Antiulcer activity of natural compounds: A review
S. Prakash Rao1*, Indu
Amrit1, Vijay Singh1, Parag
Jain2
1Columbia
Institute of Pharmacy, Tekari, Raipur India-493111
2Department
of Pharmacology, Institute of Pharmaceutical Sciences,
Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur India-495009
*Corresponding Author E-mail: spr_pharma@yahoo.co.in
ABSTRACT:
Peptic ulcer is a break in the lining of
the stomach, first part of the small intestine, or duodenum. The duodenum is
the first part of the small intestine. Contrary to popular belief, ulcers are
not caused by spicy food or stress but instead are most commonly due to either
an infection or long-term use of certain medications. The main goals for
treating a peptic ulcer include eliminating the underlying cause (particularly
H. pylori infection or use of NSAIDs), preventing further damage and
complications, and reducing the risk of recurrence. Peptic ulcer which is
mainly caused by bacterial attack or excess of acid secretion can be cured
effectively by these isolated plant compounds. A number of drugs including
proton pump inhibitors and H2 receptor antagonists are available for the
treatment of peptic ulcer, but clinical evaluation of these drugs has shown
incidence of relapses, side effects, and drug interactions. This has been the
rationale for the development of new antiulcer drugs and the search for novel
molecules has been extended to herbal drugs that offer better protection and
decreased relapse. Craving for herbal medicines are still importance due lesser
chance of adverse effects and easily available in surrounding place with low
cost. In this review attempts have been made to summarize medicinal plants and
their constituents used for peptic ulcer by the people of rural area which may
be beneficial for the modern science.
KEYWORDS: Antiulcer, Isolated compounds, Alkaloids, flavonoids, Terpenoids.
INTRODUCTION:
A history of heartburn, gastroesophageal reflux disease (GERD) and use of certain
forms of medication can raise the suspicion for peptic ulcer. Medicines
associated with peptic ulcer include NSAIDs (non-steroid anti-inflammatory
drugs) that inhibit cyclooxygenase, and most
glucocorticoids (e.g. dexamethasone and prednisolone). A major causative factor (60% of gastric and
up to 50-75% of duodenal ulcers) is chronic inflammation due to Helicobacter
pylori that colonizes the antral mucosa. The immune
system is unable to clear the infection, despite the appearance of antibodies.
Thus, the bacterium can cause a chronic active gastritis (type B gastritis). Gastrin stimulates the production of gastric acid by
parietal cells. In H. pylori colonization responses to increased gastrin, the increase in acid can contribute to the erosion
of the mucosa and therefore ulcer formation. In Western countries the
percentage of people with Helicobacter pylori infections roughly matches age
(i.e., 20% at age 20, 30% at age 30, 80% at age 80 etc.) [1].
Prevalence is higher in third world
countries where it is estimated at about 70% of the population, whereas
developed countries show a maximum of 40% ratio.
Ulcers are an open sore of the skin or
mucus membrane characterized by sloughing of inflamed dead tissue. A gastric
ulcer would give epigastric pain during the meal, as
gastric acid production is increased as food enters the stomach. Symptoms of
duodenal ulcers would initially be relieved by a meal, as the pyloric sphincter
closes to concentrate the stomach contents; therefore acid is not reaching the
duodenum [2]. Peptic ulcer disease (PUD) is an illness that affects a
considerable number of people worldwide. It develops when there is an imbalance
between the aggressive and protective factors at the luminal surface of
the epithelial cells. Aggressive factors include Helicobacter pylori, HCl, pepsins, nonsteroidal
anti-inflammatory drugs (NSAIDs), bile acids, ischemia, hypoxia, smoking and
alcohol. While defensive factors include bicarbonate, mucus layer, mucosal
blood flow, PGs and growth factors. [3] Burning or gnawing feeling in the
stomach area lasting between 30 minutes and 3 hours commonly accompanies ulcers
[4].
