Review Article
Phytoconstituents responsible for anti-inflammatory activity
Minky Mukhija, Ankush Sundriyal1
ABSTRACT
Inflammation is the response of an organism’s immune system to the damage caused to its cells and
vascularized tissues by microbial pathogens such as viruses and bacteria, as well as by injurious
chemicals or physical insults. Although painful, inflammation is usually a healing response, but in some
instances inflammation proceeds to a chronic state, associated with debilitating diseases such as arthritis,
multiple sclerosis, or even cancer. Although several anti-inflammatory drugs are available, the treatment of
inflammation is still far from adequate. The current therapy of inflammation with modern anti-inflammatory
drugs is associated with side effects and drug interactions. Several plants used for the treatment of
inflammation in different systems of traditional medicine have shown anti-inflammatory activity in experimental
animal models and many such plants claimed in the traditional system still remain to be scientifically
investigated. In this review, we have compiled the newer reported herbal anti-inflammatory constituents
with their research advancements.
Department of
Pharmacognosy, ISF
College of Pharmacy, Moga,
Punjab, and 1Department of
Pharmacognosy, S. Bhagwan
Singh Post Graduate Institute
of Biomedical Sciences
and Research, Dehradun,
Uttrakhand, India
Key words: Carrageenan and cotton pellet, inflammation, phytoconstituents
INTRODUCTION
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Website: www.jnatpharm.org
DOI: 10.4103/2229-5119.110340
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Address for
correspondence:
Asst. Prof. Ankush
Sundriyal,
S. Bhagwan Singh
Post Graduate Institute
of Biomedical Sciences
and Research, Balawala,
Dehradun, Uttrakhand,
India.
E-mail:
ankushsundriyal@gmail.
com
Inflammation is body’s response to disturbed
homeostasis caused by infection, injury,
or trauma, resulting in systemic and local
effects. The Roman writer Celsus in 1st
century AD named the famous four cardinal
signs of inflammation as Rubor (redness),
Tumor (swelling/edema), Calor (heat), and
Dolor (pain).[1]
The main symptoms of the body against
an inflammatory stimulation are increased
body temperature and pain. Inflammation
constitutes the body’s response to injury and is
characterized by a series of events that includes
the inflammatory reaction, a sensory response
perceived as pain, and a repair process. Some
causes of an inflammatory reaction are
infection (invasion and multiplication within
tissues by various bacteria, fungi, viruses,
and protozoa, which in many instances cause
damage by release of toxins that directly
destroy host cells), trauma (penetrating
injury, blunt trauma, thermal injury, chemical
injury, and immunologically mediated injury
humoral or cellular)], and loss of blood supply
(ischemia).[2]
Journal of Natural Pharmaceuticals, Volume 4, Issue 1, January-June, 2013
New drugs that inhibit selectively
cyclooxygenase-2 (COX-2) exhibit a better
gastric tolerance profile, although their
introduction into clinical practice has been
associated with severe cardiovascular adverse
events that led to the recommendation for
careful utilization in patients with previous
vascular diseases.[3,4] The side effects of the
currently available anti-inflammatory drugs
pose a major problem during their clinical
usage.[5]
So, the development of newer and more
potent anti-inflammatory drugs with lesser
side effects is necessary. Plants may serve as
the alternative sources for the development
of new anti-inflammatory agents due
to their biological activities. Several
phytoconstituents from plants have shown
anti-inflammatory activity when tested on
animal models. In this review, a number
of constituents from plants like alkaloids,
flavonoids, lignans, tannins, coumarins,
saponins, triterpenoids, steroids, etc. having
anti-inflammatory potential are reviewed.
