Suppressive effects of JCICM-6, the extract of an anti-arthritic herbal formula, on the experimental inflammatory and nociceptive models in rodents

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Abstract
JCICM-6, the extract of an anti-arthritic herbal formula composed of medicinal herbs of Sinomenium acutum, Aconitum carmichaeli DEBX., Curcuma Longa L., Paeonia lactiflora PALL., and Paeonia suffruticosa ANDR., was examined in the effectiveness and mechanism in reducing experimentally-induced inflammation and nociception using nine animal models. JCICM-6 was extracted from herbs and purified with Amberlite XAD-7HP adsorbent resin and analyzed with HPLC-fingerprint for quality consistency. In acute inflammatory models, the paw edema of rats was induced by subcutaneous injection of carrageenan or pro-inflammatory mediators, including histamine, serotonin, bradykinin, and prostaglandin E(2) (PGE(2)) into the right hind paws of animals; while the ear edema of mice was induced by applying arachidonic acid or 12-O-tetradecanoylphorbol 13-acetate (TPA) on the ear surface. In nociceptive models, the tail-flick response induced by radiant heat stimulation was measured and the numbers of abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid were recorded. JCICM-6 orally administered in a range of dosages from 0.438 g to 1.75 g/kg significantly and dose-dependently suppressed the paw edema of rats induced by carrageenan or various pro-inflammatory mediators and the ear edema of mice induced by arachidonic acid or TPA. JCICM-6 also significantly prolonged the reaction time of rats to radiant heat stimulation and reduced the numbers of writhing episodes of mice. These results indicated that JCICM-6 possesses significant anti-inflammatory and analgesic effects, which implies that it would be a potential candidate for further investigation as a new anti-arthritic botanical drug for humans.
In treating inflammatory and arthritic diseases, medical
doctors have been commonly using nonsteroidal anti-inflam-
matory drugs (NSAIDs) and immunosuppressants. Previous
studies have demonstrated that these drugs could inhibit syn-
thesis or production of pro-inflammatory cytokines or media-
tors or their interactions. However, they sometimes also
cause serious adverse effects such as gastric mucosal dam-
age, bone marrow depression, water and salt retention
(phenylbutazone, oxyphenbutazone) and even possible car-
cinogenesis (aminopyrine).
1)
Thus, alternative agents with
fewer and less severe side effects are required, and botanicals
are important candidates.
2)
Chinese herbal medicines have been becoming more and
more popular over the world. Actually, they are being widely
used in China, Japan and South Korea for treatment of vari-
ous complicated refractory diseases including arthritis.
JCICM-6 is the extract of an anti-arthritic herbal formula that
composes of Sinomenium acutum (Family Menispermaceae),
Aconitum carmichaeli DEBX.(Family Ranunculaceae), Cur-
cuma Longa L. (Family Zingiberaceae), Paeonia lactiflora
PALL.(Family Paeoniaceae), and Paeonia suffruticosa ANDR.
(Family Paeoniaceae). These five herbs are commonly pre-
scribed together with other herbs in herbal formula to treat
rheumatoid arthritis (RA) by Chinese medicine practi-
tioners.
3)
Previous chemical and pharmacological studies
showed that Sinomenium acutum contains various bioactive
alkaloids, such as sinomenine, sinoacutine, disinomenine,
and magnoflorine. Of these compounds, sinomenine is pre-
dominant in the activities of anti-inflammation, analgesia,
arthritis amelioration and immunosuppression.
4—6)
Curcuma
Longa L. contains curcumin, curlone and curcumenone.
7)
The water extract of Curcumae Longae and its chemical con-
stituent curcumin has significant anti-inflammatory and anal-
gesic activities as well as a protective effect on gastrointesti-
nal mucosa.
8)
Aconitum carmichaeli DEBX. contains Aconi-
tum parent alkaloids of aconitine, mesaconitine and hypa-
conitine and their hydrolytes of benzoylaconine, benzoylme-
saconine and benzoylhypaconine.
9)
These three parent alka-
loids are highly toxic but present in only very small amounts
in the processed herbs of the Aconitum carmichaeli D
EBX.;
while their hydrolytes with relatively higher contents in the
processed aconite roots have significant anti-inflammatory
and antinociceptive activities that are desirable for clinical
treatment.
10,11)
Paeonia lactiflora PALL. contains paeoniflorin,
oxypaeoniflorin, benzoylpaeoniflorin and albilorin. Of these
compounds, the major bioactive component paeoniflorin
was reported to have marked anti-inflammatory, analgesic
and immunomodulatory activities.
12)
Our previous studies
showed that sinomenine could significantly improve the
bioavailability of paeoniflorin in rats when orally adminis-
tered jointly and the improvement is possibly through a P-
glycoprotein mechanism.
13—15)
Paeonia suffruticosa ANDR.
contains paeonol, paeoniflorin, paeonoside, paeonollide and
apiopaeonoside. Of these compounds, paeonol is the main
bioactive component having potent anti-inflammatory and
analgesic effects in carrageenan-evoked thermal hyperalgesia
of rats.
16)
Thus, the herbal formula comprising those five
herbs with known multiple components and pharmacological
February 2006 253Biol. Pharm. Bull. 29(2) 253—260 (2006)
Suppressive Effects of JCICM-6, the Extract of an Anti-arthritic Herbal
Formula, on the Experimental Inflammatory and Nociceptive Models in
Rodents
Hua ZHOU,
a
Yuen Fan WONG,
a
Xiong CAI,
a
Zhong Qiu LIU,
a
Zhi Hong JIANG,
a
Zhao Xiang BIAN,
a
Hong Xi XU,
b
and Liang LIU
*
,a
a
School of Chinese Medicine, Hong Kong Baptist University; Kowloon Tong, Hong Kong, China: and
b
Hong Kong Jockey
Club Institute of Chinese Medicine Limited; Unit 703, 7/F, Bioinformatic Centre, No. 2 Science Park West Avenue, Hong
Kong Science Park, Pak Shek Kok, Shatin, New Territories, Hong Kong, China.
