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Volume 8, Supplement No. 5, Winter 2009
Journal of Medicinal Plants
Effects of Saffron and its Active Constituents, Crocin and Safranal, on
Prevention of Indomethacin Induced Gastric Ulcers in Diabetic and
Nondiabetic Rats
Kianbakht S (Ph.D.)1*, Mozaffari K (M.D.)2
1- Department of Pharmacology and Applied Medicine, Institute of Medicinal
Plants, ACECR, Karaj, Iran
2- Department of Pathology, Faculty of Medicine, Iran University of Medical
Sciences, Tehran, Iran
*Correspondence author: Institute of Medicinal Plants, Complex of Academic
Center for Educational and Cultural Research (ACECR), Kavosh Boulevard, Supa
Boulevard, 55th Kilometer of Tehran-Gazvin Freeway, Pouleh Kordan, Karaj, Iran
Tel: +98-261-4764010-19, Fax: +98-261-4764021
E -mail: skianbakht@yahoo.com
Received: 14 Mar. 2009 Accepted: 20 Jun. 2009
Abstract
Background: Saffron is the dried stigmata of the flowers of saffron (Crocus sativus L.,
Iridaceae). Saffron is well known for the treatment of gastric disorders in traditional
medicine.
Objectives: In the search for new potential antiulcer agents, the effects of the ethanol
extract of saffron and its active constituents crocin and safranal as compared with
omeprazole against gastric ulcer induced by indomethacin in non-diabetic and
streptozocin diabetic rats were studied.
Methods: The effects of pretreatment with saffron extract (25, 100 or 250 mg/kg, p.o.),
crocin (2.5, 5 or 10 mg/kg, p.o.) and safranal (0.25, 2, 5 ml/kg, p.o.) and omeprazole (30
mg/kg, p.o.) 30 min before administration of indomethacin (40 mg/kg, p.o. in non-diabetic
rats and 15 mg/kg, p.o. in diabetic rats) on gastric lesions, increase of lipid peroxidation
and decrease of glutathione levels induced by indomethacin in non-diabetic and diabetic
rats were evaluated.
Results: Saffron extract, crocin, safranal and omeprazol prevented the gastric lesions,
increase of lipid peroxidation and decrease of glutathione levels induced by indomethacin
in non-diabetic and diabetic rats as compared with the control group (P < 0.01). The
effects of saffron extract, crocin and safranal on the gastric ulcer index, lipid
peroxidation and glutathione levels were comparable to omeprazole.
Conclusions: Saffron, crocin and safranal may prevent the gastric mucosa damage due
to their antioxidant properties by increasing the gluthatione levels and diminishing the
lipid peroxidation in the rat gastric mucosa.
Keywords: Saffron, Crocin, Safranal, Gastric ulcers, Diabetes mellitus, Rat
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Effects of Saffron …
Introduction
Saffron is the dried stigmata of the flowers
of saffron (Crocus sativus L., Iridaceae) and is
cultivated widely in Iran, Spain, France, Italy,
Greece, Turkey, India and China. In addition
to being a widely used food additive, saffron is
used in the traditional medicine as a eupeptic,
diaphoretic, expectorant, tranquilizer,
aphrodisiac, emmenagogue, abortifacient and
in the treatment of hepatic disorders,
flatulence, vomiting, spasm, dental and
gingival pain, insomnia, depression, cognitive
disorders, seizures, lumbago, cough, asthma,
bronchitis, fever, colds, cardiovascular
disorders and cancer. Saffron is recognized as
an adaptogen in Indian ayurvedic medicine [1,
2]. Crocin, crocetin and safranal are the major
active constituents of saffron [3]. Previous
studies have demonstrated various
pharmacological effects of saffron and its
active constituents including anti-oxidant [4, 5,
6], anti-tumor [7], anti-genotoxic [8], memory
and learning enhancing [9], neuroprotective
[10], analgesic and anti-inflammatory [11],
anti - convulsant [12], antianxiety [13],
aphrodisiac [14], antidepressant [15],
antihypertensive [16], hypolipidemic [17],
insulin resistance reducing [18], tissues
oxygenation enhancing [19], bronchodilator
[20], antitussive [21], retina protective [22]
and immunostimulant [23] effects.
