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Studying the Analgesic, Anti-inflammatory and Antipyretic Properties of The Aqueous Extract of Petroselinum crispum in Experimental Animal

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The aqueous extract of Parsley (Petroselinum crispum) were investigated for anti-inflammatory, analgesic and antipyretic activity at the doses of 2 , 5 , and 10 g/kg, of body weight. The experimental paradigms used were carrageenan, dextran, histamine induced pedal edema and cotton pellet induced granuloma for anti-inflammatory activity, while hot plate and acetic acid induced writhing methods were used to assess analgesic activity. Yeast-induced hyperpyrexia was used to evaluate the antipyretic activity. In acute phase inflammation, a maximum inhibition 50.6% (P < 0.05), 51.1% (P < 0.05) and 52.3% (P < 0.05) were noted at the dose of 10 g/kg after 3 h of treatment with methanol extract of Parsley (Petroselinum crispum) in carrageenan, dextran and histamine induced pedal edema , respectively. In the chronic model (cotton pellet induced granuloma) , the parsley (10 g/kg) and standard drug (Indomethacin 10 mg/kg) showed decreased formation of granuloma tissue by 51.8% (P < 0.05) and 56.6% (P < 0.05) , respectively. The extract also produced significant (P < 0.01) analgesic activity in both paradigms. In addition, the aqueous extract of parsley potentiated the morphine and aspirin induced analgesia. A significant (P < 0.01) reduction in hyperpyrexia in rat was also produced by the extract. This study exhibits that methanol extracts of leaves of parsley possess anti-inflammatory, analgesic and antipyretic activities.
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IOSR Journal Of Pharmacy
(e)-ISSN: 2250-3013, (p)-ISSN: 2319-4219
www.iosrphr.org Volume 5, Issue 9 (September 2015), PP. 17-23
17
Studying the Analgesic, Anti-inflammatory and Antipyretic Properties of
The Aqueous Extract of Petroselinum crispum in Experimental Animal
Models
Shahbaa M. Al-khazraji
Department of Pharmacy , Medical Technical Institute-Mansour ,Middle Technical University,
Baghdad , Iraq .
Abstract : The aqueous extract of Parsley ( Petroselinum crispum ) were investigated for anti-inflammatory,
analgesic and antipyretic activity at the doses of 2 , 5 , and 10 g/kg, of body weight. The experimental
paradigms used were carrageenan, dextran, histamine induced pedal edema and cotton pellet induced
granuloma for anti-inflammatory activity, while hot plate and acetic acid induced writhing methods were used
to assess analgesic activity. Yeast-induced hyperpyrexia was used to evaluate the antipyretic activity. In acute
phase inflammation, a maximum inhibition 50.6% (P < 0.05), 51.1% (P < 0.05) and 52.3% (P < 0.05) were
noted at the dose of 10 g/kg after 3 h of treatment with methanol extract of Parsley ( Petroselinum crispum ) in
carrageenan, dextran and histamine induced pedal edema , respectively. In the chronic model (cotton pellet
induced granuloma) , the parsley (10 g/kg) and standard drug (Indomethacin 10 mg/kg) showed decreased
formation of granuloma tissue by 51.8% (P < 0.05) and 56.6% (P < 0.05) , respectively. The extract also
produced significant (P < 0.01) analgesic activity in both paradigms. In addition, the aqueous extract of
parsley potentiated the morphine and aspirin induced analgesia. A significant (P < 0.01) reduction in
hyperpyrexia in rat was also produced by the extract. This study exhibits that methanol extracts of leaves of
parsley possess anti-inflammatory, analgesic and antipyretic activities.
Keywords:, Parsley ( Petroselinum crispum ) , Anti-inflammatory, Analgesic, Antipyretic
I.Introduction
Inflammation or phlogosis is a path physiological response of living tissue to injuries that leads to the
local accumulation of plasmatic fluid and blood cells. Although it is a defense mechanism, the complex events
and mediators involved in the inflammatory reaction can be induced, maintain or aggravate many diseases [1] .
