerated rats. The ulcer indices were attenuated and the antioxidant status was improved in rats treated with 200 mg kg-1 b.wt., of ethylacetate and butanol fractions. Conclusion: The ethylacetate fraction demonstrated a better efficacy which may be attributed to presence of flavonoids thus suggesting Argemone mexicana as an alternative therapy for treating ulcer.
Asian Journal of Emerging Research, 2021
Volume 3 issues 2, 27 pages
https://doi.org/10.3923/ajerpk.2021.129.136 1
Anti-Ulcerogenic Efficacy of Leaf Fractions of Argemone mexicana
Against Indomethacin Induced-Ulceration in Rats
*O.A. Idowu1
Department of Biochemistry, College of Natural and Applied Sciences, Oduduwa University, P.M.B 5533
Ile-Ife, Osun State, Nigeria
O.A. Saliu2
Department of Environmental Health, Faculty of Health Sciences, National Open University, Abuja,
Nigeria
N.C. Fakorede1
Department of Microbiology, College of Natural and Applied Sciences, Oduduwa University, P.M.B
5533 Ile-Ife, Osun State, Nigeria
R.O Arise3
Department of Biochemistry, University of Ilorin, Ilorin Kwara State, P.M.B 1515, Ilorin, Nigeria
Corresponding Author Email: id4phemy@mail.com
Abstract
Background and Objective: Peptic ulcer disease still remains a burden in under-developed and
developing countries. Argemone mexicana is a plant locally used in folk medicine of Nigeria to treat
peptic ulcer disease. Therefore this study aimed to investigate the anti-ulcer activity of solvent-
partitioned fractions of Argemone mexicana leaves in indomethacin ulcerated rats. Materials and
Methods: Dried leaves of A. mexicana were extracted with ethanol and the crude extract was subjected
to solvent-partitioning using n-hexane, ethylacetate and butanol. Phytochemical screening of the
partitioned fractions was carried out using standard methods. A total of 36 rats were randomized into
six groups of six rats each. Group 1 serve as the control and received distilled water only, Group 2
serve as ulcerated group, Groups 3 serve as ulcerated group treated with 20 mg kg-1 b.wt., Omeprazole
while Groups 4-6 were ulcerated rats treated with 200 mg kg-1 b.wt., of ethylacetate, butanol and n-
hexane fractions respectively. The rats were ulcerated by single dose of indomethacin (25 mg kg-1
b.wt.,) administered orally followed by treatment with the fractions. Ulcer indices, antioxidant
enzymes status, levels of glutathione and lipid peroxidation were assessed. Results: The results
revealed the presence of alkaloids and flavonoids only in ethylacteate and butanol fractions. A
significant increase (p<0.05) in gastric acid, volume, malondialdehyde concentration, pepsin and
H+/K+ ATPase activities was observed in the ulcerated rats. Significant decrease (p<0.05) was
Asian Journal of Emerging Research, 2021
Volume 3 issues 2, 27 pages
https://doi.org/10.3923/ajerpk.2021.129.136 2
observed in gastric mucus content, glycoprotein concentration and antioxidant activities in ulcerated
rats. The ulcer indices were attenuated and the antioxidant status was improved in rats treated with
200 mg kg-1 b.wt., of ethylacetate and butanol fractions. Conclusion: The ethylacetate fraction
demonstrated a better efficacy which may be attributed to presence of flavonoids thus suggesting
Argemone mexicana as an alternative therapy for treating ulcer.
INTRODUCTION
Peptic Ulcer Disease (PUD) is still a burden
affecting most of the populace in under-
developed and developing countries. The
gastrointestinal tract (GIT) plays a significant
role in digestion and absorption of food
materials in the living system however,
disturbances in physiological functions of the
GIT among which are alterations in acid
secretion and osmotic effect can result to
several pathological conditions of the
gastrointestinal tract such as diarrhea,
appendicitis, cancer and ulcer1. An ulcer is an
open sore that develops in the mucosa lining
the GIT. A conglomerate of ulcer that develops
in the lining mucosa of the oesophagus
(oesophagael ulcer), stomach (gastric ulcer),
duodenum (duodenal ulcer) and meckel’s
diverticulum (meckel’s diverticulum ulcer) of
the gastrointestinal tract are referred as
gastrointestinal tract ulcers. Among these
ulcers, gastric and/or duodenal ulcers most
often referred as peptic ulcer disease are
the most common among the populace.
Peptic ulcer usually results from an
imbalance between aggressive/offensive
factors (acid, pepsin) and defensive factors
(prostaglandin, mucus, glycoprotein,
bicarbonate and antioxidant enzymes) of
the stomach especially when the
aggressive/offensive factors overwhelm the
defensive factors2. Such imbalance may be
induced by Helicobacter pylori infection,
excessive consumption of Non-Steroidal
Anti-inflammatory Drugs (NSAIDs), smoking,
alcohol consumption and diet2 as well as
physiological (oxidative) and psychological
stress3. The NSAIDs e.g. indomethacin
induce peptic ulcer by inhibiting
cyclooxygenase, an enzyme responsible for
the biosynthesis of prostaglandin which is a
major biomolecule that enhance the
defense barrier of gastric mucosal against
the damaging effect of gastric acid by
Asian Journal of Emerging Research, 2021
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stimulating mucus secretion, glycoprotein
and other defensive factors. Indomethacin
and other NSAIDs bind to the active site of
cyclooxygenase and acetylate its serine
residue thereby causing the inactivation of
the enzyme. The inhibition of this enzyme
finally suppresses the production of
prostaglandin and subsequently impedes
the secretion of mucus and result in
ulceration. Normally, an equilibrium exist
between the acid (HCl) secreted by the
stomach which help in the digestion of food
and the gastric mucosal defensive factors
however, when an imbalance between
these two is induced by any of the
exogenous agents (e.g. NSAIDs, H. pylori,
stress etc.), the mucosal becomes irritated
by the bathing of the acid which weakens it
and then result to ulcer. Symptoms of
peptic ulcer include abdominal pain,
nausea, vomiting, loss of appetite and
weight loss. Ulcers could get complicated
and show symptoms of bleeding and
perforation which ulcer may require
surgery. A number of drugs currently
available for treating gastrointestinal tract
ulcers are histamine-receptor blockers (e.g.