Besides being used as analgesics, the non-
steroidal anti-inflammatory drugs (NSAIDs)
are being increasingly used for prevention of
malignancies, stroke, pre-eclampsia,
Alzheimer's disease and many other illnesses
[24, 25]. However, the NSAIDs produce
gastroduodenal ulcers in 25% of the users,
often with bleeding and/or perforation.
Amongst the various factors known to cause
gastric ulcer, use of NSAIDs is the foremost
[26]. Gastric mucosa of diabetic rats is more
vulnerable to ulcerogens such as NSAIDs and
peptic ulcers in diabetic patients are more
severe and often associated with complications
such as gastrointestinal bleeding [27, 28].
Adequate remedy for the NSAID-induced
gastropathy has so far been elusive, despite
recent advances [29]. Further the existing
synthetic anti-ulcer drugs confer mild to severe
side effects. Thus there is a need for more
effective and safe anti-ulcer drugs. Plants are
the most important source for the new drug
development due to the resurgence of the
interest in the use of herbal preparations. Some
of the anti-ulcer drugs are known to exert their
action via anti-oxidative activity [30]. Thus in
view of the significant antioxidant effects of
saffron and its active constituents, crocin and
safranal, our aim of the present study was to
assess the possible anti-ulcerogenic activity of
saffron, crocin and safranal against
indomethacin induced acute gastric ulceration
in non-diabetic and streptozocin diabetic rats
by measuring gastric ulcer index and to
elucidate the role of antioxidant effects of
saffron, crocin and safranal in their anti-
ulcerogenic activity, gastric mucosa lipid
peroxidation and reduced glutathione (GSH)
levels were also measured.
Materials and methods
Plant material
The stigmas of Crocus sativus were
collected from the lands of Ghaen in the
province of southern Khorasan in December
and dried in shadow followed by grinding. The
identity of Crocus sativus was authenticated
by a botanist and a voucher specimen of the
plant (number 9723) was deposited in the
Tehran University Central Herbarium.
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Journal of Medicinal Plans, Volume 8,
Supplement No. 5, Winter 2009
Kianbakht & Author
Preparation of plant extract
The stigmas were extracted with ethanol
(80% V/V) by maceration for three days, and
then the mixture was centrifuged. The crude
extract was evaporated to dryness under
reduced pressure at 40 °C.
Drugs
Crocin, indomethacin and omeprazole
were purchased from Sigma, safranal from
Fluka and streptozocin from Upjohn &
Pharmacia. For dilution, all drugs and the
extract were dissolved in physiological saline.
All drugs were prepared immediately before
use.
Animals
Male adult Wistar rats (225 ± 25 g) from
our own breeding colony were used. Animals
were maintained under standard environmental
conditions and had free access to standard
rodent feed and water.
Induction of diabetes
Animals were given streptozocin in a
single intraperitoneal injection at a dose of
50 mg/kg. Five weeks after the injection of
streptozocin, diabetic rats with fasting blood
glucose levels more than 350 mg/dl were used
for testing the anti-ulcer activity of the drugs.
Anti-ulcer activity
Rats were deprived of food for 48 h prior
to starting the experiments but they had free
access to drinking water. The animals were
kept in cages with raised floors of wide mesh
to prevent coprophagia and they were divided
into groups of 10 diabetic or non-diabetic rats
each. Gastric ulceration was induced by the
administration of indomethacin suspended in
0.5% carboxymethylcellulose (CMC) in water
(40 mg/kg, p.o. in non-diabetic rats and 15
mg/kg, p.o. in diabetic rats) as the ulcerogenic
agent. Each group of animals was pretreated
with physiological saline as control, saffron
stigmas extract (25, 100 or 250 mg/kg, p.o.),
crocin (2.5, 5 or 10 mg/kg, p.o.), safranal
(0.25, 2, 5 ml/kg, p.o.) or omeprazole (30
mg/kg, p.o.) 30 min before the indomethacin
administration. All drugs and the extract were
dissolved and administered in physiological
saline in a volume of 5 ml/kg.
