Sci.

Int(Lahore),22(3),199-203,2010

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199

IN VIVO EXPERIMENTAL MODELS TO INVESTIGATE THE

ANTI-INFLAMMATORY ACTIVITY OF HERBAL EXTRACTS
(REVIEW)
*Muhammad

Ihtisham Umara, Rabia Altafa, Muhammad Adnan Iqbalb, Muhammad Bilal Sadiqc
a

School of Pharmacy, Universiti Sains Malaysia, 11800-Penang, Malaysia

School of Chemical Sciences, Universiti Sains Malaysia, 11800-Penang, Malaysia
c
University College of Pharmacy, University of the Punjab, 54000-Lahore, Pakistan
(*mihtishamu@gmail.com, mai10_che022p@student.usm.my)
b

ABSTRACT: The article reviews recent studies on the anti-inflammatory effects of herbal extracts with
emphasis on different experimental models that are frequently used to test the in-vivo anti inflammatory
activity of herbal constituents. Odema, granuloma and arthritis models are frequently used to test the anti
inflammatory activity of plant extracts where as formalin or acetic acid induced writhing test and hot plate
method are the most repeatedly used methods to evaluate anti-nociceptive potentials of these extracts.
Although adjuvant induced and collagen induced arthritis models are quite efficient, they have been used
seldom to evaluate anti-inflammatory tendencies of herbs. We suggest a double positive reference model
using both a steroid and a non steroidal anti-inflammatory drug at the same time, instead of using only one
of the either.
Key Words: Anti-Inflammatory, Herbal Extracts, Experimental models

1. INTRODUCTION
Inflammation is the reaction of the living body to cell
injury. Although it is a protective mechanism that helps the
body to identify and neutralize the noxious stimuli such as
bacterial pathogens, chemical toxicants and cancerous
cells, by increasing the blood flow towards the area of
tissue injury, inflammation is also a great hazard to the
patient. It increases the ailment and sufferings of the
patient due to pain and morbidity [1]. Arachidonic acid,
cyclo-oxygenase and lipo-oxygenase mediated activation
of local inflammatory mediators such as leukotrienes,
prostaglandins, prostacyclines, thromboxane A2 platelet
activation factor play a key role in tissue destruction and
pain associated with inflammation [1, 2]. Inflammation
often results into puss formation that further hinders the
absorption of different antibiotics into the affected tissue,
leading to the aggravation of tissue destruction. Therefore,
it becomes mandatory to administer anti-inflammatory
drugs to cure a number of disorders such as infectious
diseases in combination with antibiotics. Although a
number of different synthetic and semi synthetic drugs are
in use today to combat with inflammation, there has
always been a thirst to search for the natural antiinflammatory constituents from spices and herbs. The
medicinal importance of spices and herbs is known since
pre historic times. They have not only been used
extensively in traditional medicines, most of the todays
allopathic medicines are either consisted of herbal extract
or these are the semi synthetic derivates of herbal products.
Since ancient times, herbs are famous in traditional
medicine for their anti inflammatory, anti nociceptive and
immunomodulatory activities. Many workers have directly
tested the inhibitory effect of different herbal extracts on
the production of inflammatory mediators by using
different cell culture techniques [3, 4, 5]. Such in-vitro
studies are helpful in developing an understanding of the
mechanism of anti inflammatory activity of herbal
constituents, however, most of such in vitro studies are
secondary to a preliminary in vivo evaluation of anti

inflammatory properties of plant extracts [6, 7, 8, 9].