In order to achieve this aim, various
sources like ancient traditional books, journals, libraries and internet were
explored for each of the medicinal plants for peptic ulcers and all retrieved
articles were evaluated to achieve any in vitro, in vivo, or clinical evidence
for their efficacy and possible mechanisms.
Etiology and Pathogenesis
Peptic ulcer occurs in that part of the
gastrointestinal tract (GIT) which is exposed to gastric acid and pepsin i.e.
the stomach and duodenum. The etiology of peptic ulcer is not clearly known. It
results probably due to an imbalance between the aggressive (acid, pepsin, bile
and Helicobacter pylori) and the defensive (gastric mucus and
bicarbonate secretion, prostaglandins, nitric oxide, innate resistance of the
mucosal cells) factors [5].
A variety of psychosomatic, humoral and vascular derangements have been implicated and
importance of Helicobacter pylori infection as a contributor to ulcer
formation and recurrence has been recognized [6].
In gastric ulcer; acid secretion is normal
or low. In duodenal ulcer; acid secretion is high in half of the patients but
normal in the rest. Notwithstanding whether production of acid is normal or
high, it does contribute to ulceration as an aggressive factor, reduction of
which is the main approach to ulcer treatment.
Regulation of
Acid Secretion by Parietal Cells
The regulation of acid secretion by
parietal cells is especially important in the pathogenesis of peptic ulcer, and
constitutes a particular target for drug action. The secretion of the parietal
cells is an isotonic solution of HCl (150 m mol/l)
with a pH less than 1, the concentration of hydrogen ions being more than a
million times higher than that of the plasma. The Cl-is
actively transported into canaliculi in the cells
that communicate with the lumen of the gastric glands and thus with the stomach
itself. This Cl- secretion is accompanied by K+,
which is then exchanged for H+ from within the cell by a K+/H+ ATPase (+ and bicarbonate ions [7]. The later exchanges across the basal membrane of the parietal
cell for Cl-. The principal stimuli acting on the
parietal cells are:
Gastric: Gastrin is a
peptide hormone synthesized in endocrine cells of the mucosa of the gastric antrum and duodenum, and secreted into the portal blood.
Its main action is stimulation of the secretion of acid by the parietal cells. Gastrin also indirectly increases pepsinogen
secretion, stimulates blood flow and increases gastric motility. Release of
this hormone is controlled both by neuronal transmitters and blood-borne
mediators, as well as the chemistry of the stomach contents. Amino acids and
small peptides directly stimulate the gastrin-secreting
cells.
Acetylcholine: Acetylcholine is released from (e.g.vagal) neurons and stimulates specific muscarinic receptors on the surface of the parietal cells
and on the surface of histamine-containing cells.
Histamine: Within the stomach, mast cells (or
histamine-containing cells similar to mast cells) lying close to the parietal
cell release a steady basal release of histamine, which is further increased by
gastrin and acetylcholine. The hormone acts on
parietal cell H2 receptors, which are responsive to histamine concentrations
that are below the threshold required for vascular H2 receptor activation.
Prostaglandins: Prostaglandins (mainly E2 and I2), synthesised in the gastric mucosa mainly by
cyclo-oxygenase-1, stimulate mucus and bicarbonate secretion, decrease acid
secretion and cause vasodilatation, all of which serve to protect the stomach
against damage (Figure-1).
Animal Models Used in the Screening of Antiulcer
Activity
Various screening models are used for the screening of the anti ulcer
activity it helps to understanding the etiology of the ulcer and screening of
anti ulcer agents.