Received August 1, 2005; accepted November 11, 2005
JCICM-6, the extract of an anti-arthritic herbal formula composed of medicinal herbs of Sinomenium acu-
tum, Aconitum carmichaeli D
EBX., Curcuma Longa L., Paeonia lactiflora PALL., and Paeonia suffruticosa ANDR.,
was examined in the effectiveness and mechanism in reducing experimentally-induced inflammation and noci-
ception using nine animal models. JCICM-6 was extracted from herbs and purified with Amberlite XAD-7HP
adsorbent resin and analyzed with HPLC-fingerprint for quality consistency. In acute inflammatory models, the
paw edema of rats was induced by subcutaneous injection of carrageenan or pro-inflammatory mediators, in-
cluding histamine, serotonin, bradykinin, and prostaglandin E
2
(PGE
2
) into the right hind paws of animals;
while the ear edema of mice was induced by applying arachidonic acid or 12-O-tetradecanoylphorbol 13-acetate
(TPA) on the ear surface. In nociceptive models, the tail-flick response induced by radiant heat stimulation was
measured and the numbers of abdominal writhing episodes of mice induced by intraperitoneal injection of acetic
acid were recorded. JCICM-6 orally administered in a range of dosages from 0.438 g to 1.75 g/kg significantly
and dose-dependently suppressed the paw edema of rats induced by carrageenan or various pro-inflammatory
mediators and the ear edema of mice induced by arachidonic acid or TPA. JCICM-6 also significantly prolonged
the reaction time of rats to radiant heat stimulation and reduced the numbers of writhing episodes of mice.
These results indicated that JCICM-6 possesses significant anti-inflammatory and analgesic effects, which im-
plies that it would be a potential candidate for further investigation as a new anti-arthritic botanical drug for hu-
mans.
Key words JCICM-6; herbal formula; suppressive effect; inflammatory model; nociceptive model
© 2006 Pharmaceutical Society of JapanTo whom correspondence should be addressed. e-mail: liuliang@hkbu.edu.hk
effects may offer a comprehensive therapeutic efficacy for
human arthritis via various mechanic pathways and cellular
and molecule targets.
RA is a chronic, inflammatory, systemic autoimmune dis-
ease characterized by joint pain and swelling, pannus forma-
tion, cartilage destruction, bone erosion and joint dysfunc-
tion, in which a very complicated pathogenesis and multiple
pathological changes are implicated.
17)
Thus, a combinative
therapy and comprehensive management for RA patients
may be more appropriate to targeting on its complication of
pathology. Theoretically, an ideal treatment or drug for RA
should have multiple pharmacological potencies, such as
anti-inflammation, analgesia, anti-arthritis and immunomod-
ulation. The combinative therapeutics of herbal medicines
may provide such multiple potencies. Our previous study has
shown that QFGJS (another name of JCICM-6) had signifi-
cant anti-arthritic effect in adjuvant-induced arthritis of
rats.
18)
Therefore, our current studies aim to examine the
anti-inflammatory and analgesic effects of JCICM-6, the ex-
tract of a combination of Chinese herbal medicines, using
various animal models, so as to evaluate its potential to be
developed as a novel anti-arthritic botanical drug product. In
this paper, the results of in vivo studies of JCICM-6 in nine
inflammatory and nociceptive animal models are reported.
MATERIALS AND METHODS
Plant Materials Sinomenium acutum was purchased
form Zhong-Yue Herbal Pharmaceutical Union Company in
China. Aconitum carmichaeli DEBX. and Curcuma Longa L.,
cultivated in the Good Agricultural Practice (GAP) bases at
Jiangyou Country and Shuangliu Country of Chengdu City,
respectively, were purchased from the wholesale market of
Chengdu City, Shichuan Province, China. Paeonia lactiflora
PALL. and Paeonia suffruticosa, cultivated in the GAP bases
at Bozhou City and Tongning City of Anhui Province, re-
spectively, were purchased from the wholesale market of
Bozhou City, Anhui Province, China. Prof. Lai Xiao Ping
from the Guangzhou University of Traditional Chinese Med-
icine authenticated all herbs. The authenticated voucher
specimens are kept in the School of Chinese Medicine, the
Hong Kong Baptist University.
Preparation of JCICM-6 The five herbs were reduced
to coarse powder by pulverization. Sinomenium acutum,
Aconitum carmichaeli DEBX. and Paeonia lactiflora PALL.
were refluxed together with 80% ethanol and concentrated to
produce Extract 1. Paeonia suffruticosa ANDR. and Curcuma
Longa L. were extracted firstly with supercritical CO
2
(21.7 l/h) to produce Extract 2 and Extract 3, respectively.
The residues of the two herbs after CO
2
extraction were then
separately refluxed with 80% ethanol and concentrated to
produce Extracts 4 and 5. The mixture of Extracts 1, 4, and 5
was further purified with Amberlite XAD-7HP polymeric
resin (Rohm and Haas Company, U.S.A.), and then combined
with Extracts 2 and 3 to obtain JCICM-6. Three batches
(20040821, 20040825, 20040901) of JCICM-6 were pro-
duced and employed in the animal studies. The chemical
consistency of JCICM-6 was validated by HPLC fingerprint
analysis. The average yield rate of JCICM-6 was 6.44
0.35%, i.e., a 100 g plant material that is the clinical daily
dose of JCICM-6 yielded 6.44 g extract.
HPLC Fingerprint Analysis The HPLC fingerprint
analysis was carried out on a Phenomenex ODS (2504.6
mm I.D.; particle size 5
m
m; Alltech Associates, Inc., U.S.A.)
protected by a guard column (C
18
, 5
m
m, 7.54.6 mm I.D.).