ranitidine, cimetidine), proton-pump
blockers (e.g. omeprazole, pantoprazole),
prostaglandins analogues (e.g. misoprostol,
sucralfate) antibiotics (e.g. clarithromycin
amoxicillin, metronidazole), antacids
(Aluminum hydroxide, Sodium hydroxide),
synthetic antioxidants (e.g. dubinol, sodium
benzoate) etc. Although these conventional
drugs have been well characterized but the
adverse effects they produce such as
headache, male hormone disturbances4,
pneumonia, osteoporosis, vitamin B12
malabsorption5, hematopoietic changes and
drug-drug interaction highlight the need for
better treatment modalities of
gastrointestinal tract ulceration of any
kind1. Recent studies found that different
substances from plant sources not only
afford gastro protection and accelerate
ulcer healing but are also safe to consume6.
There are various plant used as decoction,
concoction, or even as food additive or
supplement to combat gastrointestinal
ulceration in folk medicine of many
countries6. In Nigeria, a West Africa
country, ethno botanical survey revealed
the use of Argemone mexicana as
treatment for peptic ulcer. A. mexicana
belongs to the family Papaveraceae. It is an
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annual herb commonly found in tropical
and subtropical regions of the world among
which are Indian, Mexico and Nigeria7. It
leaves are estipulate, sessile, alternate,
deeply lobed, cauline with unicostate
reticulate venation with thorny margins8.
Traditionally, in Mali, Burkina Faso and
Nigeria, the decoction leaves of the plant
are used to treat cough, uncomplicated
malaria, liver disease and ulcer9. However,
there is need to provide substantial
scientific information to validate its
purported traditional claims for treating
ulcer. This study therefore aimed to
investigate the effects of different solvent
partitioned fractions of Argemone mexicana
leaves on acid secretory parameters and
antioxidant status of indomethacin-induced
ulcerated rats.
MATERIALS AND METHODS
Study area: This study was carried out
between June and December, 2015 at the
Department of Biochemistry, University of
Ilorin, Nigeria.
Collection of plant materials and
authentication: Fresh leaves of A. mexicana
were collected from Saki Township, Oyo State,
Nigeria. They were identified and
authenticated at the Department of Botany,
University of Ilorin, Kwara State, Nigeria. A
voucher specimen number of the plant
(UIH0011171) was deposited in the Herbarium
of the Department.
Preparation of extract: The fresh leaves were
rinsed with distilled water and air-dried for 14
days in the laboratory at room temperature
(25oC) to prevent loss of bioactive agents due
to irradiation. The dried leaves were ground to
powder form using mechanical blender
(Mazeda Mill, MT 4100, Japan). Almost 500 g
of the powder was macerated with absolute
ethanol (2 L) for 72 h using cold extraction
method. The crude extract was filtered using
Whatman No 1 filter paper. The extraction
process was repeated twice with the marc and
the three filtrates obtained were combined
and concentrated using a rotary evaporator.
The crude extract was dissolved in distilled
(10% w/v) water and was subsequently
subjected to successive solvent partitioning in
order of polarity using n-hexane, ethyl acetate
and butanol. Each fraction obtained was
filtered, concentrated and the resulting
residues were reconstituted in distilled water
to give the required dose of 200 mg kg-1 b.wt.
Asian Journal of Emerging Research, 2021
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Phytochemical profiling: The phytochemical
screening for each of the fractions was carried
out using standard procedures10,11,12.
Experimental animals: A total of thirty-six (36)
albino rats (Rattus norvegicus) of both sexes
weighing 162±1.45 g were obtained from the
Animal Holding Unit, Biochemistry Department
University of Ilorin, Kwara State, Nigeria. They
were housed under standard conditions
temperature: 22±3oC; photoperiod: 12 h light
and 12 h dark; humidity: 4045% with free
access to rat pellets (Premier Feed Mills
Company Limited, Ibadan, Nigeria) and tap
water ad libitum. Full committee approval was
given by the University of Ilorin, Nigeria ethical
review committee (UERC) with protocol
approval number of UERC/ASN/2015/120.