However, studies have been continuing on inflammatory diseases and the side effects of the currly available
anti-inflammatory drugs pose a major problem during their clinical use [2]. . Phenolic phytochemicals are known
to exhibit several health beneficial activities such as antioxidant, anti-inflammatory, antihepatotoxic, antitumor,
and antimicrobialTherefore, development of newer and more powerful anti-inflammatory drugs with lesser side
effects is necessary [3].
Parsley ( Petroselinum crispum ) is a medicinal herb used in folk medicine remedy to decrease the blood
glucose level in Turkey [4] , and it shows a protective effect against hepatic toxicity caused as a complication of
diabetic state [5] .The plant therapy can provide blood glucose homeostasis and cannot regenerate the B-cells of
the endogenous pancreas [6] . Also parsley has been claimed in folk medicine to posses laxative properties
attributed to the presence of some volatile oil that are more concentrated in seeds than in stems or leaves [6] .
Parsley have advocated diuretic effect in folk medicine , and it is mediated through an inhibition of sodium
potassium pump that would lead to the reduction in sodium and potassium re absorption leading, thus, to an
osmotic water flow in to lumen and diuresis [7] . As a traditional medicine for hyperuricemia and gout, parsley
(Petroselinum crispum) has been used in folk medicine. Phytochemical screening of parsley (Petroselinum
crispum) has revealed the presence of several classes of flavonoids . Flavonols (kaempferol and quercetin) and
flavones (apigenin and luteolin), which occur as glycosidic form in nature, are major flavonoids found in parsley
(Petroselinum crispum) and other apiaceous vegetables . Kaempferol and quercetin, which belong to flavonol
group, possess a wide ra parsley (Petroselinum crispum) has revealed the presence of several classes of
flavonoids . Flavonols (kaempferol and quercetin) and flavones (apigenin and luteolin), which occur as
glycosidic form in nature, are major flavonoids found in parsley (Petroselinum crispum) and other apiaceous
vegetables . Kaempferol and quercetin, which belong to flavonol group, possess a wide range of biochemical
and pharmacological effects and have been recommended as chemopreventive agents or nutritional supplements
. The predominant mechanism of their biological actions is thought to result from antioxidant activity, enzyme
inhibition, and the capacity to scavenge free radicals . Therefore, it is speculated that the health promoting effect
Studying the Analgesic, Anti-inflammatory…
18
of parsley (Petroselinum crispum) may be due to its flavonol constituents and the content of flavonoid
compounds in parsley is about 100 mg/100 g fresh weight [8] .
However, no work has been reported on the anti-inflammatory effects on acute and chronic phases of
inflammation, analgesic and antipyretic activity of Petroselinum crispum . Keeping this in view, the present
study has been undertaken to investigate these of the aqueous extract of Petroselinum crispum in experimental
animal models.
II.Materials and Methods
Plant material and extraction
Dried parsley was obtained from commercial source and a voucher specimen of the plant was identified at the
National Herbarium of Iraq Botany Directorate in Abu-Ghraib . Parsley was shed dried at 25 C. Then a ground
material was obtained by grinding dried parsley flakes with a coffee grinder and passing the powdered material
through a standard sieve number 20, and stored at room temperature , then , the aqueous extract of parsley was
prepared by decoction process of powdered material, in brief a suspension of 25 g of the powder in 100 ml of
distilled water was stirred magnetically overnight ( 16 hours ) at room temperature , and this was repeated three
consecutive times . The residue was removed by filtration and the extract was evaporated to dryness at a low
temperature ( 40 C ) under reduced pressure in a rotator evaporator rotary vacuum (model Zirbus 302R) for
about 1 h , and kept in deep freeze . The residual extract were dissolved in normal saline whenever used in the
experiments [10] .
Animals
Swiss albino mice of both sex weighing between (18-22 g) and Albino Wister rats of the either sex
(180-200 g) were used for the study. They were maintained under standard environmental conditions
and were fed with standard pellet diet, and water ad libitum.
