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Phytomedicine
Acute and chronic antiinflammatory profile
of the ivy plant, Hedera helix, in rats
H. Süleyman1, V. Mshvildadze2, A. Gepdiremen1, and R. Elias3
1Atatürk University, Medical Faculty, Department of Pharmacology, Erzurum, Turkey
2Institute of Pharmacochemistry, Tbilisi, Georgia
3Laboratory of Pharmacognosy and Homeopathy, Pharmacy Faculty of Mediterranean University, Marseille, 13385 Marseille,
France
Summary
Hedera helix is a plant well-known as ivy or English ivy, and a member of the Araliaceae family. In
the present study, we tested the possible antiinflammatory effects of a crude saponin extract (CSE)
and a saponin’s purified extracts (SPE) of Hedera helix in carrageenan- and cotton-pellet-induced
acute and chronic inflammation models in rats. Both the CSE and SPE of Hedera helix were found
to have antiinflammatory effects. The most potent drug screened was indomethacin (89.2% acute
antiinflammatory effect), while the most potent extract screened was the CSE of Hedera helix at
100 and 200 mg/kg body wt. doses with 77% acute antiinflammatory effects. For testing chronic
antiinflammatory (antiproliferative) effects, the cotton-pellet-granuloma test was conducted.
Indomethacin was found to be the most potent drug in the chronic phase of inflammation, with
66% effect. The SPE of Hedera helix was more potent than the CSE in its chronic antiinflammato-
ry effect (60% and 49%, respectively).
Key words: Inflammation, antiinflammatory, Hedera helix, ivy plant, carrageenan, cotton pellet, rats
0944-7113/03/10/05-370 $ 15.00/0
Introduction
Inflammatory diseases are treated currently with
steroidal and nonsteroidal antiinflammatory drugs
(NSAIDs). NSAIDs exert their effects by inhibiting the
metabolism of arachidonic acid by both cyclooxyge-
nase and lipoxygenase enzyme pathways (Insel, 1996).
Despite their widespread use, NSAIDs are often asso-
ciated with severe adverse effects, the most common
being gastrointestinal bleeding (Fung and Kirschen-
baum, 1999). Because of these effects, safer com-
pounds are needed.
Hedera helix is well-known as ivy or English ivy,
and is a member of the Araliaceae family. The fresh
leaves and fruits are toxic, causing gastrointestinal irri-
tation, bloody diarrhea and death (Baytop, 1984). Its
best-known effect is to cause contact dermatitis, and
several cases have been reported (Garcia et al. 1995,
Massmanian et al. 1988, Hausen et al. 1987). Addition-
ally, antibacterial (Cioaca et al. 1978), antihelmintic
(Julien et al. 1985), leishmanicidic (Majester-Savornin
et al. 1991), in-vitro antispazmodic (Trute et al. 1997)
and antifungal (Moulin-Traffort et al. 1998) effects of
Hedera helix extracts have been reported.
To investigate the effects of drugs on the acute phase
of inflammation, models induced by pro-inflammatory
agents such as carrageenan, dextrane, formaldehyde,
serotonin histamine and bradykinin in rat paws are em-
ployed (Campos et al. 1995). Chronic inflammation
models produced by implanting a foreign body under
the skin are used to study the effects of a drug on the
proliferation phase of inflammation (Gilman et al.
1985, Süleyman et al. 1999). Carrageenan, a mu-
copolysaccaride, is perhaps the most commonly-used
Phytomedicine 10: 370–374, 2003
©Urban & Fischer Verlag
http://www.urbanfischer.de/journals/phytomed
Antiinflammatory effects of Hedera helix 371
and well-studied of these phlogistics (Leme et al.
1973), producing a maximal edematous in 3 h. While
the carrageenan model is typically associated with acti-
vation of the cyclo-oxygenase pathway and is sensitive
to glucocorticoids and prostaglandin synthesis antago-
nists, the early phase of the carrageenan response is due
to the release of serotonin and histamine (DiRosa et al.
1971).
