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2104 Current Medicinal Chemistry, 2012, 19, 2104-2127
Anti-Inflammatory Iridoids of Botanical Origin
A. Viljoen*, N. Mncwangi and I. Vermaak
Department of Pharmaceutical Sciences, Faculty of Science, Tshwane University of Technolog y, Private Bag X680, Pretoria 0001,
South Africa
Abstract: Inflammation is a manifestation of a wide range of disorders which include; arthritis, atherosclerosis, Alzheimer’s disease,
inflammatory bowel syndrome, physical injury and infection amongst many others. Common treatment modalities are usually non-
steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, paracetamol, indomethacin and ibuprofen as well as corticosteroids such as
prednisone. These however, may be associated with a host of side effects due to non-selectivity for cyclooxygenase (COX) enzymes
involved in inflammation and those with selectivity may be highly priced. Thus, there is a continuing search for safe and effective anti-
inflammatory molecules from natural sources. Research has confirmed that iridoids exhibit promising anti-inflammatory activity which
may be beneficial in the treatment of inflammation. Iridoids are secondary metabolites present in various plants, especially in species
belonging to the Apocynaceae, Lamiaceae, Loganiaceae, Rubiaceae, Scrophulariaceae and Verbenaceae families. Many of these
ethnobotanicals have an illustrious history of traditional use alluding to their use to treat inflammation. Although iridoids exhibit a wide
range of pharmacological activities such as cardiovascular, hepatoprotection, hypoglycaemic, antimutagenic, antispasmodic, anti-tumour,
antiviral, immunomodulation and purgative effects this review will acutely focus on their anti-inflammatory properties. The paper aims to
present a summary for the most prominent iridoid-containing plants for which anti-inflammatory activity has been demonstrated in vitro
and / or in vivo.
Keywords: Anti-inflammatory, botanical, inflammation, iridoid, natural products, NSAIDs.
1. INTRODUCTION
Inflammation occurs as a reaction to injurious stimuli such as
infection or in some cases, auto-immunity. Vasoactive amines,
peptides and free radicals are some of the inflammatory mediators
[1]. Inflammation is evidenced by increased temperature on site,
redness, pain and swelling. It is the body’s attempt to eliminate
exogenes, without which infections and wounds would not be able
to heal. Macrophages, dendritic cells, histiocytes, Kupffer cells and
mastocytes initiate acute inflammation after undergoing activation
and release of inflammatory mediators. Vasodilation and its
resulting increased blood flow cause the redness and increased heat.
Increased permeability of the blood vessels results in an exudation
of plasma proteins and fluid into the tissue, which manifests itself
as swelling. Some of the released mediators such as bradykinin
increase the sensitivity to pain. The mediator molecules also alter
the blood vessels for extravasation. The neutrophils migrate along a
chemotactic gradient created by the local cells to reach the site of
injury and loss of function as the result of a neurological reflex in
response to pain [2]. Eicosanoids are signaling molecules mainly
involved in inflammation and as messengers in the central nervous
system, these molecules however are not preformed in the tissues;
they are generated from phospholipids. They are implicated in the
control of many physiological processes and are among the most
important mediators and modulators of the inflammatory reaction.
The main source of eicosanoids is arachidonic acid (5, 8, 11, 14-
eicosatetraenoic acid), a 20-carbon unsaturated fatty acid containing
four double bonds. The principal eicosanoids are prostaglandins
(PG), thromboxanes (TBX) and leukotrienes (LT); other derivatives
of arachidonate such as lipoxins are also produced (Fig. 1). The
initial and rate-limiting step in eicosanoid synthesis is the liberation
of arachidonate, either in a one-step or two-step process. The one
step process involves phospholipase A2; the two-step process
involves either phospholipase C or then diacylglycerol lipase or
phospholipase D then phospholipase A2 [3]. Prostaglandins are
small lipid molecules which are involved in a number of
physiological processes including kidney function, platelet
aggregation, neurotransmitter release and modulation of the
immune system [4]. The synthesis, metabolism and signalling of the
five major prostaglandins; PGD2, PGE2, PGF2α, PGI2 and
*Address correspondence to this author at the Department of Pharmaceutical Sciences,
Faculty of Science, Tshwane University of Technology, Private Bag X680, Pretoria
0001, South Africa; Tel: +27 12 382 6360; Fax: +27 12 382 6243;
E-mail: viljoenam@tut.ac.za
thromboxane are regulated by type-specific and PG-specific
pathways. COX-1 and COX-2 enzymes convert arachidonic acid
liberated from membrane phospholipids to an unstable PGG2
intermediate which is further converted to PGH2 by
endoperoxidase activity [5].
Almost all acute and chronic diseases are either driven or
modulated by inflammation. The complexity of the interplay
between beneficial and harmful effects of the inflammatory
response may be the reason why there is a lack of effective
therapies for many diseases [6]. Cytokines are a large group of
multifunctional substances which are involved in the inflammatory
response classified either as pro-inflammatory or anti-
inflammatory, depending on the way they influence inflammation.
Pro-inflammatory cytokines including interleukin-1β (IL-1β),
tumour necrosis factor-α (TNF-α), IL-6 and IL-18 initiate and
amplify the inflammatory process whereas anti-inflammatory
cytokines such as IL-10, the inflammatory receptor agonist (IRA)
and transforming growth factor (TGF-β) negatively modulate these
events [7]. Nuclear factor kappa B (NF-κB) is a transcription factor
involved at the downstream stage of many signaling cascades and
plays an important role in chronic inflammation [8]. There is
evidence that cytokines and their receptors are involved in the
pathophysiology of many inflammatory diseases such as
Alzheimer’s disease, type two diabetes mellitus, inflammatory
bowel disease, sepsis, rheumatoid arthritis, atherosclerosis and
asthma where there seems to be an imbalance of the cytokine
network and excessive recruitment of leukocytes to inflammatory
sites [7;9]. Anti-cytokines which still require further research may
be beneficial in cystic fibrosis where there is persistent and
dysregulated inflammation, combined with exaggerated immune
response [10]. There is evidence from preclinical and clinical
studies that persistent inflammation is a driving force in the
development of carcinogenesis. Various mechanisms are involved
in this process; these include the induction of genomic instability,
alterations in epigenetic events and subsequent inappropriate gene
expression, enhanced proliferation of initiated cells, resistance to
apoptosis, aggressive tumour neovascularisation, invasion through
tumour-associated basement membrane and metastatis [11].
Inflammation has also been implicated in coronary diseases such as
atherogenesis, atherosclerotic plaque progression and acute
coronary syndrome. C-reactive protein is used as a common marker
for disease progression [12].
The common signs of arthritis such as redness, swelling and
pain occurs as a result of inflammation. This disease affects about
-;/12 $58.00+.00
© 2012 Bentham Science Publishers
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2105
1% of the US adult population, with rheumatoid arthritis being the
most common form. It is three times more common in women than
in men [13]. The joints of the knees, hips and wrists are the
common sites of the disease; however other joints may also be
affected. Patients suffering from rheumatoid arthritis often present
with ocular and pulmonary inflammation, nodules on the extensor
surfaces of the elbows, lymphadenopathy and splenomegaly
additional to the classical inflammation of the joints [13]. The
disease is likely to go undiagnosed for many years, firstly because
of its ‘wear and tear’ nature which is regarded as the normal
process of ageing and also because of the availability of drugs used
for the treatment of inflammation which is a classic sign and
symptom of rheumatoid arthritis. The exact pathophysiology of the
disease is poorly understood; and to understand it better, it is
commonly classified according to where the inflammation occurs in
the body, for example, joints, spine and soft tissue rheumatoid
arthritis [14]. It is thought that rheumatoid arthritis results from a
dysfunctioning of the immune system. Rheumatoid arthritis patients
have been shown to have elevated levels of IL-1 and TNF-α [15]
and activation-induced, T-cell derived, chemokine-related
cytokine/lymphotactin [16] as well as macrophage migration
inhibitory factor [17]. These endogenous compounds stimulate
synovial tissue effector functions, including proliferation, matrix
metalloproteinases (MMPs) expression, adhesion-molecular
expression, secretion of other cytokines and prostaglandin
production, all of which may play a role in the pathogenesis of
rheumatoid arthritis [18].
However, genetic factors have also been indicated to have an
influence on the pathogenesis of the disease [19-20]. Studies have
demonstrated that most patients express specific human lymphocyte
antigens in the major histocompatability complex located on T-
lymphocytes. Both humoral and cellular immunologic mechanisms
are involved in the pathogenesis of the disease. The mechanisms
include cytokine-mediated activation of T and B lymphocytes and
the recruitment and activation of polymorphonuclear leukocytes.
The inflammatory leukocytes then release a variety of
prostaglandins, cytotoxic compounds and free radicals that cause
joint inflammation and destruction [21]. Acute inflammation is
necessary for eliminating exogenes and promoting coagulation,
however, left unchecked this process may trigger carcinogenesis,
which increases cell differentiation and cell up-regulation which
leads to abnormal tissue growth, and ultimately cancer [22].
2. ALLO PATHIC MEDICINES COMMERCIAL LY AVAILA-
BLE USED TO TREAT INFLAMM ATORY DISEASES
Inflammation may be involved in the pathophysiology of a host
of diseases; however, rheumatoid arthritis remains an epitome of
inflammatory diseases. It is a progressive disease and lifestyle plays
an important role in disease progression and even prognosis.