Chemicals and Drugs
Carrageenan (S. D. Fine Chemicals Limited, Bom-bay), histamine (Sigma, USA), dextran (Sigma,
USA) were used in the study and indomethacin (Re-con, Bangalore), aspirin (USV, Bombay) ,
paracetamol (IPCA, Bombay), and morphine (M.M. Pharma, New Delhi) were used as the standard drugs.
I-Anti-inflammatory models
a-Carrageenan-induced paw edema in rats.
The rats were divided into 5 groups (n = 6) for eah group . The different groups were treated with
parsley ( 2, 5 and 10 g/kg PO ) , indomethacin (10 mg/kg PO ) and control vehicle per oral and the paw
volume was measured at 0 h and 3 h after carrageenan injection using a plethysmometer [11,12] . Animals
were pretreated with the extract 1 h before the administration of carrageenan. Acute inflammation was
produced by the sub planter administration of 0.1 ml of (1%, w/v) carrageenan in normal saline in the
right paw of the rats. The ratio of the anti-inflammatory effect of the aqueous extract of parsley was
calculated by the following equation:
anti-inflammatory activity (%) = (1 - D / C) x 100
where D represents the percentage difference in paw volume after parsley was administered to the rats,
and C represents the percentage difference of volume in the control groups [12] .
b-Dextran-induced paw edema in rats.
Animals were treated in a manner similar to that of carrageenan induced paw edema model; dextran (0.1
ml, 1% w/v in normal saline) was used in place of carrageenan [13]
c-Histamine-induced paw edema in rats.
The anti-inflammatory activity of parsley was measured with histamine (phlogistic agents) which acts as
mediator of inflammation. The paw edema was induced in rats by sub planter injection of 0.1 ml (1% w/v) of
freshly prepared histamine solution, and the paw edema was measured [14] .
d-Cotton pellets-induced granuloma.
The rats were divided into five groups (n = 6) for each group. After shaving the fur, the rats were anaesthetized
with ether , and 10 mg of sterile cotton pellets were inserted, one in each axils. The aqueous extract of parsley (2
, 5, and 10 g/kg, PO ), indomethacin (10 mg/kg, PO ) and control vehicle were administered orally for 7
consecutive days from the day of cotton pellet implantation. Animals were then anaesthetized on the eighth day
and cotton pellets were removed surgically and made free from extraneous tissues. The pellets were incubated at
37°C for 24 h and dried at 60°C to constant weight. Increment in the dry weight of the pellets was taken as
measure of granuloma formation [15] .
Studying the Analgesic, Anti-inflammatory…
19
II-Analgesic activity
The aqueous extract of parsley at the dose of 2 , 5 , and 10 g/kg and combination of above doses of extract
with the standard drug aspirin 100 mg/kg (Acetic acid induced writhing response in mice) and morphine 5
mg/kg (Hot plate reaction time in mice) were administered to eight groups ( six mice in each paradigm ) [16] .
a-Acetic acid-induced writhing test.
Acetic acid solution (15 mg/ml) at the dose of 300 mg/kg body weight was injected (i.p.) and the number of
writhes during the following 30 min period was observed [17] . A significant reduction in the number of writhes
by drug treatment as compared to vehicle treated animals was considered as a positive analgesic response. The
percentage inhibition of writhing was then calculated. Aspirin (100 mg/kg, i.p.) was used as standard.
b-Hot plate reaction time in mice.
Mice were screened by placing them on a hot plate maintained at 55 ± 1°C and the reaction time in seconds
for hind paw licking or jumping were recorded [18] . Only mice which reacted within 15 sec and which did not
show large variation when tested on four separated occasions, each 15 min apart, were used in this study.
Morphine (5 mg/kg, i.p.) was used as standard. The time for hind paw licking or jumping on the heated plate of
analgesiometer was taken as the reaction time.