Chemicals: Omeprazole and indomethacin
were purchased from Pauco Pharmaceutical
(Anambra, Nigeria). Trichloroacetic acid (TCA),
5,5′-dithiobis-(-2-nitrobenzoic acid) (DTNB) and
thiobarbituric acid (TBA), potassium
ferricyanide, nicotinamide adenine
dinucleotide (NADH), ferric chloride were
products of Sigma-Aldrich Inc. (St. Louis, MO,
USA). Glutathione peroxidase (GSH-px),
glutathione reductase (GSH-Red), glutathione
transferase (GST) and superoxide dismutase
were purchased from Randox Laboratories
(Antrim, United Kingdom). All other chemicals
used in this research are of analytical grade
and purchased commercially.
Experimental procedure: The animals were
assigned into six groups (I-VI) consisting of six
rats each. Group I received distilled water only
and served as the control. Group II are rats
ulcerated with indomethacin but receive no
chemical intervention. Group III are ulcerated
rats with medical intervention of 20 mg kg-1
b.wt., omeprazole as reference drug while
groups IV-VI are ulcerated rats that received
medical intervention of 200 mg kg-1 b.wt., of
ethylacetate, n-hexane and butanol
partitioned fractions of A. mexicana
respectively. The rats were fasted for 24 h
before the commencement of the experiment
but had access to water until 6 h before the
experiment after which they were ulcerated by
single oral administration of 25 mg kg-1 b.wt.,
indomethacin. The rats had access to water till
the next two days for the establishment of
ulceration after which administration of the
vehicle, reference drug and the plant fractions
began on the third day and lasted for 7 days.
The animals were again fasted for 12 h to
ensure complete gastric emptying and a steady
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state gastric acid secretion after which they
were anesthetized under diethyl ether. The
stomach of the rats was ligated at both
openings of the lower esophageal sphincter
and pyloric sphincter and injected with 3 mL of
distilled water to collect the gastric juice6
which was used for biochemical analysis.
Preparation of tissue homogenates: The
stomach and duodenum were excised and
placed in cold 0.25 M sucrose solution to
maintain the integrity of the organs. The
organs were separately homogenized in ice-
cold 0.25 M sucrose solution. The
homogenates were appropriately diluted
(1:5w/v) with sucrose and centrifuged at 1000xg
for 10 min. The supernatant were aspirated
with Pasteur pipette into sample bottles and
refrigerated until further analysis.
Ulcer index determination: After the
collection of the gastric juice, the stomach was
ligated along the greater curvature and rinsed
slowly with normal saline. It was then
stretched out on a plane paper and examined
macroscopically with a hand lens (x20) for
gastric erosion. For the ulcer index, the length
(mm) and width (mm) of ulcer on the gastric
mucosa was measured using a ruler using the
procedure of Gregory et al.13. The Ulcer Index
(UI) was then calculated in mm2 using the
expression:
Ulcer Index (UI) = Length (mm) x Breadth (mm)
of lesion
Determination of ulcer indices in the gastric
juice: The gastric juice collected was
centrifuged at 850 x g for 10 min. The volume
of the supernatant was measured using a
graduated measuring cylinder and was taken
as the volume of the gastric juice6. The pH was
measured by placing the electrode of a digital
pH meter into the gastric juice supernatant.
The procedure of Maity et al.14 was used to
determine the gastric acidity.
Pepsin activity in gastric juice: The method
described by Hirohashi et al.15 was used to
determine pepsin activity in the gastric juice.
Briefly, 1.0 mL of gastric juice supernatant and
5 mL of buffer solution (0.2N sodium citrate
and 0.2N HCl pH 1.2 in ratio 1:4) in different
test tubes were incubated at 37oC for 30 min.
Then pepsin was allowed to react with 2 mL
bovine serum albumin (10 mg) and test tubes
re-incubated at 37oC for 30 min. The unreacted
protein of bovine serum albumin was detected
by the addition of 1.0 mL of Biuret reagent and
absorbance was read at 546 nm after 30 min
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against a reagent blank. The pepsin activity
was determined from standard protein curve.
Determination of glycoprotein concentration:
Glycoprotein concentration was determined
from the total carbohydrate and protein
contents expressed as ratio of Total
Carbohydrates (TC) to Total Proteins (TP).
Total carbohydrates: The total carbohydrate in
the gastric juice was determined by the
method of Nair16. Briefly, to 0.15 mL gastric
juice and to blank containing 0.15 mL of
distilled water in a test tube, 1 mL of 5%
phenol was added separately and mixed
thoroughly. The 5 mL of 96% H2SO4 was added
and again mixed slowly. After 10 min, the test
tubes were shaken and placed in water bath
kept at 20°C for 20 min. The optical density of
the developed yellow orange chromophore
was read in a UV spectrophotometer at 482
nm. Several concentrations of glucose
standard solution were run to prepare a
standard curve. Total carbohydrates were
expressed in terms of micrograms per milliliter
liberated in gastric juice.
Total protein: The procedure described by
Lowry et al.17 was used for the determination
of total protein content in the gastric juice.
The glycoprotein concentration was thereby
expressed as the ratio of total carbohydrates
and protein content below.
Glycoprotein = Total Carbohydrate
Total Protein
Determination of biochemical parameters in
stomach and duodenum
H+/ K+ -ATPase activity: The H+/K+-ATPase
activity in the gastric mucosa was assayed for
by the method of Reyes-Chilpa et al.18.
