Foeniculum vulgare" Treatment Protects the Gastric Mucosa
of Rats against Chemically-induced Histological Lesions" />
Fennel "Foeniculum vulgare" Treatment Protects the Gastric Mucosa
of Rats against Chemically-induced Histological Lesions
This study evaluated anti-gastric ulcer and anti-secretory
effects of folkloric medicinal plant, Foeniculum vulgare L., (Family:Apiaceae)
in rats. The gastric ulcer protective potential of an aqueous suspension of
'Fennel' Foeniculum vulgare (FVS) was evaluated against different acute
gastric ulcer models in rats induced by pyloric ligation (Shay), hypothermic
restraint stress, indomethacin and by necrotizing agents (80% ethanol, 0.2 M
NaOH and 25% NaCl). Fennel suspension, 250 and 500 mg kg-1 b.wt.
administered orally (intraperitoneally in Shay rat model) showed a dose-dependent
ulcer protective effects in all the above models. Besides, the FVS offered protection
against ethanol-induced depletion of Gastric Wall Mucus (GWM); replenished the
reduced nonprotein sulfhydryls (NP-SH) concentration and modulated malondialdehyde
(MDA) contents in the gastric tissue. Ethanol induced histopathological lesions
of the stomach wall characterized by mucosal hemorrhages and edema that was
reversed by FVS. Pretreatment of rats with FVS provided significant protection
of gastric mucosa through its antioxidant capacity and/or by attenuating the
offensive and by enhancing the defensive factor.
to cite this article:
Ibrahim Al-Mofleh, Mohamed Al-Sobaihani, Saleh Alqasoumi, Mansour Al-Said, Mohammed Al-Dosari, Mohamed Al-Yahya and Syed Rafatullah, 2013. Fennel "Foeniculum vulgare" Treatment Protects the Gastric Mucosa
of Rats against Chemically-induced Histological Lesions. International Journal of Pharmacology, 9: 182-189.
Received: February 09, 2013;
Accepted: June 04, 2013;
Published: August 03, 2013
Fennel "Foeniculum vulgare Miller" (Family:Apiaceae) is a typical aromatic
plant, long been used as a medicinal and spice herb in traditional medicine
of many countries including Saudi Arabia. Fennel is used for the treatment of
liver, gall bladder and gastric ailments such as indigestion, colicky pain,
nausea and flatulence. Fennel essential oils are used in cosmetics, including
soaps, detergents, creams, lotions and perfumes (Leung, 1980;
Chomdler and Hawkes, 1984; Grieve,
1971). It is oftenly used with various purgatives to reduce their tendency
to cause gripping (Abdul-Ghani and Amin, 1988). The
boiled water extract of fennel leaves is known to cause decrease in blood pressure
of experimental animals (Ageel et al., 1987).
The ethanolic extract of fennel is known to have significant anti-inflammatory,
analgesic and antipyretic activity and is reported to increase bile flow (Mascolo
et al., 1987). Fennel water is commonly given to infants to relieve
colic. In an earlier study on Ehrlich ascites carcinoma cells in paw
of mice, anethol a major component of fennel oil was found to be anticarcinogenic,
cytotoxic and non-clastogenic (Al-Harbi et al., 1995).
In a recent study fennel extract showed beneficial against ethanol-induced gastric
mucosal injury (Birdane et al., 2007). Clinical
studies also revealed anethole to possess no carcinogenic risk for humans (Newberne
et al., 1989; Truhaut et al., 1989).
Fennel Generally Regarded as Safe (GRAS) status for human consumption. In a
study fennel extract has been reported to contain anti-oxidant components (Garga
et al., 2009). Several compounds including trans-anethole, estragole,
fenchone and polyphenolics have been found in this plant (Ghanem
et al., 2012).
To substantiate the claimed gastric antiulcer activity of fennel in the powdered dosage form (a commonly used dosage form in Arab, Ayurveda and Unani medicine practices); the present study was carried out to evaluate antiulcerogenic potential of Fennel aqueous suspension (FVS) on various in vivo experimental gastric ulcer models in rats.
MATERIALS AND METHODS
Plant material and preparation of dosage form: The fennel fruits were purchased from a local crude drugs supplier in Riyadh. The fennel was identified by an expert taxonomist; the specimen was deposited in the herbarium of the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. The fennel fruits were pulverized to a very fine powder to a particle size (mesh # 75 μ) and freshly dissolve in distilled water just before the administration to the animals.