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Mukhija and Sundriyal: Anti-inflammatory phytoconstituents
SOME PHYTOCONSTITUENTS WITH
ANTI-INFLAMMATORY POTENTIAL
Alkaloids
1. Tetrandrine [Figure 1a]: An isoquinoline alkaloid
isolated from the roots of Sephania tetrandra showed
anti-inflammatory activity by suppressing the chronic
inflammation in the arthritis model, but was not active in
the acute inflammation assay. Given orally, tetrandrine
was considerably more potent than aspirin but was not
a gastro-irritant and may be a promising lead for the
development of a safe and effective treatment of chronic
inflammatory diseases.[6]
mg/kg; i.p.). However, LPS-induced production of other
ILs, such as IL-α, has not been significantly altered by
gentianine. These results suggest that the potential antiinflammatory action of gentianine might be at least partly
based on the suppressed production of TNF-α and IL-6.[7]
3. Isoquinoline alkaloids (berberine, berbamine, palmatine,
oxyacanthine, magnoflorine, and columbamine)
[Figure 1c-h]: These are isoquinoline alkaloids isolated
as the main components of alkaloidal fraction from the
roots of Turkish Berberis species and their effects were
studied using various in vivo models in mice. All alkaloids
inhibited inflammations to varying degrees; among them,
berberine, berbamine, and palmatine were shown to
possess significant and dose-dependent inhibitory activity
against serotonin-induced hind paw edema both on oral
and topical applications and acetic acid-induced increase
in vascular permeability on oral administration.[8]
2. Gentianine [Figure 1b]: It is an alkaloid isolated
from Gentiana macrophylla. For the first time, it has
been found that oral administration of gentianine
(10–100 mg/kg) suppressed the increases in tumor necrosis
factor- (TNF-α) (ED50, 37.7 mg/kg) and interleukin
(IL)-6 (ED50, 38.5 mg/kg) in the sera from the rats
challenged with bacterial lipopolysaccharide (LPS; 100
4. (−)-Spectaline [Figure 1i]: It is a piperidine alkaloid
isolated from Cassia spectabilis. In the carrageenaninduced rat paw edema, (−)-spectaline exhibited an
a
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b
e
f
d
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h
k
i
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Figure 1: Structures of alkaloids with an -inflammatory ac vi es
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Mukhija and Sundriyal: Anti-inflammatory phytoconstituents
anti-inflammatory profile, showing an ED50 value of
56.6 mmol/kg.[9]
5. Crotalaburnine: It is a pyrrolizidine alkaloid isolated
from the seeds of Crotalaria laburnifolia Linn. It has
been found to be effective against acute edema induced
by a number of substances, such as carrageenan and
hyaluronidase, and in the cotton pellet granuloma test,
crotalaburnine was as effective as hydrocortisone.[10]
6. (5′-Hydroxymethyl-1′-(1,2,3,9-tetrahydro-pyrrolo
(2,1-b) quinazolin-1-yl)-heptan-1-one) [Figure 1j]: It is
a new alkaloid isolated from Sida cordifolia Linn. The
compound exhibited significant (P < 0.01) inhibition of
rat paw edema induced by carrageenan. The results
indicated that alkaloid possessed anti-inflammatory
activity.[11]
7. 21β-carboline alkaloids [Figure 1k and l]: Dichotomides
III−IX (1−7) [Figure 1k] and dichotomine (8) [Figure 1l]
have been isolated from the roots of Stellaria dichotoma
var. lanceolata. These isolated alkaloids have been
examined for their anti-inflammatory potential for
the inhibition of nitric oxide (NO) production in LPStreated RAW264.7 cells. All compounds tested exhibited
significant inhibition of NO production, with IC50 values
in the range of 11.3–19.3 μM.[12]
Flavonoids
1. Jaceosidin [Figure 2a]: It is a flavonoid isolated from
several plants of the Compositae family. The compound
has been administered at a unique dose of 75 mg/kg i.p.
in the acute test with carrageenan and 25 mg/kg/day in
the chronic granuloma test. It significantly inhibited the
edema response in the acute test.[13]
2. Artemetin [Figure 2b]: It is 5-hydroxy-3,6,7,3′,4′pentamethoxyflavone isolated from Cordia verbenacea
DC. It showed marked anti-inflammatory activity by
inhibiting carrageenan-induced paw edema. The doses
of 102.6 and 153.9 mg/kg showed an inhibitory effect.[14]
3. Luteolin [Figure 2c]: Oral administration of luteolin (10
and 50 mg/kg) efficiently suppressed paw edema induced
a
b
c
d
e
f
g
Figure 2: Structures of flavonoids with an -inflammatory ac vi es
Journal of Natural Pharmaceuticals, Volume 4, Issue 1, January-June, 2013
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Mukhija and Sundriyal: Anti-inflammatory phytoconstituents
by injecting carrageenan, and a similar tendency was also
observed in the cotton pellet granuloma test. Luteolin
markedly reduced the number of infiltrated leukocytes
and the elevated level of 6-keto-prostaglandin F1 (6-ketoPGF1) in the exudate in the air pouch test. The results
derived from the whole blood assay for cyclooxygenase
(COX) and from the reverse transcription-polymerase
chain reaction (RT-PCR) assay indicate that luteolin
may be a potent selective inhibitor of COX-2 and that
the inhibition is attributable to its down-regulation of the
mRNA expression of COX-2 in inflammatory responses.[15]
4. Hyperin [Figure 2d]: It has been isolated from the ethyl
acetate fraction of the roots of Acanthopanax chiisanensis.