Adherent gastric mucus content: The
adherent gastric mucus content in the stomach
was determined by the procedure of AlRashdi
et al.19. Glandular segments of the stomach
was removed and weighed. Each segment was
immediately placed into 10 mL 0.1% w/v alcian
blue solution (in 10 mL of 0.16 M sucrose
solution, buffered with 0.05 M sodium acetate
pH 5). After immersion for 2 h, excess dye was
removed by successively rinsing twice with 10
mL of 0.25 M sucrose, first for 15 min then
later for 45 min. The dye complexed with
stomach wall mucus was extracted with 10 mL
of 0.5 M MgCl2 with intermittent shaking for 1
min at 30 min intervals for 2 h. The 4 mL of the
alcian blue extract was added with an equal
volume of diethyl ether and shaken vigorously.
The emulsion obtained was span at 725 x g for
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10 min and absorbance of an aqueous layer
formed was read at 580 nm. Values were
compared with alcian blue concentration
standard curve.
Reduced glutathione concentration: The
reduced glutathione concentration was
determined in the stomach and duodenum
using the procedure of Ellman20.
Antioxidant enzymes: Superoxide dismutase
(SOD), catalase (CAT), glutathione reductase
(GSH-Red), glutathione peroxidase (GSH-Px)
and glutathione-S-transferase (GST) activities
in the stomach and duodenum were
determine21-25.
Lipid peroxidation: Lipid peroxidation in the
stomach and duodenum was determined using
the previous method26.
Histopathological examination: The procedure
described by Krause27 was used. The tissue
(stomach) was dehydrated through ascending
grades of ethanol (70%, 90% and 95% v/v). The
tissue was cleaned in xylene, embedded in
paraffin wax (melting point 56oC) and sections
were cut at 5 μm on a rotatory microtone. The
section was floated out on clean microscope
slides, which was previously lightly coated with
egg albumin preparation (albumenized) to
prevent detachment from slide during staining
procedure. It was air-dried for 2 h at 37oC and
stained with haematoxylin and eosin. The slide
was passed through ascending concentration
of alcohol (20-100%) for dehydration and
thereafter cleaned with xylene. A permanent
mounting medium was put on tissue section
and a thin glass covered slip was placed on the
covering-mounting medium and underlying
tissue section was allowed to dry and viewed
with light microscope.
Statistical analysis: Data represent the mean
of six replicates ± SEM. They were statistically
analyzed using one-way ANOVA with Duncan’s
Multiple Range Test (DMRT). Differences
between group means were considered
significant at p<0.05.
RESULTS
Table 1 shows the phytochemical screening of
the solvent-partitioned fractions from crude
ethanolic extract of A. mexicana leaf. Alkaloids
and flavonoids were present in the
ethylacetate fraction. Flavonoids were present
alongside saponins in the butanol fraction
while the n-hexane fraction did not contain
any of the secondary metabolites screened.
There was a significant increase (p<0.05) in
ulcer index (5.68±0.18 mm2), gastric volume
(5.69±0.05 mL), gastric acidity (4.89±0.29 mL)
Asian Journal of Emerging Research, 2021
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and a significant reduction (p<0.05) in pH value
(1.41±0.12) of ulcerated rats that received no
medical intervention when compared to the
control (Table 2).
Conversely, ethylacetate fraction of A.
mexicana leaf at 200 mg kg-1 b.wt.,
significantly attenuated the ulcer index
(1.64±0.12 mm2), gastric volume (3.12±0.10
mL), gastric acidity (1.45±0.04 mL) and
significantly increased the pH (4.54±0.16) to
values comparable to the omeprazole treated
group. The butanol fraction also showed a
promising effect as it also attenuated the ulcer
index (2.30±0.07 mm2), gastric volume
(3.82±0.13 mL), gastric acidity (2.26±0.20 mL)
and significantly (p<0.05) increased the pH
values (3.97±0.08) when compared to the
untreated group whereas the n-hexane
fraction did not cause any significant alteration
in the above ulcer indices when compared to
the ulcerated group that do not receive
medical intervention (Table 2). In Table 3,
gastric H+/K+ ATPase activity of the ulcerated
group (12.23±0.98 nmol-1 min-1 mg-1 protein)
increased significantly (p<0.05) upon
ulceration when compared to the control
(7.68±0.37 nmol-1 min-1 mg-1 protein) however
this proton pump activity was significantly
(p<0.05) reduced in the ethylacetate fraction
(7.74±0.47 nmol-1 min-1 mg-1 protein), butanol
(8.32±0.20 nmol-1 min-1 mg-1 protein) fraction
groups and reference drug (7.98±0.21 nmol-1
min-1 mg-1 protein) treated group when
compared to the ulcerated untreated group.
The ethylacetate fraction exhibited a better
activity than the reference drug by significantly
(p<0.05) reducing H+/K+ ATPase activity to
value similar with the control (7.68±0.37 nmol-
1 min-1 mg-1 protein). On the other hand, the
activity of H+/K+ ATPase in the hexane fraction
group (12.17 ± 1.06 nmol/min/mg protein) was
not significantly (p > 0.05) different with the
ulcerated group left with no medical
intervention (12.23±0.98 nmol-1 min-1 mg-1
protein). Figure 1 depicts pepsin activity in the
gastric juice of ulcerated rats treated with the
three solvent-partitioned fractions of A.
mexicana leaf. Administration of indomethacin
significantly increased (p<0.05) the pepsin
activity (6.4 mg mL-1) in the ulcerated
untreated group when compared to the
control (1.8 mg mL-1).