Animal and protocol: Wistar albino rats of either sex, approximately of the same age, weighing 150-200 g and fed standard chow diet were used. They were divided into groups of six animals each. The distribution of animals in groups, the sequence of trials and the treatments were randomized. The solutions of the ulcerogenic drugs and necrotizing agents were freshly prepared and the animals were killed by ether euthanasia. The stomachs were removed, opened along the greater curvature, washed with saline and examined with a 6.4 x binocular magnifier and the gastric tissues were also used for biochemical estimations and histological assessment. Lesions were also assessed by two observers unaware of experimental protocols. The animal study protocol was approved by the Research and Ethnics Committee of the Experimental Animal Care Society, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Pylorus ligated (Shay) rats: The animals were fasted for 36 h with access
to water ad libitum before the pylorus was ligated under light ether
anesthesia, care being taken not to cause bleeding or to occlude blood vessels
(Shay et al., 1945). FVS administered immediately
after pylorus ligation by intraperitoneal injection. The animals were sacrificed
6 h after the pylorus ligation, stomachs were removed and contents were collected,
measured, centrifuged and subjected to analysis for titratable acidity against
0.01 N NaOH to pH 7. Each stomach was examined for lesions.
Hypothermic restraint stress-induced ulcers: The method of Levine
(1971) was followed with slight modification. The animals were fasted for
36 h with access to water ad libitum. One hr after receiving oral drug
(FVS) treatment, they were immobilized in restraint cages and placed inside
a ventilated refrigerator maintained at a temperature of 2-4°C. After 3
h they were taken out and sacrificed. The stomachs were excised and examined
for the severity of intraluminal bleeding according to the following arbitrary
scale: 0, no blood detectable; 1, thin blood follows the rugae; 2, thick blood
follows the rugae; 3, thick blood follows the rugae with blood clots in certain
areas and 4, thick blood (Chiu et al., 1984).
After wiping the blood off, the total area of lesions in each stomach was scored.
Indomethacin-induced gastric ulcers: Indomethacin was suspended in 1%
Carboxy-methyl Cellulose (CMC) in water and administered orally to the 36 h
fasted rats at a dose of 30 mg kg-1 b.wt. Control rats were treated
similarly with an equivalent amount of vehicle (Bhargava
et al., 1973). FVS was given 30 min prior to indomethacin administration
at a dose of 250 and 500 mg kg-1. The animals were sacrificed 6 h
after treatment. The stomachs were excised, rinsed with normal saline and examined
Gastric lesions induced by necrotizing agents: Each rat was administered
1 mL of a necrotizing agent (80% ethanol, 0.2 M NaOH or 25% NaCl). Fennel suspension
was given 30 min before the administration of necrotizing agents. One hour after
the administration of ethanol and the alkalis, the rats were sacrificed and
examined for stomach lesions. The scoring of stomach lesions was as follows:
Patchy lesions of the stomach induced by ethanol and hypertonic solutions were
scored according to the method described by Robert et
al. (1983) using the following scale: 0 = normal mucosa; 1 = hyperemic
mucosa or up to 3 small patches; 2 = from 4 to 10 small patches; 3 = more than
10 small or up to 3 medium-sized patches; 4 = from 4 to 6 medium-sized or up
to 3 large patches; 6 = from 4 to 6 large patches; 7 = from 7 to 10 large patches;
8 = more than 10 large patches or extensive necrotic zones. "Small" was defined
as up to 2 mm across (max. diameter), "medium-sized" between 2 and 4 mm across
and "large" more than 4 mm across.
Determination of gastric wall mucus (GWM): Gastric wall mucus was determined
according to the modified procedure of Corne et al.
(1974). The glandular segment of the stomach was separated from the rumen
of the stomach, weighed and transferred immediately to 10 mL of 0.1% w/v Alcian
blue solution (in 0.16 mmol L-1 sucrose solution buffered with 0.05
mL sodium acetate at pH 5). Tissue was stained for 2 h in Alcian blue and excess
dye was removed by two successive rinses with 10 mL of 0.25 mmol L-1
sucrose, firstly after 15 min and then after 45 min. Dye complexed with the
gastric wall mucus was extracted with 10 mL of 0.5 mmol L-1 magnesium
chloride which was intermittently shaken for 1 at 30 min intervals for 2 h.