The animals were killed 6 h after the
indomethacin administration by using an
overdose of chloroform. The stomachs were
removed, opened along the greater curvature
and washed in physiological saline. A person
unaware of the type of treatment received by
the animals, examined the stomachs under a 3-
fold magnifier and scored the lesions as
follows: 0, no pathology; 1, each pinhead ulcer
spot; and 2-5, thread-like lesions of 2-5 mm
length. The total number of ulcer spots divided
by the number of animals gives the ulcer index
[30].
Measurement of lipid peroxidation
The levels of thiobarbituric acid reactants
(TBARS) in the gastric mucosa as index of
lipoperoxides production were measured
according to the modified method of Okawa et
al. (1979) [31]. The mucosa was scraped with
glass slides, weighed, and homogenized in 10
mL KCl (10 %). The homogenate was
supplemented with 8.1 % sodium lauryl
sulfate, 20 % acetic acid, and 0.8 % TBA, and
boiled at 100 °C for 1h. After cooling, the
reactants were supplemented with 2.5 mL n-
butanol, shaken vigorously for 1 min, and
centrifuged for 10 min at 2600 × g.
Absorbance was measured in a spectro-
photometer Perkin-Elmer Lambda 3 at 532
nm, and the results were expressed as nmol of
malondialdehyde (MDA)/g tissue.
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Effects of Saffron …
Measurement of gastric mucosa GSH level
Glutathione (GSH) content (as acid-soluble
sulfhydryl) of gastric mucosa was determined
as described earlier [30]. Gastric mucosa was
homogenized in 10 mL of 20 mM ice-cold
EDTA for 40 s and centrifuged at 2000g for 10
min. Protein was precipitated with equal
volume of 10% trichloroacetic acid. The
supernatant (2 mL) was added to 2 mL of 0.8
M Tris-Cl, pH 9, containing 20 mM EDTA
and mixed with 0.1 mL of 10 mM DTNB
(5,5'–dithio-bis (2-nitro-benzoic acid) to yield
thionitrobenzoic acid, which was measured at
412 nm using GSH as standard. The result was
expressed as nmol of GSH/g of tissue.
Statistical analysis
The results were expressed as means ± S.D.
and analyzed with the independent samples t
test. p < 0.05 was regarded as significant.
Results
Omeprazole, saffron, crocin and safranal
decreased the gastric ulcer index and lipid
peroxidation but increased the gastric tissue
glutathione levels at the doses used
significantly as compared to the saline +
indomethacin group in non-diabetic and
diabetic rats (p < 0.01) (Tables 1 and 2).
Table 1: Effects of pretreatment with omeprazole, saffron extract, crocin and safranal on gastric ulcer index,
gastric mucosa lipid peroxidation and GSH level in non-diabetic rats treated with indomethacin (40 mg/kg, p.o.).
* p < 0.01 vs. saline + indomethacin. ** p < 0.01 vs. saline + saline.