Patients suffering from this disease have been shown to be amongst
the ones who are more likely to self-diagnose and self-prescribe.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line
treatment for inflammatory disorders, with the classic example
being ibuprofen. These are widely available over the counter,
without a prescription and are prone to irrational prescribing and
abuse due to the epidemiology of the disease and its impediment on
the quality of life of these patients. However, this group of drugs
Fig. (1). Summary diagram of mediators derived from phospholipids and their physiological effects. HETE = hydroxyeicosatetraenoic acid; HPETE =
hydroperoxyeicosatetranoic acid (adapted from Rang et al. [3]).
Phospholipid
Phospholipid
Phospholipase A2
Arachidonate
Arachidonate
12
-
lipoxygenase
15
-
lipoxygenase
Cyclooxygenase 5-lipoxygenase
12
-
lipoxygenase
15
-
lipoxygenase
12
-
HETE
Lipoxins
A and B
Cyclic
endoperoxides
5
-
HPETE
12
-
HETE
(
chemotaxin
)
Lipoxins
A and B
Cyclic
endoperoxides
5
-
HPETE
(
chemotaxin
)
LTA
4
TXA
LTA
4
PGI2
(vasodilator;
TXA
2
(thrombotic;
(vasodilator;
hyperalgesic
; inhibits
(thrombotic;
vasoconstrictor)
hyperalgesic
; inhibits
platelet aggregation)
vasoconstrictor)
LTB
4
LTB
4
(chemotaxin)
LTC
4
4
LTD4
LTE
PGE
PGD
PGF
LTE
4
PGE
2
(vasodilator;
PGD
2
(inhibits platelet
PGF
2α
(
bronchoconstrictor
;
(
bronchoconstrictors
;
(vasodilator;
hyperalgesic)
(inhibits platelet
aggregation;
vasodilator)
(
bronchoconstrictor
;
myometrial
contraction)
(
bronchoconstrictors
;
increase vascular
permeability
)
vasodilator)
contraction)
permeability
)
2106 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
remains the mainstay as potent anti-inflammatory and analgesic
agents. Non-steroidal anti-inflammatory drugs are weakly acidic
drugs which exert their action by inhibiting the COX enzyme. This
forms the basis of their classification; selective and non-selective
COX inhibitors. COX is an enzyme that catalyses the conversion of
arachidonic acid into arachidonate from which the prostaglandins
are synthesised. Nonsteroidal anti-inflammatory drugs also inhibit
B and T cell proliferation by mechanisms that do not involve
inhibition of COX and prostaglandin formation. Prostaglandins are
necessary for the maintenance of the gastric mucosa and its
protection from the acidic gastric fluids. Thus, inhibition of the
COX-1 enzyme which is directly involved in this function results in
gastric erosion which ultimately leads to gastric ulceration and/or
perforation. COX-2 is the isoform which is responsible for
inflammation orchestration [23].
The coxibs, a newer class of selective COX-2 inhibitors, have
gained favour for the treatment of rheumatoid arthritis although at a
significant price increment [24]. Pharmaco-economical studies have
revealed that the risk/benefit ratio justifies the price and in addition
improves the quality of life of patients. Additionally, these drugs
have a prolonged half-life of approximately 12 h which allows for a
twice daily dosing, not only for better patient compliance, but it
also offers the much needed relief from the pain and loss of joint
function associated with rheumatoid arthritis for an extended period
of time. Although they offer several health benefits; selective COX-
2 inhibitors have been shown to be associated with cardiovascular
side effects. Using mouse models, Narasimba and co-workers
demonstrated that COX-2 deficiency contributes to the pro-
atherogenic properties of high density lipoproteins [25].
Rheumatoid arthritis is a chronic disease, thus there is a
continuous search for remedies which are safer for long-term use.
Non-steroidal anti-inflammatory drugs are generally well-tolerated.
When taken on a short-term basis, dyspepsia and stomach
discomfort are common but tolerable side effects [26]. However, on
long-term basis, gastrointestinal erosion evidenced by gastric
ulceration and perforation has been recorded and may even be
lethal [27-28]. Non-steroidal anti-inflammatory drugs are
extensively metabolised in the liver and excreted in the urine and
faeces. Liver and kidney failure has been reported in patients who
failed to adequately hydrate themselves during NSAID therapy [26;
29]. Groups at risk are the elderly and young children because of
reduced hepatic and renal function. Additionally, in young children
there is misuse of NSAIDs, where misinformed mothers use
NSAIDs for their anti-pyretic properties whereas there are safer
alternatives, but the side effects ensue nonetheless. Omeprazole, a
substituted benzimidazole is a potent inhibitor of gastric acid
secretion which interacts with the gastric proton pump (K+/H+ -
ATPase) in the parietal cell secretory membrane [30]. This drug is
often prescribed for chronic ulceration commonly associated with
NSAID treatment. Researchers have however reported that
omeprazole and its metabolites may decrease natural killer cell
cytotoxic activity [31].
Corticosteroids and their biologically active synthetic
derivatives are employed when endogenous production is impaired,
which may be the case in some inflammatory and auto-immune
diseases such as inflammatory bowel syndrome, asthma and
arthritis. Glucocorticoids are potent immuno-suppressors and anti-
inflammatory agents; and are thus frequently prescribed for
inflammatory and auto-immune diseases [2]. Use of corticosteroids
requires close monitoring because their side-effects are widespread
to every organ of the body. Side effects are dose-related, they
include, fat redistribution, rounded plethoric face and purple striae.
Their mechanism of action involves binding to the cytoplasmic
glucocorticoid receptor; the activated receptor-glucocorticoid
complex enters the cell nucleus and binds to steroid response
elements on target DNA molecules. This induces synthesis of
specific mRNA or represses genes by inhibiting transcription
factors such as NFκB. Synthetic glucocorticoids have higher
affinity for this receptor [32].
3. IRIDOID CHEMISTRY AND RESEARCHED ANTI-
INFLAMMATORY IRIDOID-CON TAINING PLANTS
Nature provides a wide range of compounds with a similarly
wide range of biological activities. One such class of compounds is
the iridoids. These metabolites are present in plants and animals; in
plants they are often bound to glucose thus referred to as iridoid
glycosides. Iridoids represent a large group of cyclopenta[c]pyran
monoterpenoids that are abundant in Dicotyledonous plant families
and especially in sympetalous families such as the Apocynaceae,
Scrophulariaceae, Verbenaceae, Lamiaceae, Loganiaceae and
Rubiaceae etc. [33]. In vitro and in vivo studies have revealed that
iridoids have neuroprotective, anti-inflammatory, immuno-
modulating, hepatoprotective, cardioprotective, anticancer, anti-
oxidant, antimicrobial, hypoglycaemic, hypolipidaemic, choleretic,
antispasmodic and purgative properties [34-40]. In terms of
chemical structure, iridoids are characterised by a six-membered
ring containing an oxygen bound to a cyclopentane ring.
O
7
65
11
4
3
8
10
9
1
The iridane skeleton is formed by the cyclisation of 10-
oxogeranial biosynthesised from geraniol through 10-
hydroxygeraniol to yield iridodial, which is subsequently oxidised
to iridotrial. Glycosylation, methylation and oxidation etc. converts
iridotrial to iridoid compounds. Various classifications have been
proposed, but most seem to agree that there are four major iridoid
groups. Iridoid glycosides have glycosidic linkages, usually formed
at the aglycone C-1 or C-11 hydroxyl. Non-glycosylated or simple
iridoids (lognic acid; loganin) have an iridane skeleton with a
methyl at C-8 and another carbon bonded to C-4. Secoiridoids, such
as gentiopicroside and sweroside, are formed through cleavage of
the 7,8-bond of the cyclopentane ring. Almost all secoiridoids are
glycosides. Dimerisation of iridoids and secoiridoids lead to the
formation of bisiridoids [33; 41-42].
Several structure-activity relationships were deduced in a study
by Recio et al. [43]. If a hydroxyl function is introduced, the topical
activity decreases. Hence harpagoside and lamiide are less effective
topically than loganin. The conversion of a –COOH moiety to its –
COOMe analogue increases topical activity. Other positive
characteristics for topical activity are hydroxyl substitution at C-5,
unsaturation at C7-C8 and methyl substitution of carboxyl C-11.
The most positive characteristic for anti-inflammatory activity is a
double bond between C-7 and C-8 [43]. Studies have shown that
the activity of iridoid glycosides increase after hydrolysis. Both
harpagide and harpagoside exhibited no inhibition of COX-1 and
COX-2 enzymes, TNF-α release or NO production. After
hydrolysis with β-glucosidase, harpagide is transformed into H-
harpagide while harpagoside is transformed to H-harpagide and
cinnamic acid. The hydrolysed product, H-harpagide significantly
inhibited COX-2 activity and it was noted that the chemical
structure of this compound was similar to PGE2 and other COX-2
selective inhibitors such as celecoxib. These compounds have a
pentanomic ring with two adjacent side-chains and the similarity
may be responsible for the binding to the COX-2 enzyme [44]. Park
et al. [45] hydrolysed several iridoid glycosides (catalpol,
gentiopicroside, loganin etc.) using β-glucosidase to show their
inhibitory effects. Species from which iridoid glycosides have been
isolated and tested are discussed hereafter; Table 1 summarises
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2107
species; compound(s) isolated; mechanism of action and whether in
vivo or in vitro data has been generated.
The species included in this review have been selected after
several searches were completed. Both Scopus and SciFinder was
consulted using various search terms such as “iridoid” AND
“inflamm*”. SciFinder was used to further explore anti-
inflammatory activity for iridoids using the compound name e.g.