Four milliliters of blue extract were then vigorously shaken with an equal volume
of diethyl ether. The resulting emulsion was centrifuged at 4000 rpm min-1
for 10 min and the absorbance of the aqueous layer was recorded at 580 nm. The
quantity of Alcian blue extracted per gram of wet glandular tissue was then
Estimation of non-protein sulfhydryl (NP-SH) in gastric tissue: Gastric
mucosal non-protein sulfhydryls were measured according to the method of Sedlak
and Lindsay (1968). The glandular part of the stomach was homogenized in
ice-cold 0.02 mmol L-1 ethylenediaminetetraacetic acid (EDTA). Aliquots
of 5 mL of the homogenates were mixed in 15 mL test tubes with 4 mL of distilled
water and 1 mL of 50% Trichloroacetic Acid (TCA). The tubes were shaken intermittently
for 10 min and centrifuged at 3000 rpm min-1. Two milliliters of
supernatant were mixed with 4 mL of 0.4 mol L-1 Tris buffer at pH
8.9. 0.1 mL of 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) was added and the
sample was shaken. The absorbance was measured within 5 min of DTNB addition
at 412 nm against a reagent blank.
Estimation of malondialdehyde (MDA) in gastric tissue: The method reported
by Utley et al. (1967) followed. The animals
were killed 1 h after ethanol administration. The stomachs were removed and
each was homogenized in 0.15 mol L-1 KCl (at 4°C) in a Potter-Elvehjem
type C homogenizer to give a 10% w/v homogenate. Aliquots of homogenate 1 mL
in volume were incubated at 37°C for 3 h in a metabolic shaker. Then 1 mL
of 10% aqueous TCA was added and mixed. The mixture was then centrifuged at
800 g for 10 min. One milliliter of the supernatant was removed and mixed with
1 mL of 0.67% 2-thiobarbituric acid in water and placed in a boiling water bath
for 10 min. The mixture was cooled and diluted with 1 mL distilled water. The
absorbance of the solution was then read at 535 nm. The content of malondialdehyde
(nmol/g wet tissue) (index of the magnitude of lipid peroxidation) was then
calculated, by reference to a standard curve of malondialdehyde solution.
Histopathological evaluation: Gastric tissue samples were fixed in neutral
buffered formalin for 24 h. Sections of gastric tissue were histopathologically
examined to study the ulcerogenic and/or anti-ulcerogenic activity of FVS. The
tissues were fixed in 10% buffered formalin and processed using a tissue processor.
The processed tissues were embedded in paraffin blocks and sections about 5
μm thick were cut using an American optical rotary microtome. These sections
were stained with haematoxylin and eosin using routine procedures (Culling,
1974). The slides were examined microscopically for pathomorphological changes
such as congestion hemorrhage, edema and erosions using an arbitrary scale for
severity assessment of these changes.
Statistical analysis: Values in tables and figures are given as Mean±SE.
Data were analyzed by using one-way Analysis of Variance (ANOVA) followed by
Dunnett's multiple comparison tests.
An increased accumulation of gastric secretory volume, titratable acidity and ulceration in 6 h, pylorus ligated Shay rats were shown significant inhibition of gastric secretory volume, acidity and ulceration in the animals treated with fennel aqueous suspension evident by ulcerative index which is 0.83±0.30, 0.33±0.21 and 0, respectively (Table 1).
Animals subjected to restraint plus cold for 3 h showed the presence of considerable ulcerogenicity as indicated by ulcerative index (18.343±0.94) in the form of hemorrhagic mucosal lesions in the stomach which were confined to the glandular segment only. There was also evidence of intraluminal bleeding in these animals. Treatment with FVS 250 and 500 mg kg-1 produced a significant and dose-dependent inhibition of ulceration and intraluminal bleeding as indicated ulcerative index (13.33±1.11 and 5.66±2.07) of both group (Table 2).
Administration of indomethacin resulted in the production of gastric lesions
mainly in the glandular segment of the stomach of rats its ulcerative index
||Effect of Fennel aqueous suspension (FVS) on the volume of
gastric secretion, titratable acidity and the degree of ulceration in 6
h pylorus ligated (Shay) rats
|Six animals were used in each group. **p<0.05; **p<0.001.