Different workers have used different experimental models
to evaluate the anti inflammatory activity of herbs. Here,
we have summarized all those methods that are repeatedly
being used to evaluate the anti inflammatory activity of
herbs and spices in animal models (in vivo).
2. EXPERIMENTAL ANIMALS
Although some workers have used big ear albino rabbits
[10], most of them have preferred using mice and rats to
test the anti inflammatory effects of herbal extracts.
Different types of mice and rats which are frequently used
to test anti inflammatory effect of herbs include ICR mice
[6, 7, 8, 11, 12, 13], Sprague- Dawley (SD) rats [6, 11, 13,
14, 15, 16], ddY mice [2], BALB/c [18] and its substrain
BALB/cj mice [12], C57BL/6 commonly called as black 6
[4], Swiss albino mice [19, 20], albino rats [21] and
winstar rats [20, 22]. The animals are allowed a free
access to food (Laboratory chow) and tap water ad libitum.
They are acclimatized in a specific pathogen free animal
facility (usually in a laminar air flow room), at a suitable
temperature of 22 1 C and 40-60% relative humidity in
a light/dark cycle of 12 hours [6, 11, 12] for two weeks or
more.
3. PARAMETERS
3.1 CARRAGEENAN INDUCED HIND PAW
ODEMA Reduction of odema induced in the hind paw of
mice by the administration of herbal extracts 1 hour prior
to the induction of odema is the most commonly used
method to identify anti inflammatory activity of herbal
extracts. A number of different agents can be used to
induce odema, including brewers yeast, formalin [23, 24],
dextran [25, 26, 27] ovalbumin [27], phospholipase A2
[28], kaolin and sulphated polysaccharides such as
carrageenaan [11, 13, 16, 17] or naphthoyalheparamine
[29]. A few workers have also used radio-labelled
phlogistic agents to demonstrate the odema reduction
mechanism [23]. Many workers have used Arachidonic
acid and TPA induced ear odema [12] to test the anti
inflammatory effect of herbal extracts.