II-Induction of Yeast-induced pyrexia
Rats were divided into five groups (six rats in each) , and were trained to remain quiet in a restraint cage. A
thermister probe was inserted 3-4 cm deep into the rectum and fastened to the tail by an adhesive tape and the
temperature was measured on a thermometer. The normal body temperature of each rat was measured rectally at
predetermined intervals and recorded. Fever was induced by a subcutaneous injection of 20 ml/kg body wt. of
20% w/v yeast suspended in methyl cellulose solution . Rats were then returned to their housing cage. After 24 h
of yeast injection, animals were again restrained in individual cages for recording of their rectal temperatures as
described previously. Then parsley was administered orally at doses of 2 , 5 , and 10 g/kg body wt. to three
groups of animals , respectively. 10% Propylene glycol (5ml/kg, body wt.) was administered orally to the
control group of animals. The fifth group of animals received the standard drug paracetamol (150 mg/kg, body
wt.) orally. Rats were restrained for recording of their rectal temperatures at intervals of one hour, after the drug
administration [15] .
Statistical analysis
The experimental results were expressed as the mean ± S.E.M. Data were assessed by the method of analysis of
ANOVA followed by student's t-test. P value of < 0.05 was considered as statistically significant.
III. Results
I-Anti-inflammatory effects
The anti-inflammatory potential of parsley 2 , 5 , and 10 g/kg against various experimental animal models
exhibited significant (P < 0.05) anti-inflammatory activity. The effects of parsley and indomethacin on the
inflammation induced by carrageenan, dextran, histamine and cotton pellet induced granuloma are summarized
in Fig 1 and Fig 2.
The percentage of inhibition was calculated according to the following equation :-
% Inhibition =(C-T)/C × 100
As shown in Fig 1, parsley showed maximum inhibition of 50.6% at the dose of 10g/kg after 3 h of treatment
in carrageenan induced paw oedema, whereas the standard drug (Indomethacin 10 mg/kg) showed 72.4% of
inhibition (P < 0.05). In case of dextran induced paw oedema, the parsley showed significant inhibition (33.0%,
43.2% and 51.1%) in a dose dependent manner as compared with control. The parsley showed 52.3% of
inhibition at the dose of 10 g/kg whereas indomethacin showed 72.1% of inhibition in histamine induced paw
oedema. In the chronic model (cotton pellet induced granuloma), the parsley ( 2 , 5 , and 10 g/kg) and
indomethacin showed decreased formation of granuloma tissue at 29.6%, 41.3%, 51.8% and 56.6% respectively
(Fig 2). Regarding the effect of parsley on acute phase of inflammation (carrageenan, dextran and histamine)
and chronic (cotton pellet induced granuloma), a maximum inhibition ( 69.9%, 74.9%, 72.5 and 91.5%
respectively ) was noted at the dose of 10 g/kg when compared with standard drug.
II-Analgesic effects
The results presented in Table 1, shows that parsley at the doses of 2 , 5 , and 10 g /kg and aspirin at 100 mg / kg
exhibited highly significant (P < 0.01) inhibition of the control writhes . The percentage of inhibition was
calculated according to the following equation
% Inhibition =(C-T)/C × 100
Studying the Analgesic, Anti-inflammatory…
20
The inhibition was at rate of 16.5%, 27.8%, 48.8% and 66.0%, respectively , when compared to that of
control. In addition, parsley at the above mentioned doses, potentiated the analgesic activity of aspirin
shown by further decreasing the writhing response when given in combination.
As shown in Table 2, the parsley produce a highly significant (P < 0.01) analgesic activity when compared
to the that of control. Additionally, parsley at different doses potentiated the analgesic activity of the
standard drug (Morphine 5 mg/kg).