ANOVA, followed by Dunnett's multiple comparison tests
||Effect of Fennel aqueous suspension (FVS) on hypothermic restraint
stress-induced intraluminal bleeding and gastric lesion in rats
|Six rats were used in each group. *p<0.05, **p<0.01,
***p<0.001. ANOVA, followed by Dunnett's multiple comparison tests
Pretreatment of animals with FVS significantly decrease the intensity of gastric
mucosal damage induced by indomethacin as indicated by ulcerative index in higher
dose group (Table 3). However, in the lower dose (250 mg kg-1)
group the protection was not statistically significant.
Lowered gastric wall mucus was observed in the animals treated with 80% ethanol and this depletion of wall mucus was significantly reversed by pretreatment with fennel suspension (Fig. 1).
Necrotic patches of the stomach, induced by noxious chemicals were found to be significantly reduced in the groups of animals pretreated with aqueous suspension of fennel as indicated by ulcerative index of (5.66±1.05, 2.66±0.42 and 1.66±0.16) of control, FVS 250 mg kg-1 and FVS 500 mg kg-1 (Table 4).
The gastric mucosal NP-SH contents were 34% decreased as compare to control after the administration of 80% ethanol. While treatment with FVS 250 and 500 mg kg-1 dose replenished ethanol-induced decrease in NP-SH level from 23 to 12% as compare with control (Fig. 2).
As depicted in Fig. 3, MDA levels in the gastric mucosa used as an index of lipid peroxidation were significantly higher in the ethanol only treated group than in the untreated control group. FVS at the dose of 500 mg kg-1) significantly decreased the MDA content of the gastric tissue.
||Effect of Fennel aqueous suspension (FVS) on the gastric mucosal
damage induced by indomethacin in rats
|*p<0.05. Dunnett's multiple comparison tests
||Effect of Fennel aqueous suspension (FVS) on the gastric lesions
induced by various necrotizing agents in rats
|*p<0.05, **p<0.01, ***p<0.001. ANOVA, followed by
Dunnett's multiple comparison tests
||Effect of Fennel aqueous suspension (FVS) on 80% ethanol-induced
gastric wall mucus changes in rats. All values represent Mean±SEM.
***p<0.001; ANOVA, followed by Dunnett's multiple comparison
tests. aAs compared with control group. bAs compared
with 80% ethanol group
||Effect of Fennel aqueous suspension (FVS) on glutathione (NP-SH)
concentration in gastric tissue of rats. All values represent Mean±SEM.
*p<0.05; ***p<0.001; ANOVA, followed by Dunnett's multiple
comparison test. aAs compared with control group. bAs
compared with 80% ethanol group
||Effect of Fennel aqueous suspension (FVS) on malondialdehyde
(MDA) concentration in gastric tissue of rats. All values represent Mean±SEM.
**p<0.01; ***p<0.001; ANOVA, followed by Dunnett's multiple
comparison test. aAs compared with control group. bAs
compared with 80% ethanol group
||Section through gastric mucosa of (a) Control rat showing
normal appearance, (b) Rat treated with ethanol (80%, 1 mL) showing evidence
of mucosal erosions, intramucosal haemorrhage and edema. A haemorrhagic
focus is also seen in the submucosal layer, (c) Foeniculum vulgare
(250 mg kg-1) and ethanol (80%, 1 mL) showing the presence of
mucosal ulceration and haemorrhage. The submucosa is edematous and (d) Foeniculum
vulgare (500 mg kg-1) and ethanol (80%, 1 mL) showing superficial
ulceration, vascular congestion and submucosal edema. Haematoxylin and Eosin
Histopathological studies (Fig. 4a-d) further
confirmed that pretreatment with FVS reduces the intensity of ethanol-induced
various indices of the gastric mucosa.
The present study demonstrated that the aqueous suspension of fennel strongly
inhibits basal gastric acid secretion by pylorus ligation and ulceration induced
by hypothermic restraint stress induced and various necrotizing agents and indomethacin.
It is well known that gastric acid is involved in the pathogenesis of peptic
ulcer disease and a correlation has been established (Howden,
2004; Hara et al., 1991) between increased
gastric acid secretion and gastric lesions in animals; in addition to that some
drugs have shown their antiulcer effect mainly via., their potent antisecretory
action (Kinoshita et al., 1997; Heim
et al., 1991). The vagus-vagal activation by stimulation of antral
gastric mucosal receptors in pylorus ligated Shay model is believed to exacerbate
the gastric acid secretion (Baggio et al., 2003).