“harpagoside” AND “inflamm” as search terms. The bibliographies
of all relevant papers were further consulted to obtain any relevant
papers. The premise on which botanical species were selected for
discussion was; 1. if an extract of that particular species had been
assayed to determine anti-inflammatory properties (in vitro and in
vivo) and 2. if iridoids were shown to possibly contribute to the
observed activity. Screening-type papers where no information was
provided on the chemical composition / profile of the extracts were
not considered. Clearly, a specific iridoid may not be restricted to a
single species but may occur in related or taxonomically distant
taxa. Although it may be reasonable to extrapolate research from
one study to another species containing the same iridoid, it was not
the purpose of this review to provide an exhaustive compilation of
all iridoid-containing species and to speculate on their possible anti-
inflammatory activity.
3.1. Ajuga bracteosa (Bugleweed)
Ajuga bracteosa Wall. ex Benth. (Lamiaceae) is a perennial
herb that grows in India and Taiwan where it is traditionally used to
treat inflammatory disorders such as hepatitis, pneumonia and bone
disease. In India it is a known remedy for malaria and in Ayuverda
for the treatment of rheumatism, gout, palsy and amenorrhoea. This
plant is also renowned for its astringent, febrifugal, stimulant and
diuretic properties [46-48]. Ajuga bracteosa contains sphingolides,
bractic acid, diterpenoids and withanolides which inhibit enzymes
such as lipoxygenase (LOX) and acetylcholinesterase (AChE) [47].
Scientific studies revealed chemopreventitive, antiplasmodial and
cardiostimulant effects [46; 48].
Gautam et al. [46] evaluated the topical anti-inflammatory
effect of a 70% ethanol extract of the whole plant in 12-O-
tetradeconoylphorbol-13-acetate (T PA)-induced ear oedema in
female Swiss albino mice. The extract showed significant dose-
dependent anti-inflammatory activity at doses of 0.5 and 1.0 mg/ear
as measured by ear thickness. Testing with an EIA kit showed
strong inhibitory activity of 50.56±1.12% (COX-1) and
42.38±0.90% (COX-2) at 25 µg/mL, and 79.33±1.09% (COX-1)
and 68.80±0.54% (COX-2) at 50 µg/mL. The COX-1 and COX-2
inhibitory activity of five compounds, ajugarin I, 6-deoxyharpagide
(1), lupulin A, reptoside (2) and withaferin A, isolated from this
extract were determined at a concentration of 30 µM. The two
iridoid glycosides (reptoside and 6-deoxyharpagide) exhibited mild
to moderate inhibitory activity of 33.55±0.76% (COX-1) and
51.30±1.56% (COX-2) for reptoside and 38.36±2.01% (COX-1)
and 59.45±0.66% (COX-2) for 6-deoxyharpagide. Of the five
isolated compounds, 6-deoxyharpagide exhibited the highest COX-
2 activity. The activity of the iridoid glycosides reptoside and 6-
deoxyharpagide as well as clerodane diterpenes and withaferin A
may thus be responsible in part for the anti-inflammatory activity of
the extract [46]. A 70% ethanolic extract produced anti-arthritic
effects in Wistar albino rats after joint oedema was induced. The
extract protected against swelling produced by administration of
turpentine oil and significant inhibition of joint oedema (81.08%;
20 mg/kg) after formaldehyde administration was seen compared to
aspirin (40.51%; 100 mg/kg). The A. bracteosa extract showed
promising anti-arthritic activity against both acute and chronic
arthritis which supports its traditional use [48].
3.2. Boschniakia rossica (Northern g roundcone)
Boschniakia rossica (Cham. & Schltdl.) Standl.
(Orobanchaceae) is a parasitic plant growing on the roots of Alnus
species (Betulaceae). It is a most valuable medicinal plant in China
and is also found in the Democratic People’s Republic of Korea,
Japan and Russia. Boschniakia rossica is widely used in Chinese
traditional medicine as a substitute for Cistanchis Herba, a famous
stamina tonic agent and it is a well-known anti-senile agent
consumed as an alcoholic infusion [49-50]. Several compounds
have been isolated from B. rossica including phenylpropranoid and
iridoid glycosides [51]. These compounds have been shown to
exhibit anti-inflammatory, anti-lipid, peroxidative and free-radical
scavenging activities [52]. Quan et al. [50] reported that a B.
rossica n-butanol extract consisted of the iridoid glycosides
boschnaloside (30.1%) (3) and 8-epideoxyloganic acid (16.6%) (4),
as well as the phenylpropanoid glycoside rossicaside B (32.2%).
Administration of the extract to rats resulted in the suppression of
TNF-α, iNOS and COX-2 protein secretion and/or enhanced the
degradation of these proteins [50]. The anti-inflammatory activity
of a water and dichloromethane extract fractionated from a
methanol extract was tested after xylene-induced ear swelling in
mice (Kunming strain). The water (8.9-28.8%) and
dichloromethane (26.2-27.4%) extracts as well as the control,
indomethacin (18.8-21.5%), inhibited the degree of swelling
significantly compared to the normal saline group [53]. The same
authors investigated the effect of the extracts in rats and mice. The
water extract exhibited inhibitory effects on acute inflammation in
the carrageenan-induced paw oedema, hot scald-induced paw
oedema, and histamine-induced oedema assays as well as on
chronic inflammation in the adjuvant-induced arthritis and cotton
pellet-induced granuloma formation assays [49].
Lin et al. [51] evaluated the anti-inflammatory activity of
boschnaloside (3) and 8-epideoxyloganic acid (4) through its effects
on N-formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol-
12-myristate-13-acetate-(PMA)-activated peripheral human
neutrophils (PMNs) and mononuclear cells. These iridoid
glycosides exhibited activity with an IC50 value of 8.9-28.4 µM in
PMA-activated PMNs and 19.1-21.1 µM in fMLP-activated
mononuclear cells. This indicated the potential of iridoid glycosides
to affect the inflammatory process through the inhibition of ROS
production and/or providing a radical scavenging effect during
oxidative stress [51]. Boschnaloside has been isolated from several
other species including Euphasia pectinata [54] and Pedicularis
verticillata [55].
3.3. Bouchea fluminensis (Wandering Jew)
The genus Bouchea has a limited geographical distribution in
the Western hemisphere with only one out of ten species, Bouchea
pterygocarya, occurring in the Eastern hemisphere. Bouchea
fluminensis (Vell.) Moldenke, a member of the Verbenaceae family,
is a herbaceous plant found in Brazil and Bolivia. Traditionally, an
infusion of its aerial parts is widely used for its bowel-stimulating
and regulating properties on digestive functions and as an anti-
inflammatory agent. Together with species of Stachytarpheta, it is
used in folk medicine in Brazil to treat gastric disorders and as an
anti-emetic [56-57]. Chemical analyses performed on extracts of
this plant have identified lamiide (5) as the main component [58].
Delaporte et al. [56] assessed lamiide (5) for anti-inflammatory
activity in the carrageenan-induced rat-paw oedema and rat-brain
phospholipid assays. Lamiide (12.5-100 mg/kg) was orally
administered to female Wistar rats 30 min prior to carrageenan
injection with indomethacin (10 mg/kg) as a positive control.
Oedema increased progressively, reaching a maximum at 4 h where
the volume of the carrageenan-injected paw was 42±1% greater
than the saline-injected paw. The administration of lamiide reduced
the oedema dose-dependently with an ED50 value of 62.3±7 mg/kg
2108 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
of weight. The increase in paw volume at 4 h was 42±1% for the
saline control, 15±3% in the indomethacin group (positive control)
and 17±3 and 9±1% in the 50 mg/kg and 100 mg/kg lamiide
groups, respectively [56].
In the rat-brain phospholipid assay, the ability of lamiide to
inhibit peroxidation of membrane lipids was tested. Phospholipids
spontaneously undergo non-enzymatic oxidation when incubated at
37 °C in the presence of Fe+2. Lamiide exhibited inhibition of
phospholipid peroxidation at an IC50 value of 0.929± 0.01 mM. The
percentage inhibition was significantly different compared to the
positive control, Trolox® C (45%; 100 µM), with 57% and 71%
inhibition at 1.20 mM and 1.40 mM, respectively. The presence of
lamiide therefore may be partially responsible for its anti-
inflammatory effect through its free radical scavenging activity
[56]. Lamiide has also been identified in other Phlomis species such
as P. sintenisii [59], P. grandiflora var fimbrilligera [60], P.
pungens var. pungens [61], P. samia [62] and P. aurea [63].
3.4. Catalpa ovata (Yellow catalpa)
The stem bark of Catalpa ovata G. Don. (Bignoniaceae),
cultivated as an ornamental tree, has been used traditionally in
Korea to treat several inflammatory diseases [64]. Pae et al. [64]
investigated the effects of the methanol extract of this folk medicine
on the production of two major macrophage-derived inflammatory
mediators, TNF-α and NO. The RAW 264.7 macrophages were pre-
incubated with the extract and then activated with the endotoxin
lipopolysaccharide (LPS). The extract dose-dependently inhibited
the secretion of TNF-α and NO synthesis with a significant
decrease in mRNA-expression of iNOS and intracellular TNF-α
synthesis. It was also found that the extract reversed toxicity in
RAW 264.7 macrophages induced by LPS and the extract itself did
not show any cytotoxicity [64].