It suppressed not only prostaglandin E2 (PGE2) production
in rat peritoneal macrophages stimulated by the protein
kinase C activator, 12-O-tetradecanoylphorbol 13-acetate
(TPA), but also NO production in vitro in a concentrationdependent manner, their IC50 being 24.3 and 32.9 μM,
respectively. Hyperin also caused a significant inhibition
of increase in acetic acid-induced vascular permeability
in mice in vivo.[16]
5. Naringin [Figure 2e]: A bitter compound in citrus
has been evaluated for its anti-inflammatory activity
in an acute model of induced colitis in mice. Colitis was
induced by feeding mice 7% dextran sodium sulfate (DSS)
dissolved in drinking water for 5 days. Treatment with
naringin significantly reduced the formation of intestinal
edema, suggesting an anti-inflammatory activity in this
model of colitis in mice.[17]
6. Ternatin [Figure 2f]: It is a tetramethoxy flavone
isolated from Egletes viscosa Less. Ternatin (25 and 50
mg/kg, i.p.) reduced the response to carrageenan at 5 h by
decreasing both exudate volume (33–40%) and leukocyte
number (60%) in 5–6month-old rats (n = 6 per group).
These results show that ternatin has anti-inflammatory
activity.[18]
7. Hesperidin [Figure 2g]: A bioflavonoid obtained from
citrus cultures at dose 50 and 100 mg/kg, s.c. reduced
the paw edema induced by carrageenan in rats by 47 and
63%, respectively. At 100 mg/kg, hesperidin decreased the
rat paw edema induced by dextran by 33%. Hesperidin
also inhibited pleurisy induced by carrageenan, reducing
the volume of exudate and the number of migrating
leukocytes by 48 and 34%, respectively, of control values.
So, hesperdin can be used as a mild anti-inflammatory
agent.[19]
8. 5,7-dimethoxy naringenin or 4′,6′-dimethoxy
chalcononaringenin derivatives: Two flavonoids,
namely, 2′-hydroxy-4′,6′-dimethoxy-chalcone-4-O-β-Dglucopyranoside (1) and 5,7-dimethoxy-flavanone-4′-O4
(β-D-apiofuranosyl-(1-2))-β-Dglucopyranoside (2), have
been isolated from the ethyl acetate fraction of the extract
from Viscum album ssp. album. The ethyl acetate fraction
in a dose of 250 mg/kg as well as compounds 1 and 2 in a
30 mg/kg dose were shown to possess remarkable antiinflammatory activities without inducing any apparent
acute toxicity as well as gastric damage in carrageenaninduced hind paw edema model in mice.[20]
Lignans
1. Arctigenin [Figure 3a]: A lignan was isolated from
ethyl acetate fraction of methanolic extract of Forsythiae
fructus. It has been shown that arctigenin (100 mg/kg)
had significantly decreased not only carrageenan-induced
paw edema 3 and 4 h after injection of carrageenan,
arachidonic acid (AA)-induced ear edema at a dose of 0.1–
1.0 mg/ear, and acetic acid-induced writhing response and
acetic acid-induced capillary permeability accentuation at
an oral dose of 25–100, and 100 mg/kg, respectively, but
also myeloperoxidase (MPO) and eosinophil peroxidase
(EPO) activities at a dose of 0.1–1.0 mg/ear in the AAinduced edematous tissue homogenate as indicators
of neutrophils’ and eosinophils’ recruitment into the
inflamed tissue. The pharmacologic mechanism of action
of arctigenin may be the inhibition of release/production
of inflammatory mediators such as AA metabolites and
free radicals.[21]
2. Cubebin [Figure 3b]: A dibenzylbutyrolactone lignan
isolated from the crude hexane extract of the leaves
of Zanthoxylum naranjillo showed a significant antiinflammatory activity in the paw edema induced by
carrageenan in rats, but did not provide a significant
reduction in the cell migration for the acute carrageenaninduced inflammatory reaction in the peritoneal cavity
of rats. Moreover, it significantly reduced the edema
induced by prostaglandin PGE2 and the number of
writhings induced by both acetic acid and PGI2 in mice.
Therefore, it may be suggested that the mechanism of
action of cubebin is similar to that observed for most of
the non-steroidal drugs.[22]
3. Phylligenin [Figure 3c]: It is a lignin isolated from
the fruits of Forsythia koreana. Phylligenin (1–100 μM)
inhibited COX-2–mediated PGE2 and inducible nitric
oxide synthase (iNOS)-mediated NO synthesis from
LPS-treated RAW264.7 cells. In the study, phylligenin
inhibited iNOS expression and nuclear factor-kappaB
(NF-kappaB) activation, but had no effect on COX2 expression. Moreover, phylligenin significantly
inhibited mouse carrageenan-induced paw edema by
intraperitoneal administration (22.1–34.7% inhibition
at 12.5–100 mg/kg). These pharmacological properties
indicate that phylligenin possesses significant antiinflammatory activity in vitro and in vivo.[23]
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Mukhija and Sundriyal: Anti-inflammatory phytoconstituents
4. (−)-Nyasol [Figure 3d]: It is {cis-hinokiresinol,
4,4-(1Z,3R)-3-ethenyl-1-propene-1,3-diyl) bisphenol}, a
norneolignan, and has been reported to be isolated from
the rhizomes of Anemarrhena asphodeloides. Its antiinflammatory activity has been examined in LPS-treated
RAW264.7 cells and A23187-treated RBL-1 cells. At >1
μM, (−)-nyasol significantly inhibited COX-2–mediated
PGE2 production and winos-mediated NO production in
LPS-treated RAW264.7 cells, a mouse macrophage-like
cell line, but did not affect the expression levels of COX2 and iNOS. (−)-Nyasol also inhibited 5-lipoxygenase
(5-LOX)–mediated leukotriene production in A23187treated RBL-1 cells. Furthermore, (−)-nyasol potently
inhibited carrageenan-induced paw edema in mice (28.6–
77.1% inhibition at 24–120 mg/kg). Therefore, (−)-nyasol
is a potential new lead compound and may contribute to
the anti-inflammatory action of A. asphodeloides, possibly
by inhibiting COX-2, iNOS, and 5-LOX.[24]
5. Anolignan B [Figure 3e]: It has been isolated from
ethyl acetate fraction of roots of Terminalia sericea.