Treatment of ulcerated rats with each of 200
mg kg-1 b.wt., of ethylacetate and butanol
fractions significantly (p<0.05) reduced the
activity of pepsin to 2 and 3.2 mg mL-1
Asian Journal of Emerging Research, 2021
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respectively when compared to the ulcerated
group left untreated. Similarly, the
ethylacetate fraction demonstrated the best
efficacy as it was able to significantly (p<0.05)
decrease pepsin activity in a manner
comparable to the reference drug (2 mg mL-1).
The adherent mucus content in ulcerated rats
that received no medical intervention (25
mg/tissue) reduced significantly (p<0.05) when
compared to the control (63 mg/tissue).
However, the administration of 200 mg kg-1
b.wt., of ethylacetate fraction resulted to a
significant increase (p<0.05) in the adherent
mucus content (60 mg/tissue) in the stomach
of rats and compete favorably well with the
reference drug (56 mg/tissue) treated group
(Fig. 2). Also the adherent mucus content of
the butanol fraction treated (55 mg/tissue)
rats was not significantly (p>0.05) different
from the reference drug treated group (56
mg/tissue). Table 4 depicts the effect of
administration of the solvent-partitioned
fractions of A. mexicana leaf on the
glycoprotein concentration in the stomach of
indomethacin-induced ulcerated rats. The
administration of indomethacin resulted to a
significant depletion (p<0.05) in the total
carbohydrate concentration (58.24±0.22 ug
mL-1), glycoprotein concentration (1.07±0.21)
and a significant increase (p<0.05) in the total
protein concentration (54.38±0.21 ug mL-1) of
ulcerated rats when compared to the control
(130.36 ± 0.42, 3.05 ± 0.21 and 54.38 ± 0.16 ug
mL-1 respectively). The glycoprotein
concentration was significantly (p<0.05)
increased upon treatment of rats with the
three fractions when compared to the
ulcerated group that received no medical
intervention.
The glycoprotein concentration of rats that
received the ethylacetate fraction
(130.05±0.42) was similar to the concentration
of glycoprotein observed in the omeprazole
treated group (129.05±0.21) and the control
(130.36±0.42). In addition, the glycoprotein
concentrations in both the butanol fraction
treated group (117.86±0.24) and the n-hexane
treated group (54.94±0.10) were significantly
lower when compared to the control and the
omeprazole treated group. Figures 3 and 4
depict the activities of superoxide dismutase
(SOD) and catalase (CAT) activities in the
stomach and duodenum of ulcerated rats
treated with solvent-partitioned fractions of A.
mexicana leaf. Activities of superoxide
dismutase and catalase were significantly
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(p<0.05) reduced in the stomach (5.50 nmol-1
min-1 mg-1 protein for SOD, 45.71 nmol-1 min-1
mg-1 protein for CAT) and duodenum (7.10
nmol-1 min-1 mg-1 protein for SOD, 25.43 nmol-1
min-1 mg-1 protein for CAT) of ulcerated rats
with no medical treatment when compared to
the control where the activities of SOD and
CAT were 19.80 and 92.65 nmol-1 min-1 mg-1
protein in the stomach respectively and 20.02
nmol-1 min-1 mg-1 protein for SOD, 70.51 nmol-1
min-1 mg-1 protein for CAT in the duodenum of
the control rats . Treatment with 200 mg kg-1
each of ethylacetate, butanol and n-hexane
fractions significantly (p<0.05) upsurge the
activity of SOD to 20.03, 13.24 and 9.48 nmol-1
min-1 mg-1 proteins in the stomach of rats
respectively when compared to the ulcerated
group left untreated whereas in the
duodenum, only the ethylacetate fraction
(18.02 nmol-1 min-1 mg-1 protein) and butanol
fraction (14.76 nmol-1 min-1 mg-1 protein)
significantly (p<0.05) elevated the activity of
this enzyme (Fig. 3).
On a similar note, both ethylacetate and
butanol fractions significantly (p<0.05)
increased the activity of CAT in stomach (91.03
and 70.70 nmol-1 min-1 mg-1 protein
respectively) and in the duodenum (72.24 and
70.53 nmol-1 min-1 mg-1 protein respectively) of
ulcerated rats. The ethylacetate fraction
increased the activities of SOD (20.03 and
18.02 nmol-1 min-1 mg-1 protein in the stomach
and duodenum of the rats respectively) and
CAT (91.03 and 72.24 nmol-1 min-1 mg-1 protein
in the stomach and duodenum of the rats
respectively) similar to the activities observed
in the omeprazole treated group (19.60, 90.75
nmol-1 min-1 mg-1 protein for SOD and CAT in
the stomach respectively and 17.40, 70.94
nmol-1 min-1 mg-1 protein in the duodenum
respectively) (Fig. 3 and 4). There was
depletion in the level of reduced glutathione
(GSH) in the stomach (0.19 ± 0.01 nmol-1 mg-1
protein) and duodenum (0.17±0.01 nmol-1 mg-1
protein) of ulcerated rats when compared to
the control (58.15±0.25 and 28.50±0.44 nmol
mg-1 protein respectively). Upon treatment of
animals with ethylacetate and butanol
fractions, the level of glutathione significantly
(p<0.05) increased in both tissues of rats when
compared to the indomethacin-ulcerated rats
as this fraction remarkably boosted the GSH
level (0.41±0.01 nmol mg-1 protein in the
stomach and 0.55±0.02 nmol mg-1 protein in
the duodenum) better than the other two
fractions (Table 5).