Catalposide (6), an iridoid isolated from C. ovata, has been
investigated for its anti-inflammatory effects. Catalposide has been
reported to inhibit the production of TNF-α, IL-1β and IL-6, as well
as the activation of NF-κB in LPS-activated RAW 264.7
macrophages. In addition, it inhibited the expression of these genes
and the nuclear translocation of the p65 subunit of NF-κB. A
possible mechanism of action was deduced in that catalposide
inhibited the binding of LPS to RAW 264.7 cells [65]. Another
study revealed that catalposide significantly inhibited the
production of NO in a dose-dependent manner in LPS-stimulated
RAW 264.7 macrophages, suppressed the expression of the iNOS
gene and protein and inhibited the activation of LPS-induced NF-
κB [66]. In human intestinal epithelial HT-29 cells, catalposide
attenuated the TNF-α-dependent expression of the pro-
inflammatory gene IL-8. The TNF-α-induced IL-8 secretion was
reduced in a dose-dependent manner with optimal inhibition at ≥
200 ng/ml. An in vivo study was done to determine whether
catalposide could affect intestinal inflammation using the
trinitorbenzene sulfonic acid (TNBS)-induced inflammatory colitis
mouse model. TNBS was administered intrarectally in 2 doses (7
days apart) to induce colitis, causing severe bloody diarrhoea, rectal
prolapse and wasting. Catalposide (10 µg/mouse) was administered
via the lumen of the colon 1 day before and 3 and 6 days after the
first TNBS administration. Treated mice showed striking
improvement of the wasting disease through a fast and dramatic
increase in bodyweight. Macroscopic analysis of the colon revealed
that catalposide prevented both hyperaemia and inflammation and
histopathologic analysis showed that catalposide restored the
histologic appearance of the mucosa and submucosa. In addition, it
was shown that catalposide inhibited NF-κΒ in vivo in addition to
its in vitro action. Therefore, oral administration of catalposide may
be helpful in the treatment of inflammatory bowel disease (IBD) in
humans [67], and clinical trials to substantiate its traditional use
should be conducted.
3.5. Cornus officinalis (Japanese cornel; Dogwood fruit)
Cornus officinalis Siebold et Zucc is a member of the
Cornaceae family. Use of this herb was first recorded in Shen
Nong’s Materia Medica about 2000 years ago in China. Cornel
iridoid glycoside (CIG) is a main component extracted from C.
officinalis. Additionally, the extract of C. officinalis is composed of
organic acids, polysaccharides, saponins and iridoids such as
oleanolic acid, ursolic acid, morroniside (7), loganin (8), sweroside
(9), and cornuside (10) [68-69]. Cornus officinalis is a traditional
Oriental medicine credited with curing inflammatory diseases and
invigorating blood circulation. Several biological activities are
ascribed to C. officinalis including hepatic function improvement,
antimicrobial activity, antineoplastic, anti-inflammatory and
antidiabetic effects [70-71].
Yao et al. [68] investigated the effects of cornel iridoid
glycoside (CIG), which is a combination of morroniside (7) and
loganin (8), on neurological function and neurogenesis after
ischaemic stroke. CIG was intragastrically administered to rats in
doses of 20, 60 and 180 mg/kg/day, starting 3 h after the onset of
middle cerebral artery occlusion. The treatment with CIG at the
doses of 60 and 180 mg/kg/day significantly improved neurological
function, and increased the number of bromodeoxyuridine-positive
cells and nestin-positive cells in the subventricular zone of rats 7,
14 and 28 days after ischaemia. The results indicated that CIG
promoted neurogenesis and angiogenesis and improved
neurological function after ischaemia in rats [68]. This shows that
C. officinalis may be beneficial in conditions such as
atherosclerosis which may be a predisposing factor for an ischaemic
stroke. The anti-inflammatory effect of Cornus officinalis
glycosides (COG) was investigated in rats using the Freund’s
adjuvant-induced arthritis method. Significant suppression of
oedema was noted as well as inhibition of IL-1, IL-6 and TNF-α in
peritoneal macrophages as well as prostaglandin E2 (PGE2) in
plasma [72]. An aqueous extract prepared from the fruit inhibited
LPS-induced expression of COX-2 and iNOS in R AW 264.7
macrophages. In addition, it suppressed PGE2 synthesis, NO
production and NF-κB levels in the nucleus. In addition, the acetic
acid-induced writhing response in mice was suppressed indicating
analgesic action [73].
Yamabe et al. [74] showed that loganin (8) exhibits protective
effects against hepatic injury and other diabetic complications
associated with abnormal metabolic states and inflammation caused
by oxidative stress and advanced glycation end-product formation.
In a recent study, a morroniside cinnamic acid conjugate was
prepared and evaluated on E-selectin mediated cell–cell adhesion as
an important role in inflammatory processes. 7-O
Cinnamoylmorroniside (11) exhibited anti-inflammatory activity
(IC50 = 49.3 µM) by inhibiting the expression of E-selectin and was
observed to be a potent inhibitor of TNF-α-induced E-selectin
expression [75]. It was also determined that morroniside isolated
from the fruits of C. officinalis inhibited the formation of reactive
oxygen species (ROS) and lipid peroxidation and down-regulated
the expression of NF-κBp65, COX-2 and iNOS which is increased
in type-2 diabetic mice [69].
Cornuside (10), a bisiridoid glycoside compound isolated from
the fruit, suppressed cytokine-induced pro-inflammatory and
adhesion molecules in human umbilical vein endothelial cells
(HUVECs). Cornuside attenuated TNF-α-induced NF-κBp65
translocation, suppressed the expression of intercellular adhesion
molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-
1) and monocyte chemoattractant protein-1 (MCP-1). Therefore, it
has an effect on vascular inflammation caused by an increase in
leukocyte-endothelium adhesion via up-regulation of endothelial
cell adhesion molecules (ICAM-1; VCAM-1) and pro-
inflammatory factors like MCP-1, which are induced by NF-κB
[70]. In another in vitro study it was determined that cornuside (30
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2109
µM) significantly inhibited LPS-induced production of NO
(67.6%), PGE2, TNF-α (50.8%), IL-6 (75.7%) and IL-1β (55.4%),
reduced mRNA expression of COX-2 and iNOS and attenuated the
translocation of NF-κBp65. Cornuside has the potential to be a
good candidate to treat inflammatory disorders if these effects could
be confirmed in an in vivo model [76].
3.6. Enicostema axillare (Indian whitehead)
The perennial herb, Enicostema axillare (Lam.) A.Raynal
(Gentianaceae) is found throughout India. Traditionally, the plant is
used in folk medicine to treat diabetes mellitus, rheumatism,
abdominal ulcers, hernia, swelling and itching in addition to being
used as an anti-inflammatory, digestive, thermogenic and liver
tonic. Anti-inflammatory, anti-oxidant, hypoglycaemic and
anticancer activities of this species have been reported [77].
Compounds isolated from this species include swertiamarin (12),
alkaloids, steroids, triterpenoids, saponins, flavonoids, xanthones
and phenolic acids. Many of these compounds exhibit anti-
inflammatory and anti-oxidant properties [78]. Vaijanathappa and
Badami [79] investigated the antioedematogenic and free radical
scavenging activity of swertiamarin (12) isolated from an ethyl
acetate extract of E. axillare. In the carrageenan-induced rat-paw
oedema test the results showed oedema inhibition 5 h after
induction of 38.60% (swertiamarin, 100 mg/kg body weight),
52.50% (swertiamarin, 200 mg/kg body weight) and 45.55%
(diclofenac sodium, 100 mg/kg/body weight). This indicated
superior activity of swertiamarin at a dose of 200 mg/kg compared
to the standard, diclofenac sodium [79]. The hepatoprotective and
anti-oxidant activity of swertiamarin (100 and 200 mg/kg body
weight) was determined after inducing liver injury in rats by
administering d-galactosamine (200 mg/kg body weight)
intraperitoneally. Swertiamarin (100 and 200 mg/kg body weight)
was administered orally for 8 days prior to d-galactosamine. A
significant normalisation of all the altered biochemical parameters
was noted indicating the anti-oxidant and hepatoprotective nature of
swertiamarin. Park et al. [45] also showed that hydrolysed
swertiamarin inhibits thromboxane-B2 (TBX2).
The in vivo antinociceptive activity of swertiamarin (12)
isolated from E. axillare was investigated using male adult albino
mice. In the hot plate method, a significant increase in the response
time was observed for the 100 mg/kg body weight swertiamarin-
treated group after 30 and 45 min and after 15, 30 and 45 min for
the 200 mg/kg bodyweight group. The paracetamol-treated group
(100 mg/kg bodyweight) showed an increase in the latency period
only after 30 and 45 min. The percent protection observed after 45
min was 109.42% for the paracetamol group, 147.42% for the
swertiamarin 100 mg/kg body weight group and 157.14% for the
swertiamarin 200 mg/kg body weight group. A significant increase
in the tail withdrawal reflex was observed for the swertiamarin-
treated group with percent protections of 150% (100 mg/kg
bodyweight) and 200% (200 mg/kg bodyweight), which was higher
compared to paracetamol at 138% (100 mg/kg bodyweight). The
intraperitoneal injection of acetic acid (0.3%, 10 ml/kg bodyweight)
into control mice produced 17.83±1.10 writhes. Swertiamarin
administered orally 30 min prior to the administration of acetic acid
reduced the number of writhes to 8.66±0.21 (100 mg/kg
bodyweight) and 7.83±0.60 (200 mg/kg bodyweight) which
translates into 51.43 and 56.08% protection, respectively.