In the anti-inflammatory assays, anolignan B showed
activity against both COX-1 (IC 50 = 1.5 mM) and COX-2
(IC 50 = 7.5 mM) enzymes.[25]
6. Dibenzylbutyrolactone lignans: These are (−)hinokinin
(2) [Figure 3g], (−)-6, 6′-dinitrohinokinin (3) [Figure 3h],
and (−)-6,6′-diaminohinokinin (4) [Figure 3i] obtained
by partial synthesis from (−)-cubebin (1) [Figure 3f].
It was observed that compounds (1) and (2) inhibited
the edema formation in the rat paw edema assay at the
same level and that all responses were dose dependent.
Also, at the dose of 30 mg/kg, compounds 1, 2, 3, and 4
inhibited the edema formation by 53%, 63%, 54%, and
82%, respectively, at the third hour of the experiment.[26]
7. Lariciresinol [Figure 3j], taxiresinol [Figure 3k],
3′-demethylisolariciresinol-9′-hydroxyisopropylether,
isolariciresinol [Figure 3l], and 3-demethylisolariciresinol
[Figure 3m]: Five lignans have been isolated from the
heartwood of Taxus baccata L. (Taxaceae). These lignan
derivatives significantly inhibited carrageenan-induced
hind paw edema in mice.[27]
8. (+)-Eudesmin [Figure 3n], (+)-magnolin [Figure 3o],
(+)-yangambin [Figure 3p], epimagnolin B [Figure 3q]:
Lignans from Magnolia fargesii have been evaluated
as the inhibitors of NO production in LPS-activated
microglia. The most potent compound epimagnolin
B inhibited the production of NO and PGE2 and the
expression of respective enzymes iNOS and COX-2
through the suppression of I-κB-α degradation and
nuclear translocation of p65 subunit of NF-κB.[28]
9. Arylnaphthalide lignans [Figure 3r]: Three lignans,
phyllamyricin C, justicidin B, and diphyllin, have been
isolated from the whole plants of Phyllanthus polyphyllus
L. The in vitro inhibitory effects of these compounds
were evaluated on the production of NO and cytokines
(TNF-α and IL-12), from LPS/IFN -(interferon) activated
murine peritoneal macrophages. The results indicated
that the 50% inhibition concentration (IC 50) values of
NO production from activated peritoneal macrophages by
compounds 1–3 were 25, 12.5, and 50 μM, respectively. In
parallel, these dilutions were approximately inhibited in
a similar manner to that observed for cytokines (TNF-α
and IL-12) production. On the other hand, at 100 μM
concentration, compounds 2 and 3 showed 50% inhibition
of NO production from peritoneal macrophages that had
been pre-activated with LPS/IFN- for 24 h, whereas
compound 1 inhibited only about 10%, respectively. These
results support the use of this plant for the treatment of
inflammatory diseases in oriental traditional medicine.[29]
Tannins
1. Corilagin [Figure 4a]: It is β-1-O-galloyl-3,6-(R)hexahydroxydiphenoyl-D-glucose. Inflammatory cellular
model has been established by LPS interfering on
RAW264.7 cell line. Levels of TNF-α, IL-1β, IL-6, NO,
and IL-10 in supernatant, mRNA expression of TNF-α,
COX-2, iNOS, and HO-1, protein expression of COX-2
and HO-1, and translocation of NF-κB have been assayed
by enzyme-linked immunosorbent assay (ELISA) or
Griess method, real-time quantitative PCR, western
blot, and immunocytochemistry method, respectively. As
a result, corilagin could significantly reduce production
of pro-inflammatory cytokines and mediators TNF-α,
IL-1β, IL-6, NO (iNOS), and COX-2 on both protein and
gene levels by blocking NF-κB nuclear translocation.