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The 200 mg kg-1 b.wt., each of the
ethylacetate, butanol and n-hexane fractions
upon administration to animals significantly
(p<0.05) elevated the activity of glutathione
peroxidase which initially reduced in the
stomach and duodenum of ulcerated rats left
untreated. More so, the ethylacetate treated
group elevated the activity of this enzyme
(19.49±0.02 nmol mg-1 protein) in the stomach
of rats to a manner that leveled up with the
omeprazole treated group (19.23±0.04 nmol
mg-1 protein). Table 6 depicts the activities of
glutathione reductase and glutathione
transferase in the stomach and duodenum of
ulcerated rats treated with each of the
fractions of A. mexicana leaf. A significant
depletion (p<0.05) in the activity of
glutathione reductase was observed in the
stomach (31.28±0.30 nmol mg-1 protein) and
duodenum (10.39±0.09 nmol mg-1 protein) of
indomethacin-induced ulcerated rats when
compared to the control (58.15±0.25 nmol mg1
protein in stomach and 28.50±0.44 nmol mg-1
protein in the duodenum). This activity was
however significantly (p<0.05) enhanced in
both tissues of rats administered ethylacetate
fraction (58.35±0.37 nmol mg-1 protein in
stomach and 19.49±0.12 nmol mg-1 protein in
duodenum) and butanol fraction (56.80±0.35
nmol mg-1 protein in the stomach and
14.29±0.17 nmol mg-1 protein). The activity of
glutathione transferase significantly (p<0.05)
increased in the duodenum of rats that
received all fractions compared to the
ulcerated group with no treatment whereas in
the stomach of rats, only ethylaceatate and
butanol fractions significantly elevated
(p<0.05) the activity of glutathione transferase.
The result showed a better activity of
glutathione transferase in both tissues for the
ethylacetate fraction and was comparable to
the omeprazole treated group (Table 6).
A significant upsurge (p<0.05) in
malondialdehyde (MDA) concentration was
observed in the stomach (9.85 mol mg-1
protein) and duodenum (13.95 mol mg-1
protein) of ulcerated rats when compared to
the control (3.52 and 6.50 mol mg-1 protein
respectively). MDA concentration significantly
(p<0.05) reduced in both tissues of the animals
treated with each of the fractions.
Furthermore, the ethylacetate fraction
recorded a better MDA reduction efficacy of
4.74 and 7.40 mol mg-1 proteins in the stomach
and duodenum respectively than other two
fractions (3.50, 6.35 mol-1 mg protein for
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butanol fraction and 8.45 mol mg-1 protein,
10.75 mol mg-1 protein for and hexane fraction
in the stomach and duodenum respectively)
when compared to the control and rats that
received 20 mg kg-1 b.wt., omeprazole which
recorded 3.75 and 6.90 mol mg-1 proteins
reduction in MDA concentration in the
stomach and duodenum respectively (Fig. 5).
The macroscopic view of the stomach of the
control rats showed no ulcer lesion (Fig. 6a)
whereas the stomach of ulcerated animals that
received no medical attention manifested
ulcer lesion with severe hemorrhage (Fig. 6b).
Rats treated with 20 mg kg-1 b.wt., omeprazole
(Fig. 6c) and ethylacetate fraction (Fig. 6d)
showed prominent amelioration of ulcer
lesions in the stomach relative to the control
(Fig. 6a). Treatment of rats with the butanol
fraction also demonstrated promising gastric
lesion amelioration (Fig. 6e) while ulcer lesion
with appearance of hemorrhage was observed
in the stomach of ulcerated rats that received
the n-hexane fraction of A. mexicana leaf (Fig.
6f). Histopathological study on the control rats
revealed a normal appearance and
architecture of the gastric mucosal layers (Fig.
7a) whereas ulcerated rats with no medical
intervention demonstrated a severe
degeneration of gastric mucosal layers in the
stomach tissue, (Fig. 7b) when compared to
the control (Fig. 7a). Treatments of rats with
omeprazole (Fig. 7c), ethylacetate (Figure 7d)
and butanol fractions (Fig. 7e) of A. mexicana
leaf ameliorated the degenerated layers of the
gastric pit. Severe degeneration of the mucosal
layer with a mild amelioration was noticed in
rats that received n-hexane fraction as
medication (Fig. f7).
DISCUSSION
The ethylacetate fraction as evident from this
study showed the best anti-ulcerogenic
activity. The activity possessed by this fraction
maybe attributed to alkaloids and flavonoids
which are the only secondary metabolites
present in this fraction. Alkaloids and
flavonoids are phytochemicals whose anti-
ulcer activities have been established.
Alkaloids such as berberine and ephedrine
derived from the plant family Papaveraceae in
which Argemone mexicana belongs are known
to impair ulcer lesions produced by aggressive
agents and alter the secretion of gastric acid
by increasing the luminal gastric output of
basal bicarbonate and pH28. Flavonoids have
been reported to exhibit anti-ulcerogenic
activity by inhibiting gastric acid secretion and
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offer gastroprotection by increasing gastric
blood flow, stimulating mucus content and
increasing the protective effects of
prostaglandins on the gastric mucosal29.