Paracetamol (100 mg/kg bodyweight) reduced the number of
writhes to 7.00±0.36 (60.74% protection). The dose of 200 mg/kg
bodyweight of swertiamarin was found to be more potent. An acute
toxicity study revealed no clinical signs of toxicity or mortality in
doses of up to 2000 mg/kg bodyweight administered orally
suggesting that it is safe for clinical use. These results suggest that
swertiamarin possess both peripheral (acetic acid-induced writhing
test) and central (hot plate and tail immersion tests) antinociceptive
activity. Swertiamarin may possess central antinociceptive activity
involving opioid-like receptor mediation as well as peripheral
antinociceptive activity by inhibiting the synthesis or actions of
prostaglandins. Further research is required to determine its
mechanism of action [77]. Swertiamarin (12) is a common
secoiridoid present in several Swertia and Gentiana species.
3.7. Eucommia ulmoides (Hardy rubber tree)
Eucommia ulmoides Oliv. belongs to the Eucommiaceae family
and is a relic plant that survived in China from the quaternary
glacial period. Later on, it was introduced into other parts of the
world, such as Japan, Korea and America. In the 1980s,
uncontrolled harvesting for the bark resulted in near extinction from
its natural habitat. Currently, almost all the forests of E. ulmoides
are commercial plantations. Historically, only the bark (cortex
Eucommiae) was officially recognised as a traditional Chinese tonic
drug [80]. However, modern scientific research has confirmed that
chemical constituents in the leaf of E. ulmoides are similar to those
in the bark and the biological activity is also comparable. The main
secondary metabolites in this plant are iridoids (e.g. geniposide (13)
and aucubin (14)), phenylpropanoids (chlorogenic acid and caffeic
acid) and flavonoids. Research has confirmed that these secondary
metabolites demonstrate profound pharmacological activities such
as lowering blood pressure and improving diabetes mellitus and
anti-oxidant and antimutation activity. Eucommia ulmoides can also
improve general health, strengthen the body, promote metabolism
and rejuvenate the body [80].
A bark water extract suppressed the COX-2 enzyme at an IC50
value of 9.92 µg/ml but showed no effect on TNF-α and NO
production in RAW 264.7 macrophages, nor on NF-κB. HPLC
analysis showed the presence of catalpol (15) and geniposide (13)
[81]. Liu et al. [82] showed that geniposide effectively inhibited
LPS-induced expression of IL-6 and IL-8 in HUVECs at the
transcription and translation levels. Additionally, geniposide (13)
suppressed LPS-induced HUVEC migration and monocyte
adhesion to HUVECs. Geniposide thus inhibits LPS-induced IL-6
and IL-8 production in HUVECs by blocking signaling pathways
[82].
Aucubin (14) is an iridoid glycoside with a variety of
pharmacological effects, such as antimicrobial and anti-
inflammatory activity, whilst also promoting dermal wound
healing. Shim et al. [83] examined the effects of 0.1% aucubin on
oral wound healing. ICR male mice were divided into two groups:
an untreated control group (n=18) and an aucubin-treated group
(n=18). Saline or 0.1% aucubin solution was injected and artificial
full thickness wounds were made on either side of the buccal
mucosa. Re-epithelisation and matrix formation of the aucubin-
treated group occurred earlier than that of the control group and the
number of inflammatory cells of the aucubin-treated group was
fewer than that of the control group.
3.8. Gardenia jasminoides (Cape Jasmine)
The dried ripe fruit of Ga rdenia jasminoides J.Ellis (Rubiaceae)
is widely used in traditional medicine for its cholagogue, sedative,
diuretic, antiphlogistic, anti-inflammatory, antioedematogenic and
antipyretic effects in Korea, Japan and China. Scientific studies
revealed anti-inflammatory, fibrolytic, anti-oxidant, anti-
thrombotic, neuritogenic and cytotoxic activities [84-85]. In a
recent study, geniposide (13), one of the main compounds of G.
jasminoides was tested for its effectivity in the treatment of ankle
sprain induced in rats. An ankle sprain was inflicted under
anaesthesia and the swelling was treated topically (200 µl/24 h)
starting from the 12th hour after induction with an ethanolic extract
of the fruit (100 mg/ml), geniposide (10 mg/ml; 100 mg/ml) and
diclofenac gel (12.5 mg/ml) as control group. All the groups
showed significant reduction in swelling compared to the vehicle-
treated control group: ethanolic fruit extract 13-18%; 10 mg/ml
2110 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
geniposide 20-23%; 100 mg/ml genipose 21-34%; diclofenac
gel 12.5 mg/ml 20-38%. These results indicate the potential
beneficial effect of the ethanolic fruit extract and geniposide for the
treatment soft tissue injuries [85].
Geniposide (13) also showed significant inhibition of IL-2
secretion by phorbol myristate acetate and anti-CD28 monoclonal
antibody co-stimulated activation of human peripheral blood T cells
thus proving to be immunosuppressive [86]. Gardenia jasminoides
ethanol extract and its constituents are reported to reduce the risks
of gastritis and reverse gastric lesions in rats [87]. In the
carrageenan-induced rat-paw oedema assay, a fruit extract inhibited
oedema at doses of 50 mg/kg (10.2%), 100 mg/kg (25.9%), 200
mg/kg (28.6%) and 400 mg/kg (35.8%). Geniposide (100 mg/kg)
inhibited oedema by 31.7% measured 3 h after carrageenan
injection. The extract also inhibited vascular permeability by
possibly protecting against the release of inflammatory mediators
and dose-dependently inhibited acetic acid-induced abdominal
writhing in mice (80.1% at 200 mg/kg). This indicated analgesic
activity in addition to anti-inflammatory activity. Geniposide (13)
also inhibited the production of carrageenan-induced formation of
exudates and nitric oxide [84]. The effect of geniposide acid on
adjuvant-induced arthritis was investigated using male Wistar rats.
Paw swelling was significantly reduced and the level of TNF-α and
IL-1β in rat serum decreased [88].
Geniposide (13) is transformed in body tissues to its aglycone,
genipin (16). Geniposide (13) is first hydrolysed to genipin (16) by
β-glucosidases and subsequently to the aglycone of geniposidic acid
(17) by esterases. Thus, when geniposide is orally administered,
genipin is produced in the intestine [89]. In RAW 264.7 cells,
functional significance of heme oxygenase-1 (HO-1) induction was
revealed by genipin-mediated inhibition of LPS-stimulated iNOS
expression or COX-2 promoter activity. The response was reversed
by the blocking of HO-1 protein synthesis or HO-1 enzyme activity
[90]. Genipin was effective at inhibiting LPS-induced nitric oxide
(NO) release from cultured rat brain microglial cells and reduced
the LPS-stimulated production of TNF-α, IL-1β, PGE2, intracellular
ROS, and NF-κB activation [91]. In a study conducted by Koo et al.
[92], genipin (16) exhibited a significant topical anti-inflammatory
effect shown through inhibition of croton oil-induced ear oedema in
mice.
3.9. Gentiana lutea (Great yellow gentian)
Gentiana lutea L. (Gentianaceae) is a yellow flowering,
perennial plant commonly found in the mountainous regions of
central and southern Europe. It contains bitter-tasting secoiridoid
glycosides; sweroside (9), swertiamarin (12) and gentiopicroside
(18), which revealed cholagogue, hepatoprotective and wound-
healing effects in pharmacological studies [93]. The genus
Gentiana contains about 400 species and is the largest genus in the
Gentianaceae family. The ethyl acetate extract of another species,
Gentiana striata Maxim., showed anti-inflammatory activity in rats
inflicted with rheumatoid arthritis. The paw volume in the treatment
group (100 and 200 mg/kg) was significantly reduced compared to
the prednisone control group and an increase in bodyweight was
noted. There was a marked decrease in the PGE2 and NO levels. Six
compounds including two iridoids, loganin (8) and sweroside (9),
was isolated from this extract [94].
On investigating gentiopicroside analgesic activities and central
synaptic modulation to the peripheral painful inflammation, Chen et
al. [95] reported that gentiopicroside (18) produced significant
analgesic effects against persistent inflammatory pain stimuli in
mice. Systemic administration of gentiopicroside significantly
reversed NR2B (NMDA Receptor 2B) over-expression during the
chronic phases of persistent inflammation in Freund’s adjuvant-
induced arthritis. The results suggested that the analgesic effect of
gentiopicroside may be due to the modulation of glutamatergic
synaptic transmission in the anterior cingulate cortex [95]. Park et
al. [45] investigated the anti-inflammatory effect of hydrolysed
iridoid products. No activity was recorded for swertiamarin (12)
before β-glucosidase treatment. However, after treatment, H-
swertiamarin (10 µM) significantly inhibited PGE2 formation in
LPS-stimulated RAW 264.7 cells. For all the iridoids tested,
activity was noted only after hydrolysis [45].
3.10. Harpaphygotum procumbens (Devil’s claw)
Harpagophytum procumbens (Burch.) DC. ex Meisn. ssp.
procumbens (Pedaliaceae) is an important traditional medicine
growing in the Kalahari region of southern Africa where it is
consumed to treat rheumatism and arthritis as an analgesic. In
addition, it is used as a cure for digestive disorders and as a general
tonic or applied topically as an ointment to treat sores, ulcers and
boils [96]. Many compounds have been isolated from H.
procumbens including harpagoside, harpagide, procumbide and
acteoside.