The separation were conducted with a mixture of acetonitrile
and the buffer (containing 0.1% phosphoric acid, adjusted
with triethylamine to pH 3.50.2) in a gradient manner.
Detection was performed at a wavelength of 240 nm at
room temperature. The correlation coefficient of each chro-
matogram to the simulative mean chromatogram was calcu-
lated.
Experimental Animals ICR mice weighing 17—23 g
and SD rats weighing 150—200 g were purchased from the
Laboratory Animal Services Center, the Chinese University
of Hong Kong, Hong Kong. The animals were acclimated for
1 week under 12 h light and 12 h dark cycle at room tem-
perature of 22C. Chow diet and water were provided ad
libitum. Animal care and treatment procedures conformed to
the Institutional Guidelines and Animal Ordinance (Depart-
ment of Health, Hong Kong Special Administrative Region).
Rats and mice were fasted for 48 and 24 h, respectively, be-
fore experiment.
Drugs and Reagents For all experiments, an aqueous
solution of JCICM-6 was used at a concentration of 0.07
g/ml as a stock solution. The dosages of JCICM-6 employ in
all experiments ranged from 0.101 to 1.75 g/kg. The highest
dosage 1.75 g/kg is approximately 3.3 times of the equivalent
dose of the human dosage in clinic and thus is an acceptable
dosage for animal studies. All dilutions were obtained from
the stock solution using a dilution vehicle that consisted of
10% peanut oil, 10% Tween ®80 and 80% distilled water.
Other drugs and reagents, indomethacin, carrageenan, hista-
mine, serotonin, prostaglandin E
2
(PGE
2
), bradykinin, ara-
chidonic acid (AA), 12-O-tetradecanoylphorbol 13-acetate
(TPA), Tween ®80 and acetic acid, were purchased from
Sigma Chemical Co. (St. Louis, MO, U.S.A.). Rotundine, an
analgesic drug derived from medical plant in China, was pur-
chased from Guangzhou Shiqiao Pharmaceutical Co., Ltd.,
Guangzhou, China.
Induction of Acute Inflammation in Rat Hind Paws by
Carrageenan The assay was conducted as previously de-
scribed by Winter.
19)
Oral administration was conducted with
three different doses of JCICM-6, or the reference drug or
the vehicle (control, the same below), at 1 h prior to the in-
duction of inflammation. At the induction, each rat was in-
jected with 0.1 ml freshly prepared carrageenan (1% w/v) in
physiological saline (0.9% w/v NaCl) into subplantar tissues
of the right hind paw. The left hind paws without injection
were used as controls. The volumes (ml) of both hind paws
of each animal were measured using a plethysmometer
(plethysmometer 7150, UGO Basile, Italy) at 1 h before the
induction and 1, 2, 3, 4, 6 and 8 h after the induction. The in-
creased rates in paw volume (paw edema) of the right hind
paws of rats were calculated by the following equation: the
increased rate (%)(BA)/A100, where A and B repre-
sent the paw volumes before and at different time points after
the induction, respectively. Indomethacin (10 mg/kg) admin-
istered orally was used as a reference drug.
Induction of Acute Inflammation in Rat Hind Paws by
Histamine, Serotonin, Prostaglandin E
2
(PGE
2
) and
Bradykinin The acute inflammation in the hind paws of
254 Vol. 29, No. 2
rats was induced by subcutaneous injection of 0.05 ml
1% freshly prepared solutions of histamine, serotonin,
bradykinin or PGE
2
(20
m
g in 0.05 ml) into right hind paws
of rats. The left hind paws were used as controls. Administra-
tion of JCICM-6 (0.438, 0.875, 1.75 g/kg), or of the refer-
ence drug, or of the vehicle, was conducted at 1 h prior to the
induction. The volumes of the injected and control paws
were measured at different time points designed from 0.5 to
6h after injection of the phlogistic agents. Indomethacin ad-
ministered orally (10 mg/kg) was used as the reference drug.
The increased rates in paw volume were calculated in the
same way as in carrageenan.
Induction of Acute Inflammation in Mouse Ears by AA
and TPA Each mouse received 2.5
m
g of TPA dissolved in
20
m
l of 70% EtOH or 2% arachidonic acid dissolved in ace-
tone. This was applied by an autopipette in 20
m
l of arachi-
donic acid solution or TPA solution to both anterior and pos-
terior surfaces of the right ear. The left ear, used as control,
received the same volume of 70% EtOH or acetone. JCICM-
6 (0.438, 0.875, 1.75 g/kg), or indomethacin (10 mg/kg), or
vehicle, was orally administrated 1 h prior to the application
of arachidonic acid solution. Ear thickness was measured be-
fore and after the induction from 0.5 to 8 h at different time
points using a caliper. The rate of increase in mouse ear
thickness was calculated by the following equation: rate of
increase (%)(BA)/A100; where A and B represent the
ear thickness before and at different time points after the in-
duction, respectively. The mean values of the treated animals
were compared with the mean values of the control animals,
using statistical methods.
Central Nociceptive Model Induced by Radiant Heat
Stimulation in Rats The antinociceptive effects of
JCICM-6 and the reference drug, expressed as the time re-
quired for rat tail flick after exposure to a source of radiant
heat, were evaluated according to the description of
D’Amour.