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Here, we summarize the method of carrageenan induced hind paw odema in rodents. Animals are divided randomly
in groups. Different doses of plant extracts are injected formaldehyde. Changes in paw size are noted daily and paw
either orally [11, 13, 17] or through intra peritoneal route size of test group is compared with that of control group
[16] 1 hour or 30 minutes, respectively, before carrageenaan [22].
injection. A subcutaneous injection of 0.1 ml [17, 21, 22, 30] 3.2.3 Collagen Induced Arthritis
or 0.05ml [9, 16] of 1% carrageenaan freshly prepared in It is the least commonly used, yet an effective method to
distilled water [16] or normal saline [9, 22] is injected into induce arthritis in rodents to study the anti-inflammatory
the subplantar region of hind paw. Vehicle is taken as effect of herbal extracts. Collagen I, III (derived from skin
negative control and either Prednisolone [9] or Indomethacin and paranchymal tissues of many organs) and collagen II
(alone [22] or with diclofenac [21]) are taken as positive (derived from cartilage) can be purified to induce arthritis in
reference. Thickness of paw is measured by plethysmometer rats and mice [40]. The xiphoid cartilage of 3 weeks old
at intervals of 1, 2, 3, 4 and 5 hours after the injection of White Leghorn chicks, rendered lathyritic by administration
carrageenaan. The right and left paws are cut under ether of -aminopropionitrile fumarate (BAPN), can be used as
anaesthesia at the tibiotarsal articulation and weighed [21]. the source of chick type II collagen [40]. Rats are
The percent increase in the weight of right paw in immunized on day 0 and 7. The collagen is solubilized
comparison with that of the left paw of each animal is (2mg/ml) in 0.01M acetic acid, mixed with equal volume of
calculated as an indication of inflammation using the Freunds incomplete adjuvant to obtain a final concentration
following equation [21].
of 1 mg/ml that is injected into rates on three sites (0.5ml
% Increase in paw weight = [(R-L) / L] 100
above and 0.25ml on either side of the tail) [34]. Diameter of
Where
ankle joints (measured by using fowler caliper) is compared
R = weight of right leg and
between test group and control group of rates.
L = weight of left leg.
3.2.4 Adjuvant- Induced Arthritis
The mean percentage reduction in the swelling can be Lyophilized heat-killed Mycobacteria tuberculosis [34, 39]
measured from the difference of percentage swelling are suspended in light mineral oil [34] or paraffin [38, 39],
between the treated group and the negative control group by ground with a mortar and pestle, and adjusted to a stock
using the following equation [21]:
concentration of 20 mg/ml in oil. The stock of Mycobacteria
% Reduction in Odema = [(C-T) / C] 100
is diluted in mineral oil or paraffin to a concentration of 2.5
Where
mg/ml and is sonicated for 15 min using a heat systems
C = control group and
model W385 sonicator equipped with a 3-inch cuphorn.
T = treated group.
Rats are injected intradermally with a total of 0.1 ml (0.25
3.2 ARTHRITIS
mg) of the Mycobacterium oil suspension [34] or 0.1ml
Animals are divided into three equal groups. One group is (1mg) of Mycobacterium oil suspension [39] at the base of
given plant extract orally throughout the experiment (test the tail. Alternatively, 0.1 ml (0.5mg) Mycobacterium
group). The second group is given only the vehicle (negative butyricum suspension in liquid paraffin can also be injected
control) while the third group is given a reference drug such at the base of rat tail to induce arthritis [38]. Thickness of
as indomethacin [22] in the same vehicle (as positive ankle in test group is measured and compared with that of
reference). Arthritis can be induced in rats by injecting a the control group.
number of agents like carrageenan [31, 32, 33], collagen [34,
3.3 GRANULOMA
35] or adjuvant [36, 37, 38, 39].
Granuloma can be induced in rats by cotton implant. A
3.2.1 Carrageenan Induced Arthritis
sterilized cotton pellet weighing 10 0.5mg [30], 30mg [22]
In carrageenan induced arthritis, test group of mice are or 50mg [28] is implanted subcutaneously in rats
subjected to mild ether anaesthesia. Carrageenan, either 10 anaesthetized by intraperitoneal injection of sodium
l [31] or 50l [32] is dissolved in vehicle such as 0.1 M pentobarbitone (30 mg/kg body wt) . A small incision is
Phosphate Bufferred Saline [31] or normal saline [32, 33] made carefully in the mid line of dorsal surface and a pocket
and is injected in knee joint [31, 33]. Control group receive is created by inserting a blunt-ended pair of scissors into the
carrageenan injection in knee joint without plant extract. incision. One pre-weighed cotton pellet is placed in the groin
Positive reference group receives dexamethasone intra region of every animal [22] however; some workers have
articularly or intraperitoneally [33]. After that, half of the implanted four pre-weighed cotton pellets (two on each side
mice of test, control and reference group are killed after 12 of the middle incision) into each animal [30]. The incised
hours and half are killed after 24 hours. As it is evident skin is stitched under antibiotic. 24 hours after the cotton
from previous studies that the concentration of nerve growth implantation, animals are given plant extract orally. Some
factor (NGF) in synovial fluid is increased in carrageenan workers have treated animals with a single dose of plant
induced arthritis [31, 32], the concentration of NGF is extract (200mg/kg [28], 400mg/kg [30], 500 mg/kg [41]),
measured in synovial fluid and the difference between NGF however, others have treated groups with different doses in
level in control group and test group indicates the inhibition ascending fashion such as four groups of animals with 25,
of arthritis by the herbal extracts.
50, 100 or 200 mg/Kg [22] for six to seven consecutive days.
3.2.2 Formaldehyde Induced Arthritis
Animals in the control group are given normal saline. In
Arthritis can be induced by injecting formaldehyde (0.1 ml reference group, animals are given a potent anti
of 4% formaldehyde) in the left paw of animals on first and inflammatory drug such as indomethacin (5 mg/Kg) [22] or
third day of experiment. Animals are given herbal extracts dexamethasone (7mg/kg) [28]. The animals are sacrificed on
(25-200mg/kg), saline or indomethacin once daily for ten the 8th day with an over dose of ether. Thereafter, the pellets
consecutive days starting from the administration of surrounded by granuloma tissue are dissected out carefully,

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washed and oven dried at 60 C to a constant weight for 24