The anti-inflammatory mechanism of action of H. procumbens
has not yet been satisfactorily elucidated. Jang et al. [97] found that
the aqueous extract of H. procumbens suppressed PGE2 synthesis
and nitric oxide production by inhibiting LPS-stimulated
enhancement of the COX-2 and iNOS protein mRNA expression in
L929 cells. These results suggested that H. procumbens exerted
anti-inflammatory and analgesic effects probably by suppressing
COX-2 and iNOS expressions. Some studies revealed that the
efficacy of H. p rocumbens in reducing pain and inflammation
associated with rheumatoid and osteoarthritis can be explained by
its ability to block the production of inflammatory mediators such
as PGE2 [93]. Kaszkin et al. [99] determined that the efficacy of H.
procumbens was dependent on the ratios of harpagoside (19),
harpagide (20), 8-coumaroylharpagide (21) and acteoside, also
reported by Abdelouahab and Heard [100]. These compounds are
believed to act synergistically or antagonistically in modulating the
enzymes responsible for inflammation. However, most official
monograph specifications are based on harpagoside content alone
[100]. Miraldi et al. [101] proposed that this species seems to
stimulate migration of interleukins and leucocytes to painful and
inflamed joints. An extract of H. procumbens showed anti-
inflammatory and antinociceptive effects in rats with Freund’s
adjuvant-induced arthritis in both the acute and chronic phases
[102].
Iridoid glycosides have been considered as the active
constituents in H. procumbens and several studies have been
completed to assess their anti-inflammatory activity. An in vitro
study with Ca2+ ionophore A23187-stimulated human whole blood
has revealed an inhibition of the biosynthesis of cysteinyl-
leukotrienes and TBX2 by H. procumbens extracts as a function of
their harpagoside (19) concentration [103]. Another whole-blood
assay revealed that a high harpagoside-containing fraction inhibited
COX-1 (37.2%), COX-2 (29.5%) and NO production (66%) [104].
Boje et al. [105] determined the ability of aqueous H. procumbens
and H. zeyheri extracts and several iridoid and phenylethanoid
glycosides to inhibit human leukocyte elastase in vitro. The release
of elastase and other proteinases from macrophages and neutrophils
is part of the inflammatory process and leucocyte elastase is found
in inflamed tissue. Low IC50 values of 542 and 1012 µg/ml for H.
procumbens and H. zeyheri water extracts, respectively, were noted.
The acteosides were more active than the iridoid compounds.
Pagoside (22) had an IC50 value of 260 µM and harpagoside (19)
was less active with values in excess of 500 µg/ml-800 µg/ml [105].
Interestingly, Zhang et al. [44] found that the hydrolysed products
of harpagide and harpagoside had a significant COX-2 inhibitory
activity (2.5-100µM) where unhydrolysed harpagide and
harpagoside did not. Therefore, the hydrolysis of the glycosidic
bonds of harpagide and harpagoside by β-glucosidase is a
prerequisite step for activity. A recent study by Gyourkovska et al.
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2111
[106] reported anti-inflammatory action from extracts and
preparations of in vitro cultured H. procumbens. Several fractions
as well as pure compounds showed inhibitory action at a
concentration of 1 mg/ml. The strongest activity was noted for
verbascoside followed by the iridoid glycosides harpagide and
harpagoside. Cytotoxicity assays revealed harpagide (1 mg/ml) as
the most toxic compound which raises concern as it is present in
commercial formulations [106].
The use of H . procumbens is approved in German Commission
E and European Scientific Cooperative on Phytotherapy (ESCOP)
monographs. In contrast to the other species in this review, more
than 20 clinical studies using H. procumbens to treat lower back
pain, osteoarthritis and arthritis have been published. In most cases,
4 weeks of treatment improved the pain index considerably. One
such example of a study assessed the treatment of patients (n=75)
with arthrosis of the hip or knee. For 12 weeks two tablets (400 mg
aqueous extract/tablet) three times daily corresponding to a total of
2400 mg containing 50 mg iridoid glycosides calculated as
harpagoside was administered. There was a strong reduction in the
pain and symptoms of osteoarthritis. Pain scores (actual, worst,
average, total) reduced by 22.6-25.8% and there was an
improvement on clinical findings such as pain on palpation
(45.5%), limitation of mobility (35%) and joint crepitus (25.4%).
Adverse events such as dyspeptic complaints (2), sensation of
fullness (1) and panic attack (1) were reported in only four patients
[107]. A systematic review on the use of H. procumbens for
osteoarthritis and lower back pain revealed effectivity on
administration of powder, as well as ethanolic and aqueous extracts
with doses containing 50-100 mg of harpagoside [108].
3.11. Himatanthus sucuuba (Sucuba; Janaguba)
Himatanthus sucuuba (Spruce ex Müll.Arg.) Woodson
(Apocynaceae), a tree found in the Amazon rain forest, is a well-
known remedy to treat various ailments. In Perú, an infusion from
the stem bark has been used as a wound-healing agent, vermifuge
laxative and hallucinogen, as well as for the treatment of tumours,
boils, oedema and arthritis. In Brazil, infusions, decoctions,
poultices and the latex of the bark are used in folk medicine for the
treatment of gastritis, inflammation, anaemia, arthritis, verminosis
and tumours [109]. The Caboclos in the Amazon use the dried stem
bark for its analgesic and anti-tussive activities. Phytochemical
studies led to the isolation of triterpene esters with anti-
inflammatory activity and iridoids with cytotoxic activity [110].
Silva et al. [111] demonstrated that plumericin and isoplumericin
may be associated with DNA damage.
The latex, bark, leaves and roots have been shown to contain
several iridoids namely plumericin, isoplumericin, plumieride,
isoplumieride, 15-demethylisoplumieride, 15-dimethylplumieride,
fulvoplumierin, b-dihydroplumericin and allamandin [110].
However, only plumericin (23) and isoplumericin (24) have been
shown to possess anti-inflammatory activity [111].
3.12. Kigelia africana (Sausage tree)
Kigelia africana (Lam.) Benth. (Bignoniaceae) is a tropical
tree, widely distributed in south, central and west Africa, used in
folk medicine [112]. Traditionally, dried fruits are used to prepare
emollients for topical application to treat psoriasis and eczema.
Extracts from the root bark are used to treat venereal disease and
naphtoquinones extracted from K. africana exhibited anti-
trypanosomal, antimicrobial and anti-tumour activities against
melanoma and renal carcinoma cells [112-113].
Analysis of a polar extract of the fruit confirmed the presence
of verminoside (25), an iridoid glycoside, as a major constituent, as
well as a series of polyphenols such as verbascoside. In vitro assays
confirmed that verminoside had significant anti-inflammatory
effects, inhibiting both iNOS expression and NO release in the
LPS-induced J774.A1 macrophage cell line [114]. Using the
carrageenan-induced paw oedema model in rats, as well as the
acetic acid-induced writhing, hot plate and formalin-induced paw
licking models in mice, Carey et al. [115] reports that the flower
extract exhibited significant anti-inflammatory and analgesic
activities at doses of 100, 200 and 400 mg/kg body weight in rats
and mice. It is reported that verminoside (25) isolated from K.
africana, exhibits cytotoxic activity in the concentration range of
70-355 µM. Additionally, apoptotic cell death due to verminoside
was observed during histological analysis of the tested cell lines
[116]. Hassan et al. [112] reports that K. africana extracts have
significant wound-healing properties observing a rapid reduction in
exudation and scab formation, classical signs of inflammation. The
study also reported that the lethal dose of the leaf extract is greater
than 3 g/kg; this suggests that K. africana is safe to be consumed
for the treatment of various ailments. It is proposed that the
mechanism of action of the leaf extracts may be due to its
angiogenic and mitogenic potential leading to increased cellular
proliferation and collagen synthesis [112]. This may assist in scar
tissue formation and reperfusion of the injured site, thus resolving
the sequela of inflammation.
3.13. Lamiophlomis rotata (Duyiwei)
Lamiophlomis rotata (Benth. ex Hook. f.) Kudô is a perennial
Lamiaceous herb growing in the Qinghai-Tibet Plateau in
northwestern China. For centuries L. rotata has been used as one of
the traditional drugs in Tibetan, Mongolian and Naxi nations for
detumescence, haemostasis, pain alleviation, blood circulation
promotion and bone marrow regeneration [117].
Iridoids and flavonoids have been isolated from the aerial parts
and roots of L. rotata. 8-O-Acetylshanzhiside methylester, 6-O-
acetylshanzhiside methylester, shanzhiside methylester, 8-
deoxyshanzhiside, sesamoside, loganin, penstemoside, phlomiol,
7,8-dehydropenstemoside, phloyoside I, phloyoside II,
lamiophlomiside, phlorigidoside C, have all been isolated from the
species in the past twenty years [117]. Only loganin (8), an iridoid
glycoside, has been demonstrated to possess anti-inflammatory
activity. In a recent study, the anti-inflammatory activity of L.
rotata was determined by cotton pellet-induced granuloma
formation in rats and xylene-induced ear oedema in mice.
Lamiophlomis rotata injection at 0.45, 0.9 and 1.8 g/kg caused a
dose-dependent inhibition of ear oedema induced by xylene
equivalent to 43.87-68.16% protection and 13.26-43.33%
protection in cotton pellet-induced granuloma at the doses of 0.225
and 0.45 g/kg, respectively. Lamiophlomis rotata injection
increased phagocytosis by mouse peritoneal macrophages, and
decreased the LPS-induced production of IL-1 [118].
3.14. Mentzelia chilensis (Blazing star; Angurate)
Mentzelia scabra subsp. chilensis Gay (Loasaceae) is a shrub
widespread in South America (Peru, Chile and Bolivia). The aerial
parts have cicatrizant, choleretic and antihelminthic properties
[119]. A crude aqueous extract of M. chilensis showed anti-
inflammatory activity in the carrageenan-induced rat-paw oedema
model. Bioassay-guided isolation yielded the iridoid glycoside,
mentzeloside (syn. deutzioside), as an active principle.