20)
Briefly, animals were placed in a plexiglas box
that allowed their tails to be free, and then the box was
placed on IITC model 336 tail flick analgesia meter (IITC
Inc., U.S.A.) with the tail occluding a slit over a photocell for
radiant heat stimulation generated by a power lamp mounted
in a reflector. The tail-flick response was elicited by applying
radiant heat to the point 1/3 of length away from the tip of
the tail. The apparatus was arranged so that when the opera-
tor turned on the lamp a timer was activated. When the rat
felt pain and flicked its tail, light fell on the photocell such
that the timer was automatically stopped. The intensity of the
heat stimulus in the tail-flick test was adjusted so that the an-
imal flicked its tail within 3 to 5 s. A 20-s cut-off time was
set in order to prevent tail tissues from damage. Before the
experiments, the heat stimulation latency of all animals was
tested, those with response time to heat stimulation 2s or
6s were excluded. The tail-flick response was measured at
1, 2 and 3 h after oral administration of JCICM-6 (0.101,
0.404, 1.62 g/kg), or rotundine (100 mg/kg) as reference
drug, or vehicle.
Visceral Nociceptive Model Induced by Acetic Acid
Stimulation in Mice The abdominal writhing test induced
by chemical stimulation of acetic acid was performed in mice
as originally described by Siegmund.
21)
Briefly, JCICM-6
(0.101, 0.404, 1.62 g/kg), rotundine (100 mg/kg), or vehicle
was orally administrated 2 h before acetic acid injection.
After intraperitoneal injection of 0.2 ml acetic acid (0.8%
w/v) in physiological saline (0.9% w/v NaCl), animals were
isolated for observation. The numbers of abdominal writhing
syndrome/events, which consisted of the contraction of the
abdominal area with extension of hind legs, were recorded
during a 15 min period in each animal.
Statistical Analysis Values were expressed as the
meansstandard error of the means (S.E.M.). The statistical
significance of the differences were assessed by ANOVA fol-
lowed by post hoc test with LSD method. p values less than
0.05 were considered statistically significant.
RESULTS
HPLC Fingerprint of JCICM-6 Figure 1 shows the
HPLC fingerprints from three batches of JCICM-6. The cor-
relation coefficient was 0.98940.0056, indicating the con-
sistence of quality among the three batches of JCICM-6.
Inhibition of Paw Edema of Rats by Treatment of
JCICM-6 Figure 2 shows that JCICM-6 significantly in-
hibited acute paw edema evoked by carrageenan injection.
The maximum phlogistic response of carrageenan was ob-
served at 4 h after the injection in the vehicle-treated animals.
Data from the JCICM-6-treated animals with the doses of
0.875 g or 1.75 g/kg at 1, 2, 3, 4, 6 and 8 h showed significant
differences in the paw edema in comparison with the data of
the vehicle-treated animals at the same time points, while the
JCICM-6-treated animals with doses of 0.438 g/kg only
showed significant differences in the paw edema at 1, 2, 3
and 4 h (Fig. 2). The reference drug, indomethacin, showed
significant differences within 8 h at the dosages of 10 mg/kg.
The left hind paws of rats which were used as controls
showed no increase of paw volume for the entire experiment,
indicating that the right hind paw edema was induced by car-
rageenan (data not shown). These results imply that the anti-
acute inflammatory effect of JCICM-6 in rats is dose-de-
pendent, and suggest that the effect can remain at least 9 h
after oral administration.
In the case of histamine, serotonin, PGE
2
and bradykinin-
induced rat paw edema, all measurements were conducted at
0.5, 1, 2, 3, 4 and 6 h after the injection of the above phlogis-
February 2006 255
Fig. 1. HPLC Fingerprints of Three Batches (from Bottom to Top:
20040821, 20040825, 20040901) of JCICM-6
Peaks 1—10, in which peaks 3, 6, 8, and 10 were identified as sinomenine, paeoni-
florin, paeonol, and curcumin, respectively, are the characteristic and representative
chemical components detected from the preparation of JCICM-6.
tic agents. Significant edema was observed in all injected
paws at 0.5 h after injection. Figures 3, 4, 5 and 6 show that
JCICM-6 could dose-dependently inhibit the acute inflamma-
tory responses evoked by histamine, serotonin, PGE
2
, or
bradykinin over all time periods. However, the figures also
show that the anti-inflammatory effect of JCICM-6, while
dose-dependent, also varies according to phlogistic agents. In
rat paw edema induced by histamine and bradykinin, all three
doses (0.438, 0.875, 1.75 g/kg) of JCICM-6 significantly in-
hibited edema (Figs. 3, 6); while in the paw edema induced
by serotonin and PGE
2
, only higher doses (0.875, 1.75 g/kg)
significantly reduced edema (Figs. 4, 5). Indomethacin (10
mg/kg) showed an anti-inflammatory effect in all animal
models, although to a lesser extent than that of JCICM-6
using the relative higher doses (Figs. 3—6). Contralateral left
hind paws (no pholgostic agents injected) remained constant
at paw volume (data not shown).
Inhibition of Ear Edema of Mice by Treatment of
JCICM-6 In Fig. 7, it can be seen that the application of
256 Vol. 29, No. 2
Fig. 2. Inhibition of Carrageenan-Induced Paw Edema of Rats by Treat-
ment of JCICM-6 at Dosages of 0.438 (), 0.875 () and 1.75 () g/kg,
and by the Reference Drug Indomethacin at Dosage of 10 mg/kg by p.o. ()
Drugs were orally administrated 1 h prior to carrageenan injection. Each point repre-
sents the meanS.E.M. (n10). ∗∗ p0.01, ∗∗∗ p0.001 vs. control animals () at
the corresponding time point.
Fig. 3. Inhibition of Histamine-Induced Paw Edema of Rats by Treatment
of JCICM-6 at Dosages of 0.438 (), 0.875 () and 1.75 () g/kg, and by
the Reference Drug Indomethacin at Dosage of 10 mg/kg by p.o. ()
Drugs were orally administrated 1 h prior to histamine injection. Each point repre-
sents the meanS.E.M. (n10). ∗∗∗ p0.001 vs. control animals () at the correspon-
ding time point.