Indomethacin a Non-steroidal anti-
inflammatory drug (NSAID) used to induce
ulcer in this study is one of the ulcer models
that has gained acceptance in assessing the
anti-ulcerogenic activity of a significant
number of plants.
The increase in gastric acidity of ulcerated rats
maybe due to the suppression of prostaglandin
by indomethacin which act through inhibition
of cyclo-oxygenase, an enzyme responsible for
the biosynthesis of prostaglandin that
stimulate the secretion of other defensive
factors (mucus, glycoprotein) and
subsequently increasing stomach gastric
output. The ulcer index measures the level of
excavation or lesion on the gastric mucosal.
The increase in ulcer index of ulcerated rats is
an indication of assault on the gastric mucosal
which may have resulted from the imbalance
between the acid/pepsin and defensive factors
of the mucosal caused by indomethacin. It has
been reported that NSAIDs like indomethacin
are capable of causing an imbalance between
gastric offensive factor and defensive factors2.
The pH is a reflection of gastric acidity known
to accompany increased gastric acid secretion.
Therefore it is evident from this study that
increased gastric acidity resulted to the
decrease in pH value observed in the ulcerated
group that received no medical intervention.
The increase in gastric acid volume is also a
reflection of increased gastric acid secretion as
gastric acid secretion is a determinant of the
gastric acid volume and increased gastric
volume is known to correlate to increased acid
secretion. The attenuation of these ulcerative
indices by the ethylacetate and butanol
fractions may indicate that the fractions
established equilibrium between the offensive
and defensive factors due to the presence of
flavonoids which stimulates prostaglandin
synthesis. Flavonoids have been reported to
increase prostaglandin production30 thus
subsequently enhance the mucosal barrier
against the damaging effect of acid.
The proton pump also called the H+/K+ ATPase
enzyme is the terminal stage involve in gastric
acid secretion and it is being directly
responsible for the secretion of H+ into the
lumen of the gastric mucosal in exchange for
K+ using the energy derived from the
hydrolysis of ATP. The increase in the H+/K+
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ATPase enzyme may indicate that
indomethacin activates or cause the up-
regulation of the proton pump thereby
subsequently increasing the gastric output in
the stomach. The decrease in the activity of
this pump which was more remarkable in the
ethylacetate treated rats may be attributed to
the presence of flavonoids causing the down-
regulation of the pump. Zerumbone, gingerol
and zingerone are flavonoids isolated from
Zingiber officinalis and have shown significant
influence in inhibiting parietal H+/K+ ATPase30.
Pepsin is responsible for proteolysis in the
stomach and its activity depends on gastric
acid output since gastric acid is required for its
acidification from pepsinogen to pepsin. The
increase in pepsin activity of ulcerated rats
may have resulted from the activated proton
pump which increased the gastric output and
subsequently increasing the pepsin activity
since gastric acid is required for acidification of
this proteolytic enzyme. Both mucus and
glycoprotein constitute the gel layer that coat
and promote the thickness of the gastric
mucosal barrier. The increase in adherent
mucus content and glycoprotein concentration
in ulcerated rats administered 200 mg kg-1
b.wt., of the ethylacetate and butanol
fractions which decreased in ulcerated rats
that received no medical intervention indicates
that both fractions were able to strengthen the
mucosal layer preventing it from the corrosive
effect of acid and pepsin. Cellular antioxidant
enzymes such as superoxide dismutase (SOD),
catalase (CAT), glutathione reductase (GSH-
Red), glutathione peroxidase (GSH-Px),
glutathione-S-transferase (GST) and non-
enzymic antioxidant reduced glutathione (GSH)
act as the first line of defense against oxidative
injury31 and once damaged ulceration may
result. The decrease in activities of SOD, CAT,
GSH-Red, GSH-Px and GST in ulcerated rats is
an indication of increased oxidative stress on
the gastric mucosa of rats induced by free
radicals resulting to an imbalance between
peroxidant and antioxidant enzymes.
Oxidative stress has been implicated in the
pathogenesis of indomethacin-mediated
ulceration32. The increase in the activities of
these antioxidant enzymes in the stomach and
duodenum of rats following their treatment
with the ethylacetate and butanol fractions
indicates that the fraction restored normalcy
from the assault caused by free radicals on
these antioxidant enzymes. This boost in the
antioxidant status may have been facilitated
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by flavonoids because flavonoids are known to
play significant role in the stabilization of the
antioxidant enzymes33. Superoxide dismutase
is a metal complexed enzyme that dismutase
superoxide anion to hydrogen peroxide and
oxygen. Hydrogen peroxide formed from
dismutation reaction catalyzed by superoxide
dismutase is capable of penetrating the
membrane where it decomposes into hydroxyl
radical a more powerful and damaging radical
therefore, scavenging hydrogen peroxide is
necessary. Catalase and glutathione
peroxidase function as enzymes to scavenge
hydrogen peroxide by reducing it to water as
well as water and oxygen respectively. GSH-Px
also catalyzes the hydrolysis of hydroperoxides
to their corresponding alcohols by using
reduced glutathione (GSH) which is later
oxidized to glutathione disulfide (GSSG).