Treatment
(N = 10 in each group) Dose (p.o.) Ulcer index Lipid peroxidation
(nmol MDA/g tissue)
GSH (nmol/g
tissue)
Saline + saline - - 110.8 ± 20.4 197.1 ± 13.6
Saline + indomethacin - 37.3 ± 5.6 217.2±23.8** 132.3±6.8**
Omeprazole 30 mg/kg 15.2 ± 7.1 * 96.6 ± 20.1* 182.1±15.7 *
Saffron 25 mg/kg 23.1 ± 2.8 * 143.1± 12.4* 157.5±4.5 *
Saffron 100 mg/kg 14.2 ± 5.1 * 112.9± 10.2* 179.3±11.7 *
Saffron 250 mg/kg 11.3 ± 3.3 * 123.2± 18.7* 162.8±16.2 *
Crocin 2.5 mg/kg 19.5 ± 4.9 * 129.1± 14.3* 178.3±5.6 *
Crocin 5 mg/kg 10.6 ±2.8 * 92.1± 17.2* 201.9±12.2 *
Crocin 10 mg/kg 12.3 ± 3.4 * 89.6± 14.5* 192.3±8.6 *
Safranal 0.25 ml/kg 24.8 ± 3.8 * 118.6± 9.8* 162.7±17.3 *
safranal 2 ml/kg 13.2 ± 4.5 * 93.1± 11.6* 218.9±9.2 *
Safranal 5 ml/kg 11.2 ± 2.6 * 87.4± 12.8* 197.6± 14.4*
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Journal of Medicinal Plans, Volume 8,
Supplement No. 5, Winter 2009
Kianbakht & Author
Table 2- Effects of pretreatment with omeprazole, saffron extract, crocin and safranal on gastric ulcer index,
gastric mucosa lipid peroxidation and GSH level in diabetic rats treated with indomethacin (15 mg/kg, p.o.).
* p < 0.01 vs. saline + indomethacin. **p < 0.01 vs. saline + saline.
Treatment
(N = 10 in each
group)
Dose (p.o.) Ulcer index Lipid peroxidation
(nmol MDA/g tissue)
GSH (nmol/g
tissue)
Saline + saline - - 101.8 ± 15.6 224.8 ± 16.8
Saline + indomethacin - 42.6 ± 6.7 197.2±27.1** 111.3±15.6**
Omeprazole 30 mg/kg 23.7 ± 6.2 * 82.7 ± 12.5* 189.1 ± 8.6*
Saffron 25 mg/kg 27.8 ± 7 * 111.7± 10.1* 148.4 ± 9.4*
Saffron 100 mg/kg 14.7 ± 3.7 * 88.9 ± 5.7* 165.2 ± 5.4*
Saffron 250 mg/kg 10.3 ± 6.2 * 74.3 ± 9.8* 178.5± 15.6*
Crocin 2.5 mg/kg 27.5 ± 5.1 * 101.7± 10.3* 172.1 ± 8.2*
Crocin 5 mg/kg 17.4 ± 2.8 * 74.2 ± 13.6* 201.3 ± 13.2*
Crocin 10 mg/kg 14.2 ± 4 * 65.6 ± 17.5* 192.4 ± 8.1*
Safranal 0.25 ml/kg 26.6 ± 5.2 * 89.6 ± 8.3* 168.2± 12.8*
safranal 2 ml/kg 16.7 ± 3.1 * 72.1 ± 6.6* 211.5 ± 9.7*
Safranal 5 ml/kg 12.1 ± 3.8 * 62.4 ± 7.8* 197.1± 15.1*
Discussion
The main findings of this study are as
follows: (1) indomethacin has caused gastric
lesions in diabetic rats at a dose (15 mg/kg,
p.o.), less than half the dose used in non-
diabetic rats (40 mg/kg, p.o.), in addition to
increasing lipid peroxidation and decreasing
glutathione levels in the gastic mucosa, (2)
There is no significant differences between the
ulcer indexes, lipid peroxidation and
glutathione levels induced by indomethacin at
the dose of 40 mg/kg and the dose of 15 mg/kg
in the non-diabetic rats and diabetic rats, (3)
Omeprazole (30 mg/kg, p.o.) has prevented the
gastric lesions, increase of lipid peroxidation
and decrease of glutathione levels induced by
indomethacin in non-diabetic and diabetic rats
as compared with the control group (p < 0.01),
(4) Saffron extract, crocin and safranal have
prevented dose dependently the gastric lesions,
increase of lipid peroxidation and decrease of
glutathione levels induced by indomethacin in
non-diabetic and diabetic rats as compared
with the control group (p < 0.01), (5) The
effects of saffron extract, crocin and safranal
on the gastric ulcer index, lipid peroxidation
and glutathione levels are comparable to
omeprazole (Tables 1 and 2).