Fig. 4. Inhibition of Serotonin-Induced Paw Edema of Rats by Treatment
of JCICM-6 at Dosages of 0.438 (), 0.875 () and 1.75 () g/kg, and by
the Reference Drug Indomethacin at Dosage of 10 mg/kg by p.o. ()
Drugs were orally administrated 1 h prior to serotonin injection. Each point repre-
sents the meanS.E.M. (n9—10). p0.05, ∗∗ p0.01, ∗∗∗ p0.001 vs. control an-
imals () at the corresponding time point.
Fig. 5. Inhibition of PGE
2
-Induced Paw Edema of Rats by Treatment of
JCICM-6 at Dosages of 0.438 (), 0.875 () and 1.75 () g/kg, and by the
Reference Drug Indomethacin at Dosage of 10 mg/kg by p.o. ()
Drugs were orally administrated 1 h prior to PGE
2
injection. Each point represents
the meanS.E.M. (n9—10). p0.05, ∗∗ p0.01, ∗∗∗ p0.001 vs. control animals
() at the corresponding time point.
Fig. 6. Inhibition of Bradykinin-Induced Paw Edema of Rats by Treat-
ment of JCICM-6 at Dosages of 0.438 (), 0.875 () and 1.75 () g/kg,
and by the Reference Drug Indomethacin at Dosage of 10 mg/kg by p.o. ()
Drugs were orally administrated 1 h prior to bradykinin injection. Each point repre-
sents the meanS.E.M. (n10). p0.05, ∗∗ p0.01, ∗∗∗ p0.001 vs. control ani-
mals (
) at the corresponding time point.
AA could effectively induce mouse ear edema with a peak at
1h and with rapid decrease from 2 h after the induction of in-
flammation. Oral treatment with JCICM-6 1 h prior to the in-
duction could significantly inhibit ear edema of mice at 0.5
and 1 h after the induction (Fig. 7). Similar result was found
in the animals treated orally with indomethacin. However, at
2 and 3 h after application of AA this anti-inflammatory ef-
fect of JCICM-6 and indomethacin had almost disappeared.
No ear edema was found in the contralateral left ear lobes of
rats tested (data not shown).
Figure 8 shows the inflammatory pattern of TPA in the ear
edema of mice as well as the inhibitory effect of JCICM-6 on
this inflammatory model. It can be seen in Fig. 8 that TPA-
induced ear edema appeared at a relatively later phase of the
experiment in comparison with the inflammatory model
evoked by AA, i.e., the peak of the inflammation induced by
TPA was observed at 4 h after the induction and then the ear
edema lasted until the end of the experiment. The effect of
JCICM-6 was also observed at later phases of the experi-
ment, i.e., at 4, 6 h even 8 h after the induction (Fig. 8). Ear
edema was significantly reduced with administration of in-
domethacin. The left ear lobes which were used as controls
showed no increase of thickness of the ear lobes for the en-
tire experiments (data not shown).
Analgesic Effect of JCICM-6 in Nociceptive Model of
Rats Both the tail flick test evoked by radiant heat simula-
tion in rats and the writhing assay induced by peritoneal in-
jection of acetic acid in mice were employed in the study. In
Fig. 9, it is seen that the tail flick reaction time of the control
animals was around 9 s at 1, 2 and 3 h after orally taking the
vehicle; while JCICM-6 with the higher dose of 1.62 g/kg
had significant anti-nociceptive effect, markedly prolonging
tail flick reaction time. Moreover, the effective peak of
JCICM-6 was seen at 60 min after oral administration and
then gradually decreased (Fig. 9). Rotundine, a positive
analgesic agent, prolonged the reaction time of the animals
and demonstrated significant anti-nociceptive action with
a slightly stronger pharmacological intensity than that of
JCICM-6.
Figure 10 shows the numbers of the abdominal writhing
episodes evoked by intraperitoneal injection of acetic acid in
mice as well as the anti-nociceptive effect of JCICM-6. It can
be seen that treatment with JCICM-6 could dose-dependently
reduce the number of writhing episodes of mice in compari-
son with that of vehicle-treated animals; while the reference
drug rotundine which showed stronger analgesic effect than
JCICM-6 in this nociceptive model.
DISCUSSION
As Chinese herbal medicines have been becoming more
and more popular over the world, pharmacological evidences
to understand the action of these medicines and the underly-
ing mechanisms, hence to support the proper and safe use of
these medicines in clinic are indispensable. Chinese herbs
are commonly prescribed as combined herbal formulae to
achieve sufficient treatment in complex conditions such as
February 2006 257
Fig. 7. Inhibition of Arachidonic Acid-Induced Ear Edema of Mice by
Treatment of JCICM-6 at Dosages of 0.438 (), 0.875 () and 1.75
() g/kg, and by the Reference Drug Indomethacin at Dosage of 10 mg/kg
by p.o. ()
Drugs were orally administered 1 h prior to the topically administration of arachi-
donic acid. Each point represents the meanS.E.M. (n10). ∗∗ p0.01, ∗∗∗ p0.001
vs. control animals (
) at the corresponding time point.
Fig. 8. Inhibition of TPA-Induced Ear Edema of Mice by Treatment of
JCICM-6 at Dosages of 0.438 (), 0.875 () and 1.75 () g/kg, and by the
Reference Drug Indomethacin at Dosage of 10 mg/kg by p.o. ()
Drugs were orally administered 1 h prior to the topically administration of TPA. Each
point represents the meanS.E.M. (n10). p0.05, ∗∗ p0.01, ∗∗∗ p0.001 vs.
control animals (
) at the corresponding time point.
Fig. 9. Analgesic Effect of JCICM-6 at Dosages of 0.101(), 0.404 ()
and 1.62 () g/kg and of the Reference Drug Rotundine at Dosage of 100
mg/kg () on Radiant Heat Stimulation-Induced Tail Flick Reaction of Rats
Drugs were orally administered and the measurements of the tail flick time were con-
ducted at 60, 120 and 180 min after the administration. Each point represents the
meanS.E.M. (n8—10). p0.05, ∗∗ p0.01 vs. control animals () at the corre-
sponding time point.