Mentzeloside (26) showed a marked and significant dose-dependent
inhibitory activity on carrageenan-induced rat-paw oedema with an
ED50 of 40.4 µg/kg [120].
3.15. Phillyrea latifolia (Mock privet)
Phillyrea latifolia L. (Oleaceae) is mainly found in the
Mediterranean coastal region. Dioscorides (1st century BC)
described the medicinal use of the leaves of privet, which were
2112 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
chewed to offer relief of oropharyngeal inflammation, while a
decoction of the aerial parts was claimed to be active against burns
and headaches [121]. Despite the known anti-inflammatory activity
of the species, P. latifolia is cited rarely in ethnobotanical literature,
the use of the leaves seems to survive still in some areas of South
West Sardinia Latium and in Morocco for diuretic, spasmolytic and
diaphoretic purposes. Moreover, the fruits of P. latifolia were once
eaten in South Europe [121-122]. Diaz et al. [123] tested two
iridoid glycosides, oleuropeoside (27) and ligustroside (28) isolated
from P. latifolia for activity against the COX and 5-lipoxygenase
(5-LOX) mediated arachidonate metabolism in calcium ionophore-
stimulated mouse peritoneal macrophages and human platelets, and
for their effect on cell viability. Oleuropeoside (IC50=47 µM) and
ligustroside (IC50=48.53 µM) showed a significant effect on PGE2
release, with inhibition percentages similar to the reference drug
indomethacin (IC50=0.95 µM). The effect on TXB2 release induced
by calcium ionophore in human platelets was also investigated.
Ligustroside (IC50=122.63 µM) showed a significant effect,
although with less potency when compared to the reference drug
ibuprofen (IC50=1.27 µM) [123].
3.16. Picrorhiza kurroa (Katurohini; Kutki)
Picrorhiza kurroa Royle ex Benth. (Scrophulariaceae) grows in
the northwestern Himalayan region and is utilised in India as part of
Ayurvedic medicine for the treatment of jaundice, indigestion,
common fever, acute viral hepatitis and bronchial asthma. The root
is considered to be a valuable bitter tonic, cholagogue and laxative
in small doses. In addition, it is useful to treat gastrointestinal and
urinary disorders, leukoderma, snake bite, scorpion sting and
inflammatory disorders. Pharmacological studies have revealed
hepatoprotective, anti-inflammatory, anti-asthma,
immunostimulatory and free radical scavenging activities [124].
Picrorhiza kurroa contains iridoid glycosides such as picroside-I;
picroside-II; picroside-IV, picroside-V, kutkoside, minecoside,
veronicoside, 6, O-trans-ferulloyl catalpol, 6-O-cis-ferulloyl
catalpol, pikuroside, as well as cucurbitacin glycosides and
phenolic compounds [125].
A 50% ethanolic extract of P. kurroa was found to stimulate the
cell-mediated and humoral components of the immune system as
well as phagocytosis in experimental animals [124]. Anti-
inflammatory activity was observed for kutkin (a mixture of
kutkosides and picrosides) in experimentally induced arthritis,
oedema, vascular permeability, and leukocyte migration in rodents
[126]. Aucubin (14) was also shown to inhibit phorbolester-induced
oedema in mice ears, while catalpol (15) and picroside II (29) were
not active (100 mg/kg p.o.). The latter iridoids showed only minor
anti-inflammatory effects upon topical administration [43].
Moderate anti-inflammatory activity of picroside II (29), when
administered topically, was confirmed later, while pikuroside was
ineffective [127]. Picrosides II (29), III (30), V (31), 6-
feruloylcatalpol (32) and minecoside (33) moderately inhibited
chemiluminescence generated by activated polymorphonuclear
neutrophils (PMNs); scavenging effects of these compounds were
excluded. Picroliv, an iridoid glycoside mixture containing
picroside I (34) and kutkoside (35), was shown to be moderate
superoxide scavengers, while kutkoside alone showed only weak
activity [128]. Furthermore, Picroliv (34 & 35) protected cells
against hypoxia, enhanced the expression of vascular endothelial
growth factor and hypoxia inducible factor-1, selectively inhibited
protein tyrosine kinase activity, and reduced protein kinase C [129].
3.17. Plantago asiatica (Chinese Plantain; Arnoglossa)
Plantago asiatica L. belongs to the Plantaginaceae and has a
history of use for the treatment of many conditions such as
bronchitis, diarrhoea, constipation and wounds. This herbal
medicine has also been shown to exhibit antileukaemia,
anticarcinoma and antiviral activities, as well as activities which
modulate cell-mediated immunity. The seeds of P. asiatica were
regarded as a traditional medicine in ancient Chinese medical
literature. Its chemical components, including phenylethanoid
glycosides, phenolics and various polysaccharides have been
widely studied. Aucubin (14) is an iridoid glycoside that has been
isolated from P. asiatica [130]. Shim et al. [83] investigated the
effects of 0.1% aucubin on oral wound-healing. Re-epithelisation
and matrix formation of the aucubin-treated group occurred earlier
and the number of inflammatory cells was fewer than that of the
control group. Thus aucubin may be applied as a topical agent to
accelerate the healing of oral wounds.
RAW 264.7 cells were used by Kyoung and Chang [131] to
elucidate the mechanism of action of aucubin and its hydrolysed
product produced by β-glucosidase treatment. The hydrolysed
product suppressed m-RNA expression for both the TNF-α and
subsequent TNF-α protein, whereas aucubin did not. This occurred
in a dose-dependent manner with an IC50 value of 9.2 µM.
Additionally, the hydrolysed product blocked both I-κBα
degradation and the translocation of NF-κB from the cytosol
fraction to the nuclear fraction (55% inhibition). Treatment with
hydrolysed aucubin did not affect the intracellular level of cAMP
formed by forskolin treatment in human monocytes U937 culture,
implying that there is no influence on the cAMP level in other cell
systems [131].
3.18. Rehmannia glutinosa (Chinese foxglove)
Rehmannia glutinosa Steud. which belongs to the
Scrophulariaceae is a medicinal herb that is believed to maintain
haemostasis, promote blood circulation and improve kidney
function. Traditionally, the steamed root of the plant is used to treat
allergic inflammatory diseases such as contact dermatitis and
rhinitis. Mite allergen-treated NC/NGa mice were treated with an
ethanol extract to observe its effect on skin inflammation. In vitro
tests revealed a decrease in the mRNA expression of Il-4, TNF-α,
VCAM-1 and ICAM-1 as well as a decrease in dermal thickening
and infiltration by inflammatory cells. In addition, ear thickness and
serum histamine levels were significantly reduced in vivo [132].
Catalpol (15), an iridoid glycoside, isolated from the species, has
been verified to be neuroprotective and may be a potential agent for
the treatment of neurodegenerative disease [133]. Glia-mediated
inflammation is significant in the pathogenesis of Alzheimer's
disease. Catalpol (15) reduces the release of inflammatory factors
including TNF-α, ROS, NO and iNOS, which accelerates the
progression of Alzheimer's disease.
3.19. Russelia equisetiformis (Firecracker, coral plant)
Russelia equisetiformis (Schltdl. & Cham.) belongs to the
Scrophulariaceae family. This small tree, native to tropical
America, is commonly used for ornamental and slope protection
purposes. It is reported that the plant is traditionally used in Nigeria
for the treatment of diabetes, leukemia and pain and inflammation.
Scientific studies have revealed analgesic, anti-inflammatory,
antimicrobial, free radical scavenging and membrane-stabilising
activity [134-136]. Whole organic plant extracts and isolated
phenolic compounds exhibited antinociceptive activity in male
Swiss mice [134] in both the writhing and tail-flick tests. Oral
administration of a methanol extract (100 mg/kg) showed
significant inhibition or reduction in both egg albumin and agar-
induced paw oedema in female albino Wistar rats, comparable to
indomethacin (5 mg/kg). The authors suggested a possible
mechanism of action through inhibition of pro-inflammatory
mediators. In addition, free radical scavenging and anti-oxidant
properties were found [135]. A new iridoid glycoside, 10-O-
cinnamoyl sinuatol (36), was isolated from a leaf extract of R.
equisetiformis together with 24 known compounds including
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2113
iridoid, phenyl propane, lignin and flavonoid glycosides as well as
phenyl ethanoids. Mild alkaline hydrolysis of 10-O-cinnamoyl
sinuatol yields sinuatol which has previously been isolated from
Verbascum sinuatum. The isolated compounds, including
rehmaglutin B (37), catalpol (15), 6-O-cis-p-coumaroylcatalpol, and
verminoside (25) amongst others were assayed for their inhibitory
activity towards NO production in vitro using RAW 264.7 cells.
The iridoid compounds verminoside (±8%) (25) and rehmaglutin B
(70%) (37) showed NO inhibitory activity at 100 µM and
rehmaglutin B (IC50 = 52.8±2.0 µM) inhibited NO production more
strongly than the control (L-NMMA) [136].
3.20. Scrophularia auriculata (Water figwort)
Scrophularia auriculata L. ssp. pseudoauriculata
(Scrophulariaceae) is a Mediterranean plant used in folk medicine
to treat inflammatory skin diseases. Two iridoid glycosides,
scropolioside A (38) and scrovalentinoside (39), isolated from the
species have been described as anti-inflammatory and
immunomodulatory compounds. Scropolioside A (38) showed anti-
inflammatory properties against different experimental models of
delayed-type hypersensitivity. Scropolioside A (38) reduces
oedema both in vivo and in vitro. In vivo, it reduced oxazolone-
induced oedema by 79% (0.5 mg/ear) and in vitro, by 43% (10
mg/kg) in ovine red blood cells. In vivo it reduced both oedema
formation and cell infiltration whereas in vitro it reduced the
proliferation of activated T-lymphocytes with an IC50 value of
67.74 µM [39]. Scropolioside A (38) inhibited the production of
PGE2, leukotriene B4, NO, IL-1β, IL-2, IL-4, TNF-α and interferon-
γ, but has no effect on the production of IL-10. Moreover,
Scropolioside A (38) modified the expression of both nitric oxide
synthase-2 and COX-2, as well as the activated NF-κB in RAW
264.7 macrophages [40].