III-Anti-pyretic effects
The subcutaneous injection of yeast suspension markedly elevated the rectal temperature after 24 h of
administration . Treatment with the parsley at the dose of 2 . 5 , and 10g / kg., body weight decreased the rectal
temperature of the rat in a dose dependent manner. The antipyretic effect started from the first hour and was
maintained for 4 h, after administration of the extract. The result obtained from both the standard and parsley
treated rats were compared with the control group and a high significant reduction(P < 0.01) in the yeast
induced elevated rectal temperature was observed (Table 3).
Figure 1: Effect of parsley and indomethacin on carragennan , dextran , histamine induced rat paw oedema .
Differences of mean oedema volume (ml) between control and treatment values at different doses SEM ±
Variation compared to the control animals . ANOVA followed by Students t test . * p<0.05 .
Figure 2 : Effect of Parsley and Indomethacin on the proliferative phase of inflammation in rats Difference
of means of dried cotton pellet weight (mg) between control and treatment values at different doses
S.E.M±Variation compared to the control animals. ANOVA followed by Student's t- test * P < 0.05.
Table 1: Effects of parsley and aspirin on writhing induced by acetic acid in mice.
Treatment
Dose
Number of writhes (per 30
Inhibition
(g/kg)
min)
(%)
Control
-
30.33±2.68
-
parsley
2
25.00±2.23
*
16.5
parsley
5
21.33±1.18
*
27.8
parsley
10
14.54±1.49 *
48.8
Aspirin
0.1
9.11 ±1.40 *
66.0
parsley
2+0.1
9.82±1.43 *
67.5
+Aspirin
parsley
5+0.1
6.9 4±0.62
*
71.7
+Aspirin
parsley
10+0.1
5.96±0.46
*
79.4
+Aspirin
*P< 0.01 means highly significant difference compared with control
Studying the Analgesic, Anti-inflammatory…
21
Table 2: Effects of parsley and morphine on hot plate reaction time in mice.
Treatment
Dose (g/kg)
Initial
After 30 min
Control
-
9.94±0.62
8.14±0.56
parsley
2
10.43±0.53
*
13.34±0.93
**
parsley
5
10.77±0.91
*
14.25±1.22
**
parsley
10
10.32±0.59
*
15.74±1.26
**
Morphine
0.005
10.94±0.79
*
19.17±1.33
**
parsley +Morphine
2+0.005
10.77±0.48
*
21.37±1.57
***
parsley +Morphine
5+0.005
9.93±0.29
*
23.68±1.32
***
parsley +Morphine
10+0.005
10.43±0.59*
27.53±1.21
***
*P< 0.01 ,**P<0.001, P<0.005 , means highly significant difference compared with control
Table 3: The effect of parsley and paracetamol on yeast-induced pyrexia in rats.
Treatment Rectal temperature
After yeast injection
After drug administration
0 h
24 h
1 h
2 h
3 h
4 h
Control
Vehicle
5ml/kg
39.9±0.02
41.9±0.03
42.1 ±0.02
41.9±0.05
41.9±0.05
41.9±0.04
Paraceta
mol
150mg/kg
39.9±0.02
42±0.038*
40.9±0.02*
40.3±0.02*
39.8±0.04*
39.7±0.03*
Parsley
2 g/kg
39.7±0.04
41.8±0.03*
41.2 ±0.02*
40.7±0.02*
40.4±0.04*
40.1±0.06*
parsley
5g/kg
38.9±0.02
41.7±0.04*
41.8±0.05*
40.5±0.05*
40.1±0.03*
39.8±0.06*
Parsley
10mg/kg
39.7±0.07
42.1±0.06*
41.8±0.02*
40.2±0.03*
39.7±0.05*
39.6±0.04*
*P< 0.01, means highly significant difference compared with control
IV. Discussion
Parsley was evaluated for its anti inflammatory activity in acute and chronic models. A significant ( p
< 0.05) anti-inflammatory activity was observed for parsley in carrageenan, dextran, histamine induced edema
and cotton pellet-induced granuloma models. Carrageenan-induced rat paw edema has been used as an
inflammation model in order to investigate the anti-inflammatory effect of drug [18] . There are two phases of
carrageenan-induced inflammatory reaction: early or ( first phase ) and later or ( second phase ). It has been
proposed that early phase results from histamine, serotonin and bradykinin liberation , while late phase is
associated with the release of prostaglandin [19] . In carrageenan induced paw edema , the parsley showed
maximum inhibition of 50.6% at the dose of 10 g/kg after 3 h of drug treatment. Dextran induced paw edema is
known to be mediated both by histamine and serotonin. Dextran induces fluid accumulation, which contains
little protein few neutrophils, whereas carrageenan induces protein rich exudation containing large number of
neutrophil [18] . The parsley also exhibited significant anti-inflammatory activity in dextran induced paw edema.