RA through possible mechanisms known as multiple compo-
nents directing to multiple targets. According the theory of
Chinese medicine, not only can herbs using in proper combi-
nation exert synergistic effects to each other, but also the un-
desirable effects of herbs could be therefore reduced. This
might be what the formula of JCICM-6 did. Traditionally, pa-
tients would cook these herbs by themselves at home. But
this would make a non-standard decocting procedure as well
as unstable extract that might influence the desirable thera-
peutic effects in clinic. Preparing Chinese herbal medicines
with standardized pharmaceutical extraction processes could
probably avoid this problem. In this study, JCICM-6 was pre-
pared with an optimized standard process which mainly fo-
cused on maximizing the contents of known bioactive chemi-
cal compounds or clusters in the extract as well as preserving
the major pharmacological activities of the formula. Because
individual Chinese herb per se already contains multiple
components, let alone the combination of herbs, therefore the
most important issue to be considered prior to the pharmaco-
logical study of an herbal extract coming from a formula is
to keep the extract chemically consistent, and thus to make
the pharmacological results reliable, repeatable, and compa-
rable. In this study, we utilized qualified plant materials from
GAP bases and conducted rigorous in-process control to
achieve this goal. The chemical consistency of JCICM-6 was
proved by the HPLC fingerprint analysis in which the finger-
prints of the three batches of JCICM-6 were almost identical.
The fingerprint analysis also revealed that JCICM-6 contains
the known bioactive compounds of these five Chinese herbs,
including sinomenine, paeoniflorin, paeonol, and curcumin
(Fig. 1). By using this extract with consistent quality, our
study showed that JCICM-6 inhibited experimental inflam-
mation and nociception in 9 animal models.
The pharmacological results of our current studies re-
vealed that JCICM-6 elicited significant anti-inflammatory
activities in carrageenan model. Carrageenan induced paw
edema in rats is one of the most commonly used models of
inflammation and has been accepted as a useful phlogistic
tool for the investigation of new anti-inflammatory agents.
Development of paw edema of rats induced by carrageenan
is commonly correlated with the early exudative stage of in-
flammation, one of the important processes of inflammatory
pathology.
22)
Soon after carrageenan injection, there is sud-
den elevation of paw volume, correlating with the action of
histamine and serotonin on vascular permeability.
23,24)
At ap-
proximately 1 h after induction, inflammation begins to in-
crease and paw edema gradually elevates to a peak during
4—6 h after induction. This second phase could be due to the
liberation and over-production of bradykinin, prostaglandins
and kinins in paw tissue, which accompanies leukocyte mi-
gration.
25)
The inflammatory pattern in the inflamed paws of
rats evoked by carrageenan in our present study is in close
accordance with previous reports
23—25)
; while the dose-de-
pendent inhibition, 1—8 h after the induction of inflamma-
tion, suggests that JCICM-6 may act in both earlier and later
phases of inflammation.
These results further induce us to think that the anti-in-
flammatory activity of JCICM-6 could be related to the im-
pairment of pro-inflammatory mediators in the cyclooxyge-
nase pathway, because most of the NSAIDs take their anti-in-
flammatory effects via inhibition of the production of pro-in-
flammatory mediators including eicosaloids. Thus, different
inflammatory mediator-induced paw edema, i.e. histamine,
serotonin, prostaglandin E
2
and bradykinin, have been stud-
ied in this experiment, so as to elucidate the anti-inflamma-
tory effect of JCICM-6, including the underlying pharmaco-
logical mechanisms. The results here show that JCICM-6 had
marked dose-dependent inhibitory effect with different phar-
macological intensities on various acute inflammatory mod-
els induced by histamine, serotonin, prostaglandin E
2
or
bradykinin in rats, which, moreover, suggests that the under-
lying anti-inflammatory mechanisms of JCICM-6 are possi-
bly linked to the inhibition of either the synthesis, or the re-
lease, or the actions of those pro-inflammatory mediators.
Topical application of AA and TPA offers a skin inflam-
mation model appropriate for evaluating anti-inflammatory
agents. AA-induced ear edema is a good in vivo test useful
for evaluating lipoxygenase inhibitors.
26)
The present study
shows that oral administration of JCICM-6 at doses of 0.438,
0.875 and 1.75 g/kg could significantly inhibit AA-induced
ear inflammation, suggesting this herbal extract might act as
a lipoxygenase inhibitor. In TPA-test, when JCICM-6 at
doses of 0.438, 0.875 and 1.75 g/kg also produced a signifi-
cant reduction in mouse ear edema. The majority of the ac-
tivities of this phorbol ester appears to be involved or to be
dependent on AA release and metabolism. All phospholipase
A
2
, or cyclooxygenase, or lipoxygenase inhibitors as well as
corticoids are effective at suppressing ear edema after topical
application of TPA at high doses.
26)
Moreover, the topical
application of TPA could induce a transient increase in
prostanoid production. Using this model, orally administered
inhibitors of cyclooxygenase and lipoxygenase such as
phenidone and BW755C appeared to be effective at inhibit-
ing ear edema.
27)
Thus, the results of the present study sug-
gest that JCICM-6 may have pharmacological properties
similar to both lipoxygenase and cyclooxygenase inhibitors.
In arthritis, joint inflammation and pain are the most com-
monly co-existing symptoms. An ideal therapy for human
arthritis should at least possess activities of anti-inflamma-
tion and analgesia. Thus, in the current studies, to assess the
analgesic effect of JCICM-6, two nociceptive animal models
were developed. According to previous reports, the tail flick
test of rats evoked by radiant heat stimulation is more sensi-
258 Vol. 29, No. 2
Fig. 10. Analgesic Effect of JCICM-6 at Different Dosages on Acetic
Acid-Induced Writhing Response of Mice
Drugs were orally administered 2 h prior to the peritoneal injection of acetic acid.