In the present study, we tested the possible antiin-
flammatory effects of the crude saponin extract (CSE)
and the saponin’s purified extracts (SPE) of Hedera
helix in the carrageenan- and cotton-pellet-induced
acute and chronic inflammation models in rats.
Materials and Methods
Hedera helix
The leaves of Hedera helix were collected in Marseille,
France, in September 1999. The material was identified
by Riad Elias, a staff member of Laboratory of Phar-
macognosy and Homeopathy, Pharmacy Faculty of the
Mediterranean University, Marseille, France.
Hedera helix extract
The materials were shade-dried. One kg of crushed
plant leaves were extracted three times with seven
liters of 80% EtOH. After evaporation of the organic
solvent, the aqueuos phase was treated with one liter of
CHCl3four times, and then with one liter of BuOH
three times. The BuOH was evaporated and the residue
was dried in a vacuum oven at 50 °C. The yield of CSE
was 100 g for Hedera helix. The obtained CSE was dis-
solved in 400 ml of MeOH and precipitated in 2 liters
of acetone. After filtration, the residue was dried in a
vacuum oven at 50 °C. The yield of SPE was 80 g for
Hedera helix. Both extracts contain mono- and bi-
desmoside triterpene glycoside derivatives of oleanolic
acid and hederagenin, as described previously (Elias
et al. 1991).
Animals
In this study, 66 adult male Wistar albino rats weighing
180–210 g each, obtained from Atatürk University,
Faculty of Medicine, Department of Pharmacology Ex-
perimental Animal Laboratory, were used. The rats
were fed standard laboratory chow and tap water be-
fore the experiment. The animal laboratory was
equipped with automatic temperature (22 ± 1 ºC) and
lighting controls (14 hours light/10 hours dark). Rats
were divided into groups, each containing 6 individuals
and each of the groups were kept in different cages.
The ethical guidelines for investigations using con-
scious animals were obeyed and the procedures were
approved by the University ethics committee.
Antiinflammatory Studies
Antiinflammatory effects of CSE and SPE of Hedera
helix were investigated in an aseptic arthritis model,
which was induced by carrageenan and cotton-pellet-
granuloma tests in subsequent doses. The ratio of the
antiinflammatory effects of Hedera helix extracts were
calculated using the following equation: Antiinflam-
matory activity (%) = (1 – D/C) · 100 where D repre-
sents the percentage difference in paw volume after the
compounds were administered to the rats, and C repre-
sents the percentage volume difference in the control
group (Süleyman et al. 1999).
Carrageenan-induced paw edema in rats
Hedera helix CSE and SPE in 50, 100 and 200 mg/kg
body wt. doses, and indomethacin 20 mg/kg body wt.
doses were given to rats orally by feeding tube once
daily for 4 days. Two h after final administration of the
compounds, 0.1 ml (1%, w/v) carrageenan solution in
distilled water was injected subcutaneously into the
plantar surface of the right hind paw. The paw volume
was measured using a plethysmometer: before injec-
tion and 5 times at 1-h intervals (Birch et al. 1992). The
antiinflammatory activity in animals receiving Hedera
helix extracts was compared with that in indomethacin
and control groups.
Cotton-pellet-granuloma test
In this series, the effects of Hedera helix extracts and
indomethacin on the proliferation phase of inflamma-
tion were studied using a cotton-pellet-granuloma test.
Doses of 100 mg/kg body wt. CSE; and 100 mg/kg
b
ody wt. SPE of Hedera helix, and of 20 mg/kg body wt.
indomethacin were administered orally to 3 groups
separately. The same volume of distilled water (1 ml)
was administered to the control group. After 30 min,
the animals were anesthetized with 25 mg/kg thio-
penthal sodium, intraperitoneally. Under sterile condi-
tions, cotton pellets, weighing 7 mg each, were im-
planted an interscapular distance under the skin. The
same doses of Hedera helix extracts and indomethacin
were administered once a day for a period of 7 days.