Meanwhile, corilagin could notably promote release of
anti-inflammatory factor HO-1 on both protein and gene
levels, but suppresses the release of IL-10. In conclusion,
the anti-inflammatory effects of corilagin are attributed
to the suppression of pro-inflammatory cytokines.[30]
2. Phlorofucofuroeckol A [Figure 4b]: It is a phlorotannin
isolated from Ecklonia stolonifera. Phlorofucofuroeckol
A significantly inhibited the LPS-induced production of
NO and PGE through the down-regulation of NOS and
COX-2 protein expressions. In conclusion, these results
suggest that phlorofucofuroeckol A has a potential for
with anti-inflammatory activities.[31]
3. Gallotannin 1,2,3,6-tetra-O-galloyl-beta-D-allopyranose
(GT24): It has been isolated from Euphorbia jolkini. GT24
dose-dependently decreased LPS-induced NO production
and iNOS expression in J774A.1 macrophages. In
addition, GT24 inhibited LPS-induced activation of NFκB as indicated by inhibition of degradation of I-κBα,
nuclear translocation of NF-κB, and NF-κB–dependent
gene reporter assay.[32]
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Mukhija and Sundriyal: Anti-inflammatory phytoconstituents
a
b
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Figure 3: Structures of lignans with an -inflammatory ac vi es
Coumarins
1. Libanoridin [Figure 5a]: It has been isolated from
Corydalis heterocarpa. Treatment with libanoridin
inhibited the protein expression levels of inflammatory
mediators such as iNOS, COX-2, TNF-α, and interleukin1β (IL-1β) in a dose-dependent manner in LPS-stimulated
HT-29 cells. Also, it has a higher inhibitory effect on
production of cytokines such as IL-1β and TNF-α in
LPS-stimulated HT-29 human colon carcinoma cells.
Furthermore, LPS-induced transcription activity of NFκB was inhibited by libanoridin. So, it can be considered
as a potential anti-inflammatory agent.[33]
2. Glycyrol [Figure 5b]: A benzofuran coumarin isolated
from Glycyrrhizae radix. Glycyrol at 5, 25, and 50 μM
dose-dependently inhibited NO production by downregulating iNOS and alleviated COX-2 expression in LPS6
stimulated RAW264.7 macrophages, in both the mRNA
and the protein. Furthermore, glycyrol dose-dependently
decreased the mRNA of the pro-inflammatory cytokines
IL-1β and IL-6. LPS-induced NF-κB activation was
prevented in RAW264.7 macrophages by inhibition of
I-κBα phosphorylation. In addition, administration of
glycyrol (30 and 100 mg/kg, i.p.) reduced the thickness of
carrageenan-induced mouse-paw edema swelling. Results
indicate that the anti-inflammatory activity of glycyrol
is attributed to the inhibition I-κBα phosphorylation.[34]
Steroids
1. Polyhydroxylated steroids [Figures 6a, 6b]: These
are the steroids isolated from a formosan soft coral
Sinularia sp. Furthermore, at a concentration of
10 mM, both compounds 1(24S-24-Methylcholest-5-ene1α,3β-diol) and 2 (24-Methylenecholest-5-ene-1α,3β-diol)
Journal of Natural Pharmaceuticals, Volume 4, Issue 1, January-June, 2013
Mukhija and Sundriyal: Anti-inflammatory phytoconstituents
demonstrated an ability to inhibit the accumulation of
two pro-inflammatory proteins, iNOS and COX-2, in LPSstimulated RAW264.7 macrophage cells.[35]
2. Stigmasterol [Figure 6c] and stigmasterol 3β-glucoside:
Two steroids isolated from the Hertia cheirifolia (L.) have
been evaluated for their anti-inflammatory activity using
carrageenan-induced paw edema in rats. Screening of
steroids showed anti-inflammatory positive results.[36]
3. Stigmastane steroids: (24R)-5α-stigmast-3,6-dione,
5α-stigmast-23-ene-3,6-dione, and 3β-hydroxy-5αstigmast-24-ene have been isolated from the hexane
extract of Alchornea floribunda leaves. All the compounds
at 50 and 100 μg/ear doses significantly (P < 0.05)
inhibited xylene-induced ear edema in mice. At 20 mg/kg
(i.p.), all the compounds significantly (P < 0.05) inhibited
acute inflammation induced by subplantar injection of
egg albumen in rats. All the compounds also showed (50
μg/ml) significant (P < 0.05) inhibition of heat-induced
hemolysis of human erythrocytes in vitro, but had no
effect on hypotonicity-induced hemolysis. The results
of this study show that these compounds may, in part,
account for the anti-inflammatory effect of A. floribunda
leaves.[37]
4. Griffinisterones [Figure 6d]: Three new steroids have
been isolated from the Octocoral dendronephthya griffini.