Cold restrain stress induced
ulcer: Animal
of different groups were subjected to cold stress after 45 min of the formulation
and OMZ treatment. Rats were deprived of food, but not water, for about 18 h
before the experiment. Rats were immobilized by strapping the fore and hind
limbs in restraint cage and kept for 2 hr, at a temperature of 4°C. After 2 hr,
animals were sacrificed, the stomach was incised along the lesser curvature and
ulcer was scored as: Red coloration (0.5), Spot ulcer (1), hemorrhagic streak
(1.5), Ulcers (2), Perforation (3). Mean ulcer score for each animal was
expressed as ulcer index. The percentage of ulcer protection was calculated as- Mean ulcer index of control-mean ulcer
index of test / mean ulcer index of control x 100. [8]
Aspirin induced ulcers: The above sections. After 45 min of formulations (6
ml/kg, p.o.) or ranitidine (50 mg/kg, p.o.) treatment to different groups, the animals were
administered with aspirin in dose of 500 mg/kg. The animals were sacrificed
after 4 h and the stomach was then excised and cut along the greater curvature,
rinsed gently with saline to remove the gastric contents and blood clots. Ulcer
index was then calculated by adding the total number of ulcers and calculate
ulcer index. [9]
Figure 1-Formation of ulcer
Ethanol induced ulcer: The
animals were divided into five groups as described above except that catechin (200 mg/kg, p.o.) was
used as standard. The gastric ulcers were induced in rats by administrating
absolute ethanol (99%) (1 ml/200 g) orally, after 45 min of formulations. They
were kept in specially constructed cages to prevent coprophagia
during and after the experiment. The animals were anaesthetized one hour later
with anesthetic ether and stomach was incised along the greater curvature and
ulceration was scored. The percentage of ulcer protection was calculated as
mean ulcer index of control-mean ulcer index of test / mean ulcer index of
control x 100. [10]
Pylorus Ligation Induced Ulcer: After 1 hr of treatment to different groups, the animals were
anaesthetized using thiopentone sodium (35 mg/kg, i.p.), the abdomen was opened and pylorus ligation was done
without causing any damage in its blood supply. After 4 hr their stomachs were
dissected and its contents were collected into tubes for analysis of volume of
gastric juice, pH, total and free acidity. The ulcers were scored as described
under cold stress induced ulcers. The gastric juice was collected after 4 hr of
Pylorus ligation induced ulcers and centrifuged for 5 min at 2000 rpm. The
supernatant was collected and the volume of gastric juice was expressed as
ml/100 g body weight. Total acidity was determined in the supernatant by
titrating against 0.01 N NaOH, using 2-3 drops of topfers reagent as indicator until canary yellow color was
observed. Volume of NaOH required was noted and this
corresponds to free acidity. Further 2-3 drops of phenolphthalein was added and
titrated with 0.01 N NaOH until pink color was
restored and this gives total acidity. Free acidity and total acidity is
expressed in terms of 0.1 N HCL per 100 g of gastric contents. [11]
Water immersion stress
induced ulcers: Stress induced ulcers were induced by force swimming
in the glass cylinder (height 45cm diameter 35cm) containing water up to 35cm
maintained at 35oc for 3 hrs. Animals were fasted 24 hrs prior to the
experiment. After the drug treatment (standard/test) animals were allowed to
swim for 3hrs then animal were dissected stomachs were removed. All stomachs
were opened along the greater curvature ulcer index and % inhibition was
calculated and Histopathological studies conducted.
[12]
Indomethacin induced ulcers: All the animals were fasted 36 hours before
administration of Indomethacin. The animals were
divided into groups. Each rat was administered with the 20mg/kg Indomethacin orally.30 min prior to the administration of
the Indomethacin standard/test drug was administered.
The rats were anaesthetized with ether 1 hour latter the stomach was incised
through the greater curvature and examined for the number of lesion under the
dissecting microscope by titrating with 0.01N NaOH
using phenolphthalein as an indicator. gastric juice estimated for pepsin.