Values are the meanS.E.M. (n11—14). p0.05, ∗∗ p0.01, ∗∗∗ p0.001 vs. con-
trol animals.
tive in centrally acting analgesics whereas acetic acid-in-
duced abdominal writhing assay in mice is commonly used
for detecting both central and peripheral analgesia.
28,29)
With
the former test model, it was found that JCICM-6 had a sig-
nificant ability to prolong the response latencies to the radi-
ant stimulation, indicating significant increase of the noci-
ceptive threshold in treated animals in comparison with that
of non-treated animals. There are also previous reports indi-
cating that the effectiveness of analgesic agents in tail flick
pain model of rats was highly correlated with pain relief in
human.
30)
In Chinese and Japanese medical practice, Sinome-
nium acutum and Aconitum carmichaeli DEBX. are usually
prescribed for relieving joint and muscular pain of arthritis;
both of these herbs are ingredients of JCICM-6. Thus, the
anti-nociceptive effect of JCICM-6 in tail flick rat model is in
good agreement with the clinical experience and therapy. In
the writhing response model, acetic acid is injected into the
peritoneal cavity of mice to cause nociception in abdomen
due to the release of various substances that excite pain nerve
endings.
31)
JCICM-6 showed an ability of diminishing the
numbers of the writhing episodes in a dose-dependent man-
ner, indicating significant inhibition of the acetic acid-in-
duced visceral nociception. The results with these two noci-
ceptive animal models suggest that JCICM-6 might act as
central and peripheral analgesic agent like rotundine (dl-
tetrahydropalmatine). Rotundine possesses analgesic, seda-
tive, hypnotic and antihypertensive effects. It is the active
compound isolated from medical plant Corydalis yanhusuo
and has been widely used in China as an analgesic drug in
human.
32—34)
While the mechanism of the analgesic effect of
JCICM-6 is not readily apparent in these two models, it can,
nevertheless, be speculated that this effect may be linked to
processes in the prevention of sensitization of the nociceptor,
down-regulation of the sensitized nociceptor and/or blockade
of the nociceptor at peripheral and/or central levels.
35)
An-
other possible mechanism may be that JCICM-6 could in-
hibit cyclooxygenase pathway in peripheral tissues (which
has been shown in the study of anti-inflammatory activity),
thus, interfering with the mechanism of transduction in pri-
mary afferent nociceptors.
36)
Or JCICM-6 could be involved
in AA metabolic pathway which inhibits production of
prostaglandins and thromboxanes similar to acetylsalicyclic
acid.
37)
Moreover, JCICM-6 may block the effect or the re-
lease of endogenous substances, including PGE
2
that excites
pain nerve endings and is found in writhing response test
model of mice.
38)
Taken together, JCICM-6 could act in earlier and later
phases of inflammation. The underlying mechanisms may be
that JCICM-6 could inhibit the synthesis, release, or actions
of pro-inflammatory mediators; meanwhile, JCICM-6 could
also act as a lipoxygenase or cyclooxygenase inhibitors.
Therefore, our up-coming studies will focus on the synthesis,
formation and production of some important pro-inflam-
matory mediators such as cytokines, nitric oxide (NO),
prostaglandins, cyclooxygenase 2 (COX-2) as well as neu-
trophil infiltration in the sites of inflammation impaired by
treatment of the herbal extract. Particularly, the impairment
of JCICM-6 on tumor necrosis factor-
a
(TNF-
a
) will be
stressed, since TNF-
a
has an early and crucial role in the
cascade of pro-inflammatory cytokine production.
39)
TNF-
a
induces the production of interleukin-1
b
(IL-1
b
) and IL-6,
thus resulting in the production of cyclooxygenase products;
and it induces another cytokine, IL-8, stimulating the local
production of sympathetic amines.
40,41)
In contrast to the pro-
inflammatory cytokines, some ‘antagonist cytokines’ such as
IL-10 have been reported to have an inhibitory effect on the
production of pro-inflammatory cytokines produced by
murine Th1 lymphocytes.
42,43)
In conclusion, the anti-inflammatory and anti-nociceptive
effects of JCICM-6, the extract from an anti-arthritic herbal
formula, have been effectively evaluated using nine experi-
mental animal models in rodents. The results demonstrated
that JCICM-6 possesses significant properties of anti-inflam-
mation and analgesia like reference drugs of indomethacin
and rotundine, respectively, indicating JCICM-6 would be a
potential candidate for further investigation as a novel anti-
arthritic botanical drug.
Acknowledgements The research is funded by the Hong
Kong Jockey Club Charities Trust. The authors wish to thank
Dr. Martha A. Dahlen for her kind editing of English writing
of this paper.