At 10 μM, all compounds were found to significantly
inhibit the accumulation of the pro-inflammatory iNOS
protein of the LPS-stimulated RAW264.7 macrophage
cells. At the same concentrations, one of the steroids
could significantly inhibit the accumulation of the proinflammatory COX-2 protein.[38]
a
b
Figure 4: Structures of tannins with an -inflammatory ac vi es
a
b
Figure 5: Structures of coumarins with an -inflammatory ac vi es
5. 3β-Acetoxy-17β-hydroxy-androst-5-ene: It has been
isolated from aerial parts of Acacia nilotica (L.). The
model used for the investigation of its anti-inflammatory
activity was TPA-induced mouse ear edema. The steroid
showed dose-dependent anti-inflammatory activity.[39]
Triterpenoids
1. Dihydrocucurbitacin B (DHCB) [Figure 7a]: This is a
cucurbitacin-derived compound isolated from the roots
of Wilbrandia ebracteata. Intraperitoneal treatment of
mice with DHCB reduced both carrageenan-induced
paw edema (0.3, 1, and 3 mg/kg caused inhibitions of
26, 44, and 56%, respectively, at 2 h after stimulation)
and pleurisy (10 mg/kg inhibited leukocyte numbers and
leukotriene B4 (LTB4) levels in the pleural fluid by 51 and
75%, respectively, at 6 h after cavity challenge). DHCB
(up to 10 μg/ml) failed to modify LTB4 production by
human neutrophils or PGE2 production by COS-7 cells
transfected with COX-1, but PGE2 production by COX2 transfected COS-7 cells was markedly inhibited (by
72%). The levels of COX-1 or COX-2 proteins in IL-1α–
stimulated NIH3T3 cells has been unaffected by DHCB.
a
b
c
d
Figure 6: Structures of steroids with an -inflammatory ac vi es
This shows the anti-inflammatory activity of DHCB.[40]
2. β-amyrin acetate [Figure 7b]: It is a triterpenoid
compound obtained from the stems and leaves of Acer
Journal of Natural Pharmaceuticals, Volume 4, Issue 1, January-June, 2013
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Mukhija and Sundriyal: Anti-inflammatory phytoconstituents
mandshuricum. It has been evaluated for its antiinflammatory activity in vitro for the inhibitory activity of
TNF-α secretion in the LPS-stimulated murine RAW264.7
macrophage cell line. It showed anti-inflammatory activity
with the inhibition rate up to 38.40% at a concentration
of 100 nM.[41]
3. Oleanolic acid [Figure 7c]: This is a widespread
3-hydroxy-17-carboxy oleanane-type compound, a
bioactive triterpenoid. Different tests were carried out
on oleanolic acid, which was obtained from Pistacia
terebinthus galls. It showed activity on ear edema induced
by 12-deoxyphorbol-13-phenylacetate (DPP), dermatitis
induced by multiple applications of TPA, and paw edema
induced by bradykinin and phospholipase A2. It was
more active on the dermatitis by TPA and on the in vitro
leukotriene formation.[42]
4. β-D-glucopyranosyl 2α,3β,6β-trihydroxy-23-galloylolean12-en-28-oate: A new oleanane-type triterpene saponin
together with four known oleanane-type pentacyclic
triterpenoids, combregenin, arjungenin [Figure 7d],
arjunglucoside I [Figure 7e], and combreglucoside has
been isolated from the stem bark of Combretum molle. All
these compounds were investigated for anti-inflammatory
activity against carrageenan-induced paw edema in rat.[43]
carrageenan-induced paw edema swelling test and the
acetic acid-induced vascular permeability assay, and
has shown concentration-related inhibitory activities.[44]
Saponins
1. Mannioside A [Figure 8a]: This was a new steroidal
saponin obtained from the stem bark of Dracaena mannii.
It significantly inhibited paw edema in the rat, induced
by carrageenan.[45]
2. Furostanol saponins: 5β-furost-Δ25(27)-en1β,2β,3β,4β,5β,7α,22ξ,26-octaol-6-one-26-O-β- D glucopyranoside (1) [Figure 8b] and 5β-furost-Δ25(27)en-1β,2β,3β,4β,5β,6β,7α,22ξ,26-nonaol-26-O-β- D glucopyranoside (2) [Figure 8c] have been obtained
from the rhizomes of Tupistra chinensis bark. Both
compounds displayed marked inhibitory action against
NO production in rat abdomen macrophages induced by
LPS at 40 μg/ml.[46]
3. Saponins [Figure 8d]: Six new saponins were isolated
from n-BuOH and EtOAc fractions of the Polygala
japonica methanol extract. Further, all compounds (1–6)
were evaluated for their anti-inflammatory activity in the
carrageenan-induced mouse paw edema test, and saponins
1, 4, and 5 showed significantly anti-inflammatory effects
on both phases of carrageenan-induced acute paw edema
in mice. Saponin 5 was also found to significantly inhibit
the production of inflammatory mediator NO in LPSstimulated RAW264.7 macrophages, with no effects on
macrophage viability.[47]
5. Hispidol A 25-methyl ether [Figure 7f]: A triterpenoid
isolated from Ponciri immaturus fructus has been studied
for its anti-inflammatory property in vitro and in vivo.