Ulcer index and % inhibition were calculated and histopathological
studies conducted for the stomach tissues. [13]
Histamine induced ulcers: Guinea pigs weighing (300-400 gm) were divided into
groups of six each and the animals were fasted for 36 hours (water allowed)
before experiment. One ml of histamine acid phosphate (50 mg base) was
administered intraperitoneally. Promethazine
hydrochloride 5 mg was injected intraperitoneally 15
min before and 15 min after histamine administration. The standard/test
drugs were administered by gavage 45 minutes before
histamine. Four hours after administration of histamine, the guinea pigs were
sacrificed by stunning. The anterior abdominal wall was opened and the stomach
dissected out. Stomach was opened along the greater curvature ulcers were
identified. Severity scores were calculated. Histopathological
studies were conducted on the stomach tissues. [14]
Reserpine induced ulcers: Adult albino rats weighing 150-180gms were fasted for
24 hr. Animals were divided into different groups following water ad libitum. Reserpine (5mg/kg)
administered intramuscularly rats. 30 min after the administration of the
standard or test drug or control vehicle (Distilled water) intraperitoneally.
All the animals were sacrificed after 18 hr, their stomachs were removed,
opened along the greater curvature and sum of lengths (mm) of all lesions for
each rat was used as ulcer index and percentage protection of ulcers were
calculated. Histopathological studies were performed
on the stomachs tissues. [15]
Serotonin induced ulcers: Rats weighing 120-150gms were taken and they were
randomly divided into groups. Animals kept fasting for 24hrs and water
withdrawn 2hr before the experiment. Serotonin creatinine
sulphate (20mg/kg) was administered subcutaneously to
rats. The standard drug/test drug/ control vehicle (Distilled water) was
administered intraperitoneally after 30 min prior to
the serotonin injection. The animals were sacrificed after 18 hr, their stomachs
were removed and opened along the greater curvature, and the ulcer index was
determined. Percentage protection of the ulcers calculated. Histopathological
studies were conducted. [16]
Acetic acid induced ulcers: Rats were anaesthetized with pentobarbitone
(35 mg/kg, ip). The abdomen was opened and the
stomach was visualized. A cylindrical glass tube (6 mm in diameter) was tightly
placed upon the anterior serosal surface of the
glandular portion of stomach 1 cm away from the pyloric end. 50% acetic acid
(0.06 ml/animal) was instilled into the tube and allowed to remain for 60 sec
on the gastric wall . After removal of acid solution, the abdomen was closed in
two layers and animals were caged and fed normally. Standard and test drug
administered orally 4 h after the application of acetic acid and continued up
to 9 days after induction of ulcer. The animals were then sacrificed after 18 h
of the last dose of drug on 10th day of experiment to assess the ulcer size and
healing. Ulcer index was calculated based upon the product of length and width
(mm2/ rat) of ulcers. [17]
Hydrochloric acid induced ulcers: Rats weighing 150-180gms are taken and they were
divided into groups. Thirty minutes after the test or reference drug or the
control vehicle treatment, 0.6 M HCl was orally
administered to each rat. After 1 h the rats were anaesthetised
with excess of anaesthetic ether and stomach was cut
open along the greater curvature, cleared of residual matter with saline and
the inner surface was examined for ulceration. Ulcer index and % ulcer protection.
Histopathological were conducted by Gastric tissue
samples from each group were fixed in 10% formalin for 24 h. The formalin fixed
specimens are embedded in paraffin and section (3-5μm) and stained with haematoxylin and eosin dye. The histochemical
sections are evaluated by light microscopy. [18]
Active
Principles with Antiulcer Activity
Chemical constituents of plants are
responsible for various pharmacological activities. These constituents may be
alkaloids, trepenoids, flavonoids,
glycosides, terpens and resins. The list of
biological sources provided which gives active compounds with antiulcer
activity (Table-1).
Table 1- Chemical Constituents from
medicinal plants with Antiulcer Activity
2.
Harsh Mohan. Text book of pathology .sixth edition, jaypee publishers. 2009, 549-555.
Received on 01.05.2015 Modified
on 14.05.2015