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260 Vol. 29, No. 2
    • "Previous studies demonstrated that the nociceptive behaviors in acute and inflammatory pain models, including hot plate test and carrageenan model, decreased in animals treated with processed Aconitum plant. [6, 22] In the current study, i.t. PA produced not only acute, but also chronic anti-allodynic effects following daily i.t. "
    [Show abstract] [Hide abstract] ABSTRACT: Background For their analgesic and anti-arthritic effects, Aconitum species have been used in folk medicine in some East Asian countries. Although their analgesic effect is attributed to its action on voltage-dependent sodium channels, they also suppress purinergic receptor expression in dorsal root ganglion neurons in rats with neuropathic pain. In vitro study also demonstrated that the Aconitum suppresses ATP-induced P2X7 receptor (P2X7R)-mediated inflammatory responses in microglial cell lines. Herein, we examined the effect of intrathecal administration of thermally processed Aconitum jaluense (PA) on pain behavior, P2X7R expression and microglial activation in a rat spinal nerve ligation (SNL) model. Methods Mechanical allodynia induced by L5 SNL in Sprague-Dawley rats was measured using the von Frey test to evaluate the effect of intrathecal injection of PA. Changes in the expression of P2X7R in the spinal cord were examined using RT-PCR and Western blot analysis. In addition, the effect of intrathecal PA on microglial activation was evaluated by immunofluorescence. Results Intrathecal PA attenuated mechanical allodynia in a dose-dependent manner showing both acute and chronic effects with 65 % of the maximal possible effect. The expression and production of spinal P2X7R was increased five days after SNL, but daily intrathecal PA injection significantly inhibited the increase to the level of naïve animals. Immunofluorescence of the spinal cord revealed a significant increase in P2X7R expression and activation of microglia in the dorsal horn, which was inhibited by intrathecal PA treatment. P2X7R co-localized with microglia marker, but not neurons. Conclusions Intrathecal PA exerts anti-allodynic effects in neuropathic pain, possibly by suppressing P2X7R production and expression as well as reducing microglial activation in the spinal cord.
    Full-text · Article · Dec 2016
    • "However, in the research and development of pharmaceutical natural products, especially for the preparations derived from complex herbal prescriptions, the most serious obstacle is to establish optimum quality control [3] standard by determining representative active components contained in the preparation. The previous studies showed that GJK preparation has significant suppressive effects on arthritic [4] and acute inflammatory animal models [5] . These 6 herbs in the GJK preparation contain the following major active chemical constituents: astragaloside IV (S1) and calycosin-7-O--d-glucopyranoside (S2) in Astragali Radix, mesaconitine (S3), hypaconitine (S4), aconitine (S5), benzoylmesaconitine (S6), benzoylaconitine (S7) and benzoylhypaconitine (S8) in Aconiti Lateralis Radix Praeparata, liquiritin (S9) and ammonium glycyrrhizinate (S10) in Glycyrrhizae Radix et Rhizoma, tetrahydropalmatine (S11) in Corydalis Rhizoma , paeoniflorin (S12) in Paeoniae Radix Alba and sinomenine (S13) in Sinomenii Caulis [1], respectively. "
    [Show abstract] [Hide abstract] ABSTRACT: An ultra high performance liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-QQQ-MS/MS) method has been developed to evaluate the quality of a pharmaceutical herbal preparation, Guanjiekang (GJK), through a simultaneous determination of 13 major active compounds with a huge difference in level of content. Chromatographic separation was achieved on a Waters Acquilty UPLC C18 column (2.1×100mm, 1.7μm) with a mobile phase consisting of acetonitrile and buffer solution (10mM ammonium acetate containing 0.1% acetic acid) under a gradient elution manner. A triple quadrupole mass spectrometer was operated in positive ionization mode with multiple reaction monitoring for the detection of the 13 compounds. All calibration curves showed excellent linear regressions (R(2)>0.999) within the test range. The precision, repeatability and stability of the 13 compounds were below 5.0% in terms of RSD. The recoveries were 99.2-103.9% with RSD of 0.23-3.30% for GJK samples. The method was successfully used for the analysis of samples of GJK preparation and showed that the lowest level was in aconitine (0.582±0.143ng/g) and the highest was in paeoniflorin (16.80±0.886mg/g), with a 41800 folds of difference. In conclusion, a rapid, sensitive, precise, accurate, and reliable UHPLC-QQQ-MS/MS method has been developed for the simultaneous detection of 13 active compounds with massive difference in level of content in the pharmaceutical samples of GJK preparation, which can be applied for the quality control of GJK product.
    Full-text · Article · Nov 2015
    • "P. suffruticosa Andr contains five compounds including paeonol, paeoniflorin, paeonoside, paeonollide and apiopaeonoside; among them, paeonol is the main bioactive component [32]. It had potent anti-inflammatory and analgesic effects in a rat model of carrageenan-evoked thermal hyperalgesia [32]. "
    [Show abstract] [Hide abstract] ABSTRACT: Large-scale pharmaco-epidemiological studies of Chinese herbal medicine (CHM) for treatment of urticaria are few, even though clinical trials showed some CHM are effective. The purpose of this study was to explore the frequencies and patterns of CHM prescriptions for urticaria by analysing the population-based CHM database in Taiwan. This study was linked to and processed through the complete traditional CHM database of the National Health Insurance Research Database in Taiwan during 2009. We calculated the frequencies and patterns of CHM prescriptions used for treatment of urticaria, of which the diagnosis was defined as the single ICD-9 Code of 708. Frequent itemset mining, as applied to data mining, was used to analyse co-prescription of CHM for patients with urticaria. There were 37,386 subjects who visited traditional Chinese Medicine clinics for urticaria in Taiwan during 2009 and received a total of 95,765 CHM prescriptions. Subjects between 18 and 35 years of age comprised the largest number of those treated (32.76%). In addition, women used CHM for urticaria more frequently than men (female:male = 1.94:1). There was an average of 5.54 items prescribed in the form of either individual Chinese herbs or a formula in a single CHM prescription for urticaria. Bai-Xian-Pi (Dictamnus dasycarpus Turcz) was the most commonly prescribed single Chinese herb while Xiao-Feng San was the most commonly prescribed Chinese herbal formula. The most commonly prescribed CHM drug combination was Xiao-Feng San plus Bai-Xian-Pi while the most commonly prescribed triple drug combination was Xiao-Feng San, Bai-Xian-Pi, and Di-Fu Zi (Kochia scoparia). In view of the popularity of CHM such as Xiao-Feng San prescribed for the wind-heat pattern of urticaria in this study, a large-scale, randomized clinical trial is warranted to research their efficacy and safety.
    Full-text · Article · Aug 2013
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