The rats were killed by a higher dose of thiopenthal
sodium on the eighth day, and the pellets surrounded by
granuloma tissues were dissected out. The moist pellets
were weighed and then dried at 70 ºC, after which, they
were weighed again and the antiproliferative effect of
Hedera helix extracts compared with the control and
indomethacin groups.
Statistical analysis
Values are presented as mean ± SEM. Independent
samples-t test and analysis of variance (ANOVA, Dun-
net method) were used for the evaluation of data and
p < 0.05 was accepted as statistically significant.
372 H. Süleyman et al.
Results
Despite the fact that they have weaker antiinflammato-
ry effects than indomethacin, both CSE and SPE of
Hedera helix were found to have antiinflammatory ef-
fects. For the acute phase of inflammation, car-
rageenan-induced paw-volume increase, and the ef-
fects of the indomethacin and Hedera helix extracts
were evaluated. Because of the most potent effect was
seen in the fourth hour, prior to others, statistical data
for that period was regarded to evaluate acute antiin-
flammatory effect. The most potent drug was found to
be indomethacin (89.2% acute antiinflammatory ef-
fect) while the most potent extract was found to be
CSE of Hedera helix at doses of 100 and 200 mg/kg
body wt., with 77% acute antiinflammatory effects.
The same drug in a dose of 50 mg/kg body wt. exerted
a 51% antiinflammatory effect. For the SPE of Hedera
helix, acute antiinflammatory effects of 41.5% for 50,
60% for 100 mg/kg doses and 67.7% for 200 mg/kg
doses were found. For further information, please refer
to Table 1.
For testing chronic antiinflammatory (antiprolifera-
tive) effects, the cotton-pellet-granuloma test was con-
ducted. Indomethacin was found to be the most potent
drug in the chronic phase of inflammation, with 66%
effect. The SPE of Hedera helix was found to be more
potent than the CSE in terms of chronic antiinflamma-
tory effect, at 60% and 49%, respectively. For further
information, please refer to Fig. 1.
Discussion
Triterpene saponins of Hedera helix have already been
tested in several applications. Buddlejasaponin’s and
saikosaponin’s in-vivo antiinflammatory effects on
mouse ear edema (Bermejo-Benito et al. 1998) and
zanhasaponin’s acute and chronic antiinflammatory ef-
fects in different models (Cuellar et al. 1997) have been
reported. For the first time in the literature, we have
demonstrated the antiinflammatory effects of Hedera
Table 1. The effects of CSE (Crude saponin extract) and SPE (Saponin’s Purified Extract) of Hedera helix in subsequent
doses and indomethacin (Indomet.) in carrageenan-induced acute paw edema.
Drugs Dose n Right paw volume (ml ×100)
mg/kg
body wt. Before 1 h 2 h 3 h 4 h 5 h
Vehicle – 6 77 ± 2.5 104 ± 6.4* 134 ± 2.1**** 139 ± 2.7**** 142 ± 1.7**** 140 ± 1.6****
Indomet. 20 6 101 ± 2.9 112 ± 3* 110 ± 2.4* 109 ± 2.1 108 ± 4.1 105 ± 3.7
CSE 50 6 112 ± 1.6 113 ± 1.4 129 ± 4.5* 142 ± 3.1**** 145 ± 3.2**** 156 ± 5.1****
CSE 100 6 117 ± 3.2 128 ± 3.2* 130 ± 4.5* 131 ± 4.4* 132 ± 5.1* 129 ± 5.1
CSE 200 6 113 ± 3.1 113 ± 3.6 119 ± 4.4 126 ± 4* 128 ± 3.3** 124 ± 3.4*
SPE 50 6 110 ± 1.3 115 ± 2.5 150 ± 3.2**** 149 ± 4.4**** 149 ± 6.5* 146 ± 5.7****
SPE 100 6 115 ± 4 123 ± 3 137 ± 3.3*** 139 ± 3**** 141 ± 4.2**** 138 ± 4***
SPE 200 6 113 ± 1.3 130 ± 3.6*** 147 ± 4.8**** 136 ± 2.4**** 134 ± 1.7**** 130 ± 2****
*p < 0.05, **p < 0.01, *** p < 0.005 and ****p < 0.001 in respect to the values “before injection” for each group.