The lower dose of indomethacin needed to
induce gastric lesions in diabetic rats as
compared to non-diabetic rats is in line with
the fact that gastric mucosa of diabetic rats is
more vulnerable to ulcerogenic agents [27,
28].
The results conform to a variety of studies
in which saffron, crocin and safranal had
protective effects against oxidation induced
tissue injuries due to their antioxidant
properties. Crocin prevented the death of the
neuronally differentiated pheochromocytoma
(PC-12) cells deprived of serum/glucose more
effectively than α-tocopherol by inhibiting the
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Effects of Saffron …
formation of peroxidized lipids [32]. Crocin
suppressed serum-deprivation induced death of
PC-12 cells by increasing glutathione
synthesis and inhibition of membrane lipids
peroxidation [33]. Saffron, crocin and safranal
had protective effects against lower limb
skeletal muscle injury during ischemia-
reperfusion by elevating total sulfhydryl
contents, antioxidant capacity and decreasing
malondialdehyde [34]. Safranal protected
against neuronal cell death in the rat
hippocampus following cerebral ischemic
injury by elevating total sulfhydrl
concentrations and antioxidant capacity and
diminishing malondialdehyde in the
hippocampus [35]. Crocin protected the rat
brain against excessive oxidative damage in
transient global cerebral ischemia by
decreasing malondialdehyde levels and
elevating gluthatione peroxidase activity [36].
Saffron had protective effects against
genotoxins induced oxidative stress by
increasing glutathione levels and reducing
lipid peroxidation in mice [37].
Indomethacin induced gastric ulcer is a
multifactorial process where reactive oxygen
species (ROS) play a vital role in gastric
damage either by its direct oxidative action or
through apoptotic cell death. Among various
ROS, H202 can act as a signal transduction
messenger to activate transcription factors
NFκB (Nuclear Factor Kappa B) and AP-1
(Activator Protein 1) for gene expression of
various inflammatory cytokines and proteases
to cause cell damage. In fact, involvement of
TNF-α (Tumor Necrosis Factor Alpha) and
matrix metalloproteinases has been evident in
indomethacin-induced gastric hypermotility
and increased microvascular injury also cause
ischemia to generate ROS through the
mitochondrial electron transport chain.
Mitochondria from gastric mucosal cells
contain a highly active peroxidase to scavenge
H202 and protect the cells from ROS-mediated
oxidative damage. Indomethacin significantly
inactivates the gastric peroxidase to generate
H202 and H202–derived ˙OH. Thus
indomethacin significantly increases
endogenous ˙OH to cause oxidative damage by
increased lipid peroxidation and thiol
depletion [38].
In this study, omeprazole has prevented
gastric lesions, increase of lipid peroxidation
and decrease of glutathione level as compared
to control (p < 0.01) which is in line with the
previous studies [39, 40]. The fact that proton
pump inhibitors such as omeprazole have
pronounced antioxidant properties and
scavenge hydroxyl radicals may explain the
observed effects of omeprazole [41, 42].
In conclusion, the results of the present
study suggest that saffron, crocin and safranal
may prevent the indomethacin-induced gastric
mucosa damage due to their antioxidant
properties by increasing the gluthatione levels
and diminishing the lipid peroxidation in the
rat gastric mucosa. Thus further investigations
concerning efficacy and safety of saffron and
its active constituents in prevention of NSAID-
induced gastric ulcers in humans seem to be
warranted.
Acknowledgements
We are grateful to the Pharmaceutical
Research Network affiliated with the Research
Deputy of the Iranian Ministry of Health and
Medical Education for sponsoring this study.
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Journal of Medicinal Plans, Volume 8,
Supplement No. 5, Winter 2009
Kianbakht & Author
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