The current data demonstrated that, fennel suspension possesses the ability
to inhibit the basal gastric acid secretion and ruminal ulceration. These findings
substantiate the use of fennel alone or in combination with other herbs for
the management or treatment of hyperacidity and gastralgia in Unani System of
Medicine (Kabiruddin, 1921). It has been reported by
Bhargava et al. (1980) that simultaneous cold
(2-4°C) and restraint stress provoke gastric ulceration in rats. The cold
plus restraint-induced ulcers are probably mediated by an increased secretion
(Kitagawa et al., 1979), reduced mucus generation
(Koo et al., 1986), impaired gastric microcirculation
(Guth, 1972). The stress-over-activity which results
in gastric hypersecretion is often termed as 'aggressive factor' (Goa
and Monk, 1987).
The data revealed that pre-treatment with FVS significantly protected gastric
mucosa against cold plus restraint induced ulcers which could be due to the
inhibition of gastric mucus coat depletion and/or diminishing basal gastric
acid secretion. Earlier, File and Pearce, 1981 have
suggested that sedatives, anxiolytic and antisecretory substances have the ability
to protect gastric ulcer inflicted by stress. Fennel suspension, in this study
has shown to have antigastric ulcer potential in cold plus stress model, as
fennel is known to possess soothing and calming effects (Al-Harbi
et al., 1995). Results on indomethacin induced gastric mucosal damage
showed inhibition of gastric lesions by fennel suspension. A significant increase
in gastric wall mucus in fennel suspension treated animals might be responsible
for its gastroprotective effect against indomethacin-induced gastropathy. The
gastric mucus coat is thought to be important in both preventing damage and
to facilitate repair of the gastric epithelium (Wallace
and Whittle, 1986; Rainsford and Willis, 1982).
Evidence is accumulating that Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
are linked to ulceration of the stomach (Odabasoglu et
al., 2006). The mechanism of action seems to be both topical damage
to the mucosal barrier and the systemic effect of reduction in levels of mucosal
prostaglandins (Firulescu et al., 2010). The
ability of fennel suspension to protect gastric mucosa, possibly, through prostaglandin
mediation cannot be ruled out.
On the other hand, decreased levels of endogenous non-protein sulfhydryls (NP-SH)
have been associated with gastric mucosal lesions produced by various chemicals
(Robert et al., 1983; Szabo
et al., 1981; Rafatullah et al., 1994).
Hence, the replenishment of (NP-SH) levels in gastric mucosa by fennel suspension
may contribute to its antiulcer activity. The chemical constituents of fennel
responsible for its gastric protective activity are not known. However, fennel
was found to contain essential oil which possesses a strong antioxidant property
(Marotti et al., 1994). The above findings are
in accordance with a previous study which has shown that Fennel extract possesses
strong antiulcer activity (Wiseman et al., 1987).
Natural antioxidants have been shown to possess the ability to protect the cellular
damage (Marotti et al., 1994). Fennel suspension
also significantly protected gastric mucosa against several known necrotizing
agents including ethanol and strong alkalis. These necrotizing agents cause
an insult to gastric mucosal cell which resulted in the generation of free radicals
and oxidative stress (Repetto and Llesuy, 2002). Pretreatment
of rats with fennel suspension significantly protected gastric lesions produced
by necrotizing agents. These findings further indicate the ability of FVS to
enhance the gastric mucosal defensive factor.
On the other hand, the treatment of rats with FVS significantly decreased the
induced elevated concentration of MDA; an end product of lipid peroxidation
caused by a free radical mediated injury in gastric tissue. This finding further
confirms that fennel possesses an antioxidant potential. Recently, Ghanem
et al. (2012) have reported an in vitro antioxidant activity
of fennel extract.
The histopathological results showed that ethanol treatment caused mucosal erosion, edema, intramucosal hemorrhage. Pretreatment with FVS showed vascular congestion, superfacial ulceration and submucosal edema. These results partially support the pharmacological and biochemical observations.
The present observations demonstrate the gastro-protective efficacy of the FVS probably due to its antisecretory and antioxidant nature by which it strengthens mucosal defensive factor.
The authors are thankful to the Research Center of the College of Pharmacy, King Saud University and the Deanship of the Scientific Research, King Saud University, Riyadh, Saudi Arabia for their support.
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