Fig. 1. The effects of indomethacin (20 mg/kg body wt.),
Hedera helix CSE (Crude saponin extract) and SPE (Sapon-
in’s Purified Extact, 100 mg/kg body wt. for both) on granu-
loma tissue formation induced by the cotton-pellet-granulo-
ma test. *p < 0.001.
Antiinflammatory effects of Hedera helix 373
helix due to mono and bidesmoside triterpene glyco-
sides. Despite the fact that they have weaker antiin-
flammatory potential than indomethacin, in all of the
groups tested, we found quite effective antiinflamma-
tory action. The CSE of Hedera helix was more potent
than the SPE form in the acute phase, while the SPE
form showed better results than the CSE form of Hed-
era helix in the chronic phase of inflammation.
It was reported that the antiinflammatory effects of
several agents result in the partial inhibition of inflam-
mation-mediator release (Amadio et al. 1993). Subcu-
taneous injection of carrageenan into the rat paw pro-
duces plasma extravazation (Szolcsanyi et al. 1998),
and inflammation characterized by increased tissue
water and plasma protein exudation with neutrophil ex-
travazation and metabolism of arachidonic acid by
both cyclooxygenase and lipoxygenase enzyme path-
ways (Gamache et al. 1986). There are biphasic effects
in carrageenan-induced edema. The first phase begins
immediately after injection and diminishes in 1 h. The
second phase begins at 1 h and remains through 3 h
(Garcia-Pastor et al. 1999). It is suggested that the early
hyperemia of carrageenan-induced edema results from
the release of histamine and serotonin (Kulkarni et al.
1986). Both Hedera helix extracts and indomethacin
started to block inflammation in the first measurement.
So it seems possible that Hedera helix blocks histamine
and/or serotonin release in the first phase of acute in-
flammation. On the other hand, the delayed phase of
carrageenan-induced edema results mainly from the
potentiating effect of prostaglandins on mediator re-
lease, especially of bradykinin. Hydrocortisone and
some NSAIDs inhibit strongly the second phase of car-
rageenan-induced edema, but some others are effective
against both phases (Kulkarni et al. 1986). In the light
of these data and Table 1, Hedera helix extracts seem
more effective in the first phase of acute inflammation
than in the second phase. Therefore, Hedera helix ex-
tracts may block histamin and/or serotonin release bet-
ter than the prostaglandin and/or bradykinin.
It was also observed that both extracts of Hedera helix
are effective in chronic inflammation, despite the fact
that the effect was not strong as indomethacin. Chronic
inflammation is a reaction arising when the acute re-
sponse is insufficent to eliminate proinflammatory
agents, and induces a proliferation of fibroblasts and the
infiltration of neutrophils and exudation (Dunne, 1990).
Chronic inflammation occurs by means of the develop-
ment of proliferative cells. NSAIDs cause a decrease in
granuloma tissue arising as a result of cellular reaction,
released by inhibiting granulocyte infiltration to the for-
eign body implanted (Ionac et al. 1996). According to
the chronic inflammation model of the cotton pellet, the
Hedera helix SPE and CSE may exert their effects by in-
hibiting the functions of macrophages and fibrosis.
The results of the present study show that Hedera
helix CSE and SPE are potent inhibitors of acute and
chronic inflammation. The mechanism of the effect
may depend on inhibition of the formation of several
inflammation mediators. Detailed studies are needed to
clarify the mechanism(s) of the antiinflammatory ef-
fects of Hedera helix triterpene saponins.
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Address
H. Süleyman, Atatürk University, Medical Faculty, De-
partment of Pharmacology, TR-25240 Erzurum, Turkey
Tel.: ++90-442-2361212/2423; Fax: ++90-442-2360968;
e-mail: suleyman@atauni.edu.tr