The study was done in LPS-stimulated RAW264.7 murine
macrophages. Hispidol A 25-Me ether dose-dependently
inhibits NO production by down-regulating iNOS. It
also reduces PGE2 production by inhibiting COX-2
expression proven on both mRNA as well as on protein.
Furthermore, administration of hispidol A 25-Me ether
(1 and 10 mg/kg, i.p., v/w) has been tested in two animal
experiments involving acute inflammation, namely, the
1. Globulusin A and eucaglobulin [Figure 9a-b]: The
two monoterpene glycosides concentration-dependently
suppressed inflammatory cytokine production, TNF-α
and IL-1β in cultured human myeloma THP-1 cells
co-stimulated with phorbol myristate acetate. These
a
a
e
b
c
d
Glycosides
b
c
f
d
Figure 7: Structures of triterpenoids with an -inflammatory ac vi es
8
Figure 8: Structures of saponins with an -inflammatory ac vi es
Journal of Natural Pharmaceuticals, Volume 4, Issue 1, January-June, 2013
Mukhija and Sundriyal: Anti-inflammatory phytoconstituents
accumulation of NO, and level of reactive oxygen species
(ROS). The results showed that both methyl salicylate
glycosides inhibited the production of TNF-α, IL-1β, and
IL-6 dose-dependently. Both the compounds significantly
suppressed the accumulation of NO, with inhibitory
rates of 56.20% and 51.72%, respectively, at 3.0 μg/
ml concentration. Furthermore, both methyl salicylate
glycosides reduced the level of ROS induced by LPS. These
results showed that the isolated compounds possess antiinflammatory properties through inhibition of production
of pro-inflammatory cytokines, NO and ROS.[51]
compounds also inhibited melanogenesis in cultured
murine melanoma B16F1 cells, without any significant
cytotoxicity.[48]
2. Triterpene glycosides: Seven new triterpene glycosides,
bryoniosides A–G (1–7), along with two known
triterpene glycosides, cabenoside D and bryoamaride
[Figure 9c-d], have been isolated from the methanol
extract of the roots of Bryonia dioica. All the compounds
tested showed marked anti-inflammatory effects, with
50% inhibitory doses (ID50) of 0.2–0.6 mg/ear in TPAinduced inflammation (1 μg/ear) in mice ear. In addition,
all of the compounds tested except for compound 5 showed
potent inhibitory effects on Epstein-Barr Virus (EBV-EA)
induction [100% inhibition at 1 × 10 (3) mol ratio/TPA].[49]
Lipids
α-linolenic acid (ALA) [Figure 10a]: It is a polyunsaturated
fatty acid which has been separated from the fruit of
Actinidia polygama. ALA significantly inhibited the
acetic acid-induced vascular permeability in a dosedependent manner (34.2 and 37.7% inhibition at doses
of 5 and 10 mg/kg, respectively). ALA also significantly
reduced rat paw edema induced by a single treatment
of carrageenan. The effects of ALA on LPS-induced
responses in the murine macrophage cell line, RAW264.7,
have been examined to investigate the mechanism of
the anti-inflammatory action of ALA. Exposure of LPSstimulated cells to ALA inhibited the accumulation of
nitrite and PGE2 in the culture medium. Consistent with
these observations, the protein and mRNA expression
levels of iNOS and COX-2 enzymes were markedly
inhibited by ALA in a dose-dependent manner. These
results suggest that the anti-inflammatory activity of
ALA might be due to the suppression of the expressions
of iNOS and COX-2 mRNA.[52]
3. Phenolic glycosides: 4-((2′-O-acetyl-α-l-rhamnosyloxy)
benzyl) isothiocyanate, 4-((3′-O-acetyl-1-l-rhamnosyloxy)
benzyl) isothiocyanate, and S-methyl-N-{4-((α-lrhamnosyloxy)benzyl)}thiocarbamate have been isolated
from the ethyl acetate extract of Moringa oleifera. The antiinflammatory activity of the isolated compounds has been
investigated with the LPS-induced murine macrophage
RAW264.7 cell line. Western blots demonstrated these
compounds reduced LPS-mediated iNOS expression.