Histamine is one of the important inflammation mediators and it is a potent vasodilator substance and increases
the vascular permeability [20.21] . This study showed that all the doses of parsley effectively suppressed the
edema produced by the histamine, which indicates that the extract exhibit its anti-inflammatory action by means
of either inhibiting the synthesis, release or action of inflammatory mediators via. histamine, serotonin and
prostaglandin might be involved in the inflammation .
Studying the Analgesic, Anti-inflammatory…
22
From these results , it is suggested that the anti- oedematogenic effect of parsley on carrageennan , dextran and
histamine induced edema may be related to the inhibition of inflammatory mediator formation .
Chronic inflammation is a reaction arising when the acute response is insufficient to eliminate pro inflammatory
agents. Chronic inflammation includes a proliferation of fibroblasts and the infiltration of neutrophils and
exudation [22.23] . Chronic inflammation occurs by means of the development of proliferative cells. These cells
can be either spread or granuloma form . Efficacy of anti-inflammatory agents in chronic inflammatory states is
indicated by their ability to inhibit the increase in the number of fibroblasts and synthesis of collagen and
mucopolysaccharides during granuloma tissue formation [24.25]. The parsley showed significant (P < 0.05) anti-
inflammatory activity in cotton pellet induced granuloma and , thus , found to be a effective in chronic
inflammatory condition.
In order to distinguish between the central and peripheral analgesic action of parsley , acetic acid induced
writhing responses in mice were used to examine the effect. This method is not only simple and reliable but also
affords rapid evaluation of peripheral type of analgesic action. In this test, the animals react with characteristic
stretching behavior, which is called writhing. It was found that parsley significantly (P < 0.01) inhibited the
acetic acid induced writhing response and potentiated the analgesic activity of aspirin as well. The abdominal
constriction is related to the sensitization of nociceptive receptors to prostaglandins. It is , therefore , possible
that parsley produced analgesic effect by inhibition of synthesis or action of prostaglandins [25].
The hot plate method was originally described by Woolfe and Mac Donald [26] .This test has been found to be
suitable for the evaluation of centrally but not of peripherally acting analgesics. The validity of this test has been
shown even in the presence of substantial impairment of motor performance [27] .The present findings of the
study indicate that the parsley may be centrally acting.
Fever may be a result of infection or one of the sequel of tissue damage, inflammation, graft rejection, or other
disease states. Antipyretics are drugs, which reduce elevated body temperature. Regulation of body temperature
requires a delicate balance between production and loss of heat, and the hypothalamus regulates the set point at
which body temperature is maintained . In fever , this set point is elevated and a drug like paracetamol do not
influence body temperature when it is elevated by factors such as exercise or increases in ambient temperature
[28] . The present result show that the parsley possesses a significant antipyretic effect in yeast-provoked
elevation of body temperature in rats and its effect is comparable to that of paracetamol .
Based on the results of the present study , it can be concluded that parsley has potential activity against both
acute and chronic phases at a dosage range of 2-10 g/kg. PO . Of the three doses , the dose of 10 g/kg is found to
be more potent and efficacious towards the anti-inflammatory, analgesic and antipyretic activity, when
compared with control , and the activity is in a dose-dependent manner. More detailed phytochemical studies
are, however, necessary to identify the active principle(s) and exact mechanism(s) of action.
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