hours. The mean weight of the granuloma tissue formed
around each pellet is obtained and the percentage inhibition
is determined [22].
3.4 ANALGESIC EFFECT
Anti-nociceptive activity of plant extracts can be determined
by administering plant extracts to the animals over a
specified period of time. Pain is then induced in animals
either by injection of chemicals such as acetic acid [7, 12,
16, 20, 42, 43, 44] or formalin [16, 43, 44, 45], or by using
hot plate method [20, 43, 46]. We briefly discuss these
methods here.
3.4.1 Formalin Test
The mice are treated (intraperitonially) with different doses
of the plant extracts, 30 min prior to administration of
formalin. Either 2.5l of 25% formalin into the subplantar
region [44]; 20l of 1% formalin into the dorsal surface of
hind paw [16] or 20l of 25% formalin in normal saline [43]
in the hind paw is injected subcutaneously. The mice are
individually placed in a Plexiglas cage observation chamber
[44]. All mice injected with formalin immediately start to
lick or bite the injected paw, that indicates the procedure is
painful. The period of the first 15 minutes is considered the
early phase of the formalin pain, while the late phase is
referred to time between 15 and 45 minutes after formalin
injection. The time in seconds spent in licking and the biting
responses of the injected paw is noted. Diclofenac (10
mg/kg, i.p.) [16] or aspirin (200mg/kg) [43] is used as
positive control. Control animals receive the vehicle (normal
saline, 0.1 mL/10 gm) [16]. The paw licking time of the
animals is compared to the control group and represented as
percent inhibition.
3.4.2 Acetic Acid Induced Writhing Test
Most of the workers have used acetic acid to induce pain.
Plant extracts are administered either through oral route or
intra peritoneal route 60 minutes or 30 minutes before acetic
acid administration respectively [7]. Mice are given 0.1 ml
of 0.7% acetic acid solution (v/v) in normal saline [16] or
0.2ml of 0.8% aqueous solution of acetic acid [7] through
intra peritoneal rout thirty minutes after the administration of
the plant extracts or pure compounds. Five minutes after the
injection of acetic acid, the number of writhes produced in
these animals are counted for another 20 minutes. A writhe
is indicated by stretching of the abdomen with simultaneous
stretching of at least one hind limb [16]. Indomethacin
(10mg/kg) [20], aspirin (200mg/kg) [43] or diclofenac
(10mg/kg) [16] is administered through intra peritoneal rout
as positive reference. Vehicle such as normal saline
(10mg/kg) [16] or a co-solvent of water, propylene glycol
and tween (10mg/kg) [20] is given to the control group.
3.4.3 Hot Plate Method
Instead of inducing pain by administration of acetic acid or
formalin, Hot plate method can also be used to test the anti
nociceptive activity of herbal extracts. Mice are placed on a
hot plate maintained at 55 1C [20] or 52 C [44, 47] for a
maximum nociceptive response of 45 seconds. The mice are
observed for the occurrence of either licking of hind paws or
jumping off of the surface. The latency of nociceptive
responses is recorded when the animals lick their hind limb
or jump. Mice are treated with plant extract 30 minutes
before the test and the control group received the same
volume of sterile saline. Morphine (5 mg/kg) is injected

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subcutaneously 30 minutes before the test as reference [20,

47]. Observations are recorded at (0 time) and then 30, 60,
and 90 minutes after treatment, with a 45 seconds cut-off
time to avoid animal paw lesion. Mice with baseline
latencies of more than 20 seconds are rejected [47].
3.4.4 RandallSoletto Test
This test is based on the principle that sensitivity to pain is
increased due to inflammation and the threshold of pain can
be increased by injecting a compound with analgesic activity
[29]. Plant extract is administered to the animals orally.
Inflammation is induced in the mice by injecting 0.1ml of
20% Brewers yeast solution in the sub plantar region of
mice and pressure is used to evoke pain in the area of
inflammation. Threshold of pain is measured at time O, 30
and 60 minutes after the injection of yeast and is compared
with that in control group [29].
4. CONCLUSION
This review gives an insight of the frequently used in-vivo
methods to test anti-inflammatory activity of herbal extracts.
Although some workers have relied only on carrageenan
induced odema in rats to evaluate the in-vivo antiinflammatory properties of herbal extracts, most of the
workers have preferred to use more than one experimental
model at the same time. We suggest to use collagen and
adjuvant induced arthritis models also to test the antiarthritic potential of herbs along with other methods like
formalin and carrageenan induced arthritis. Most of the
workers have used either none steroidal anti inflammatory
drugs (NSAIDs) such as indomethacin, diclofenac and
aspirin, or steroid such as dexamethasone as positive
reference. We suggest to use both, an NSAID and a steroid
as positive reference in the same study to evaluate that the
anti-inflammatory activity of the herbal extract is more
comparable with steroid or with NSAID.
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