In the concentration range of the IC (50) values, no
significant cytotoxicity has been noted.[50]
4. Methyl salicylate glycosides: Methyl benzoate-2-Oβ- D -xylopyranosyl(1-6)-O-β- D -gluco-pyranoside and
methyl benzoate-2-O-β- D -xylopyranosyl (1-2)(O-β- D xylopyranosyl(1-6))-O-β-D-glucopyranoside have been
isolated from Gaultheria yunnanensis. Investigation of
anti-inflammatory activity of both compounds has been
done on LPS-induced RAW264.7 macrophage cells by
measuring the production of pro-inflammatory cytokines,
a
b
DISCUSSION AND CONCLUSION
With the advent of allopathic system of medicine which
c
d
Figure 9: Structures of glycosides with an -inflammatory ac vi es
a
Figure 10: Structure oflipids with an -inflammatory ac vi es
Journal of Natural Pharmaceuticals, Volume 4, Issue 1, January-June, 2013
9
Mukhija and Sundriyal: Anti-inflammatory phytoconstituents
is based on the fast therapeutic actions of synthetic
drugs as in the case of inflammation, herbal medicine
gradually lost its popularity among people. Almost a
century has passed and limitations of allopathic system
have been witnessed. Herbal medicine has again gained
the momentum and it is evident from the fact that
certain herbal remedies peaked at par with synthetic
drugs as it is shown in this review. The present review
clearly revealed the anti-inflammatory potential of herbal
constituents that are now reported scientifically.
The rapid pace in research and development in herbal
medicine has made it an interdisciplinary science. The
Research and Development thrust in the Pharmaceutical
sector is focused on development of new innovation/
indigenous plant-based drugs through investigation of
leads from the traditional system of medicine. Due to
better cultural acceptability, better compatibility with
human body, wide biological activities, higher safety
margin, and lesser costs than the synthetic drugs, there
is great demand of herbal medicines in the developed
as well as developing countries. It is interesting to note
that the value of animal testing to establish safety and
toxicity is not so critical in botanicals if they are time
tested and used widely in traditional forms. On the
contrary, synthetic molecules’ drug development requires
about 12–15 years. The traditional medicine provides
new functional leads to reduce time, money, and toxicity
– the three main hurdles in drug development.[53,54] The
golden triangle consisting of various traditional systems
of medicines across the globe, modern medicine, and
science will converge to form a real discovery engine that
can result in newer, safe, cheaper, and effective therapies.
Ayurveda and modern medicine techniques must be
coupled in order to bring out high-quality herbal products
with rapid onset of action and good bioavailability.
Despite the divergent bioactivities of plant medicines
against various diseases, active components of most
plant extracts have not been elucidated thoroughly due
to their complex mixtures containing up to hundreds of
ingredients. However, the core chemical classes of antiinflammatory agents from natural sources have been
usually reported to engage a vast range of compounds
such as polyphenols, flavonoids, terpenoids, alkaloids,
anthraquinones, lignans, polysaccharides, saponins, and
peptides.[55,56] From the exhaustive study done so far, some
striking findings come into light. It has been elucidated
that flavonoids are the major anti-inflammatory agents.
Some of them act as phospholipase inhibitors and some
have been demonstrated as TNF-α inhibitors in different
inflammatory conditions. Biochemical investigations
have also shown that flavonoids can inhibit both COX
and lipooxygenase pathways of arachidonic metabolism
depending upon their chemical structures.[57,58]
10
Alkaloids in asserted skeletal type based on pyridine
ring system have been presented with striking antiinflammatory activity, e.g. berberine from berberis is a
traditional remedy against rheumatism.[8]
Curcumin, the principal curcuminoid, is the active antiinflammatory agent found in the spice turmeric. It has
been shown to inhibit the activity of the 5-lipoxygenase
and COX enzymes, blocking the synthesis of proinflammatory eicosanoids (PG-2, LTB-4). It has also been
shown to be effective in the treatment of post-surgical
inflammation.[59]
Terpenoids significantly inhibit the development of
chronic joint swelling. In western medicine, the treatment
often involves topical application of corticosteroids
which are symptomatically effective but have inherent
disadvantages. Terpenoids may affect different
mechanisms relevant to inflammation arising in response
to various etiological factors.[60]
White Willow bark extract provides anti-inflammatory
phenolic glycosides, such as salicin, which have been
shown to be effective in the treatment of arthritis, back
pain, and other joint inflammatory conditions. These
phenolic glycosides are known to inhibit COX, blocking
the production of PG-2, and exert a mild analgesic effect.[61]
However, still many herbal folk medicines for
inflammation and rheumatism have not undergone
through scientific investigations and careful assessment
of their toxic effects. Hence, it is the need of the hour
to consider all such folk-based herbal medicines for
determining their pharmacological activities, isolating
the single drug entity responsible for anti-inflammatory
effect, and developing suitable formulation showing
beneficial against inflammatory disorders.
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Cite this article as: Mukhija M, Sundriyal A. Phytoconstituents responsible
for anti-inflammatory activity. J Nat Pharm 2013;4:1-12.
Source of Support: Nil. Conflict of Interest: None declared.
Journal of Natural Pharmaceuticals, Volume 4, Issue 1, January-June, 2013
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