Glutathione reductase (GSH-Red) generates
and recycles GSH for GSH-Px as substrate to
scavenge radicals and reduce hydrogen
peroxide. The depleted level of GSH may also
be due to the reduction in the activity of GSH-
Red resulting in concomitant reduction in the
level of GSH since GSH-Red is known to recycle
GSH. The level of glutathione which
remarkably increased in ulcerated rats treated
with ethylacetate and fractions in this study
might have resulted from the increased
activity of GSH-Red which replenishes GSH by
causing reducing GSSG. Lipid peroxidation is
the oxidative deterioration of polyunsaturated
fatty acids of the lipid components of the
plasma membrane.
Lipid peroxidation result from the reaction of
radicals such as hydroxyl radical with lipid
component of the plasma membrane and
malondialdehyde is a product used as a major
biomarker for lipid peroxidation. The increased
concentration of malondialdehyde observed in
ulcerated rats is a reflection of increased
oxidative stress induced on the gastric mucosal
membrane induced by indomethacin which is
one of the mechanisms of indomethacin in
ulcer formation34,35. The reversal of the lipid
peroxidation in rats treated with the fractions
(particularly ethylacetate and butanol) is an
indication that the fractions caused a marked
suppression in oxidative stress facilitated by
the presence of flavonoids in both fractions
acting as free radical scavengers in lipid
peroxidation31.
Histological changes are late manifestation of
assault on tissues36. The severe degenerated
architecture of the stomach is an indication of
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level of assault caused by indomethacin on
sub-mucosal layer of the stomach as seen in
the histological and microscopic view of the
stomach. Treatment of rats with ethylacetate
fraction of A. mexicana administered at 200
mg kg-1 was able to ameliorate the assault
caused by indomethacin on the gastric mucosa
and this amelioration was similar to what was
observed in the omeprazole group. This is an
indication of the wound healing property of
the plant facilitated by the presence of
flavonoids. From the study, the ethylacetate
fraction exhibited better activity in attenuating
the acid-secretory parameters and as well
ameliorating the antioxidant status of
ulcerated rats. Similarly, the butanol fraction
also exhibited a promising effect thus the
study suggest that the bioactive type of
flavonoids responsible for the anti-ulcerogenic
activity of A. mexicana may actually resides in
the ethylacetate fraction than the butanol
fraction since the ethylacetate fraction was the
most effective. In view of this, there is need to
further isolate the flavonoids in order to
establish this.
CONCLUSION
The study validates the anti-ulcerogenic
activity of Argemone mexicana leaf as
acclaimed in folk medicine of Nigeria with
evidence of attenuation of acid secretory
parameters, enhancement of both mucosa
mucus content and antioxidant enzymes in the
stomach and duodenum of rats. Study is
already on going to isolate and identify the
active principles in this plant and to propose
their mechanism of action.
SIGNIFICANCE STATEMENT
This study discovered that partitioned
fractions of Argemone mexicana leaves can
offer gastro-protection and ameliorate gastric
lesions in rats which can be beneficial for
treating peptic ulcer. This study will help in the
search for the development of a more
effective anti-ulcerogenic drug of plant origin.
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How to Cite this paper?
O.A. Idowu, O.A. Saliu, N.C. Fakorede and R.O Arise , 2021. Anti-Ulcerogenic Efficacy of Leaf
Fractions of Argemone mexicana Against Indomethacin Induced-Ulceration in Rats Asian J. Emerg.
Res., 3(2): 129-136.
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Background & Aims There is controversy over whether psychological stress contributes to development of peptic ulcers. We collected data on features of life stress and ulcer risk factors from a defined population in Denmark and compared these with findings of confirmed ulcers over the next 11−12 years. Methods We collected blood samples and psychological, social, behavioral, and medical data, in 1982−1983, from a population-based sample of 3379 Danish adults without a history of ulcer participating in the World Health Organization’s MONICA Study. A 0−10 point stress index scale was used to measure stress, based on concrete life stressors and perceived distress. Surviving eligible participants were re-interviewed in 1987−1988 (n=2809) and 1993−1994 (n=2410). Ulcer was diagnosed only for patients with a distinct breach in the mucosa. All diagnoses were confirmed by review of radiological and endoscopic reports. Additional cases of ulcer were detected in a search of 3379 subjects in the Danish National Patient Register. Results Seventy-six subjects were diagnosed with ulcer. Based on the stress index scale, ulcer incidence was significantly higher among subjects in the highest tertile of stress scores (3.5%) than the lowest tertile (1.6%) (adjusted odds ratio, 2.2; 95% confidence interval [CI], 1.2−3.9; P<.01). The per-point odds ratio for the stress index (1.19; 95% CI, 1.09−1.31; P<.001) was unaffected after adjusting for the presence of immunoglobulin G antibodies against H pylori in stored sera, alcohol consumption, or sleep duration, but lower after adjusting for socioeconomic status (1.17; 95% CI, 1.07−1.29; P<.001), and still lower after further adjustments for smoking, use of non-steroidal anti-inflammatory drugs (NSAIDs), and lack of exercise (1.11; 95% CI, 1.01−1.23; P=.04). The risk for ulcer related to stress was similar among subjects who were H pylori seropositive, those who were H pylori seronegative, and those exposed to neither H pylori nor NSAIDs. On multivariable analysis, stress, socioeconomic status, smoking, H pylori infection, and use of NSAIDs were independent predictors of ulcer. Conclusions In a prospective study of a population-based Danish cohort, psychological stress increased the incidence of peptic ulcer, in part by influencing health risk behaviors. Stress had similar effects on ulcers associated with H pylori infection and those unrelated to either H pylori or use of NSAIDs.
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