3.21. Scrophularia deserti (Afinah, Zetah, Maseelah)
Scrophularia deserti Delile (Scrophulariaceae) is the most
common figwort found in Kuwait and is fairly abundant in
limestone-rich areas [137]. It is also found in Saudi Arabia, where it
is used as an antipyretic, a remedy for kidney diseases, cardiotonic,
hypoglycaemic, as a diuretic in typhoid fever, to treat galactorrhoea
and inflammation of the mouth, lungs, large intestine, bladder, and
heart, as well as a remedy for tumours, abscesses, cancer of the
lung, goiter, and aching bones [138]. Ahmed et al. [138] isolated
five iridoid glycosides, including two “new” compounds
scropolioside-D2 (40) and harpagoside-B, from the aerial parts of S.
deserti which were found to possess significant antidiabetic and
anti-inflammatory activity, respectively. However, in 2007 Jensen
and co-workers [139] demonstrated that the structure proposed as
harpagoside-B by Ahmed et al. [138] is structurally identical to
harpagoside (19). When tested on carrageenan-induced rat-paw
oedema at a dose of 10 mg/kg, harpagoside (=harpagoside-B) and
the iridoid diglycoside koelzioside (41) were the most active
compounds and showed a decrease in oedema by 30% and 26%
respectively after 3 h [138]. These results allowed the researchers to
speculate on possible structure activity relationships (SAR) as the
two most active compounds both has cinnamoyl moieties in place
of acetyl groups.
3.22. Scrophularia frutescens
The Scrophulariaceae is represented by several iridoid-
containing genera such as Scrophularia with many species
accumulating high levels of harpagoside (19). This iridoid
glycoside has found wide use in clinical practice for the treatment
of pain in the joints and lower back for its neuroprotective and anti-
inflammation activities [140]. An aqueous and methanolic extract
together with harpagoside (19) obtained from Scrophularia
frutescens were tested for anti-inflammatory activity using the rat-
paw oedema assay. The aqueous extract exhibited a low yet
significant anti-inflammatory effect on carrageenan-induced
oedema, while the methanolic extract produced lower anti-
inflammatory activity. The activity of the isolated harpagoside (19)
was negligible in the same assay leading the authors to conclude
that the observed anti-inflammatory activity may not be ascribed to
harpagoside alone [141]. This finding concurs with Zhang et al.
[44] who reported that harpagoside had no effect on COX-1/2
enzyme activity, TNF-α release and NO production in vitro.
However, after treating harpagoside with β-glucosidase, the
hydrolysed product, H-harpagide showed a significant inhibitory
effect on COX-2 at 2.5-100 µM in a concentration-dependent
manner. It is noteworthy that this hydrolysed product has a
backbone similar to commercially available COX-2 inhibitors such
as celecoxib. Although this review is acutely focused on iridoids
one needs to be cognisant of other phytochemicals which may elicit
an anti-inflammatory response, either alone or in combination with
iridoids.
3.23. Scrophularia scorodonia (Balm-leaved figwort)
Scrophularia scorodonia L. is widespread in the southwestern
parts of Spain and in the northwest of Africa [142]. Seven iridoid
glycosides isolated from different extracts of S. scorodonia,
namely, aucubin (14), harpagoside (19), harpagide (20), 8-
acetylharpagide (42), scorodioside (43), scropolioside B (44) and
bartsioside (45), were evaluated for their in vitro anti-inflammatory
activity in cellular systems generating COX and LOX metabolites.
Most compounds assayed did not exhibit a significant effect on
PGE2 and LTC-4 release from calcium ionophore-stimulated mouse
peritoneal macrophages. In the LTC-4 assay, only aucubin (14)
showed a significant effect, with an IC50 value of 72 µM.
Harpagoside (19) and harpagide (20) also inhibited release of LTC-
4. The release of PGE2 by mouse peritoneal macrophages
stimulated with calcium ionophore was inhibited by harpagoside
(19) and 8-acetylharpagide (42). Most iridoids assayed showed a
significant effect on TXB2 release from calcium ionophore-
stimulated human platelets, with inhibition percentages slightly
lower than the reference drug ibuprofen. Harpagide (20),
scorodioside (43) and scropolioside B (44) had no significant effect
on TXB2 release. These findings indicate that selective inhibition of
the TX-synthase enzyme may be the primary target of action of
most of these iridoids, and one of the mechanisms through which
they may exert their anti-inflammatory effects [143].
3.24. Sideritis perfoliata (Mountain tea)
Sideritis perfoliata L. subsp. perfoliata is a plant widely used in
folk medicine in Greece mainly for its anti-inflammatory, anti-
rheumatic, antiulcer, digestive and vasoprotective properties. The
genus Sideritis comprises more than 150 perennial and annual
species distributed in the Mediterranean area. The infrageneric
taxonomy is complex due to hybridisation events. Traditionally, it
is consumed as a herbal tea, used as a flavouring agent and
extensively used in folk medicine as an anti-inflammatory, anti-
ulcerative, antimicrobial, vulnerary, anti-oxidant, antispasmodic,
anticonvulsant, analgesic and carminative. Phytochemical studies of
the polar extracts afforded four flavonoid glycosides, four
phenylpropanoic glycosides, caffeic acid and one iridoid, ajugoside
(46) [144]. These compounds were evaluated for their anti-oxidant
activity (DPPH assay) as well as for their anti-inflammatory activity
using the soybean lipoxygenase bioassay. All extracts and isolated
compounds showed significant anti-oxidant and inhibitory activity
against soybean lipoxygenase. Ajugoside (46) however, was one of
the least active molecules tested [144].
3.25. Stachytarpheta cayennensis (Brazillian tea)
Stachytarpheta cayennensis (Rich.) Vahl (Verbenaceae) is
widely spread throughout tropical and suptropical America where it
2114 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
is extensively used in Brazilian folk medicine as an anti-
inflammatory, analgesic, antipyretic, hepatoprotective, laxative and
to treat gastric disturbances. This species has an extensive
ethnobotanical history of use by the Caboclo inhabiting the Marajo
island in the Amazon delta. Several of the traditional uses allude to
anti-inflammatory properties and in the early nineties
Stachytarpheta cayennensis was one of four species recommended
by the United Nations Development Programme for possible
pharmaceutical development [145]. A tea prepared from the dried
leaves or a tincture is used to treat gastrointestinal diseases and
pain. Topical application of the macerated leaves and roots is used
to treat skin wounds [146]. Penido et al. [147] assessed the anti-
inflammatory properties of ethanolic extracts of S. cayennesis.
Chromatographic analysis of the crude ethanolic extract revealed
high concentrations of the iridoid ipolamiide (47). The oral
administration of the extract (100 mg/kg) to Swiss albino mice
failed to inhibit paw oedema and pleural exudation induced by
carrageenan and zymosan. Ipolamiide (47) inhibited total leukocyte
accumulation into the pleural cavity 4 and 24 h after the
intrathoracic injection of carrageenan, due to the inhibition of
neutrophil and mononuclear cell influx. Ipolamiide also selectively
inhibited neutrophil influx. A structurally related compound,
lamiide (5) which is devoid of the C7-OH group, was also reported
to possess dose-dependent anti-inflammatory activity (79%) against
carrageenan-induced oedema [56] in similar experimental protocols
and at the same dose levels.
Schapoval et al. [146] investigated the alcoholic and n-
butanolic extracts of dried leaves of S. cayennensis in anti-
inflammatory and antinociceptive models. Intraperitoneal
pretreatment with the dried extracts at doses ranging from 100 to
200 mg/kg, significantly inhibited carrageenan-induced
inflammation. The active extracts were fractionated and monitored
using the same bioassay. The iridoid ipolamiide (47) and the
phenylethanoid glycoside acteoside were isolated from the active
fraction and showed an inhibitory effect on histamine- and
bradykinin-induced contractions of guinea-pig ileum. Ipolamiide
(47) and acteoside also showed in vivo anti-inflammatory activity
when administered orally to rats mainly in the fourth hour after the
administration of the phlogistic agent, 70.22% and 93.99%,
respectively. An adverse effect of many NSAIDs is gastric
disturbances. As a secondary objective the authors explored the
rationale for the traditional use of S. cayennensis to treat gastric
disorders and ulcers. The in vivo model proved that an extract
protected the gastric mucosa against damage caused by diclofenac,
a classic NSAID [148].
3.26. Syringa species
The term folium syringae is used to collectively refer to the
leaves of several species of Syringa (Oleaceae) such as S. oblata, S.
ditaata S. vulgaris and S. chinensis. These species are popular
ornamental and holticultural bushes cultivated in Eurasia and North
America. Folium syringae have been used as a folk medicine to
treat inflammatory diseases, especially intestinal inflammations
such as acute enteritis, icteric hepatitis, acute mastitis, bacillary
dysentery and upper respiratory tract infection in China. Two
folium syringae preparations have been listed in the Drug Standard
of the Ministry of Public Health of China. Phytochemical studies
demonstrated that iridoid glycosides are the main active fraction of
the leaves. The iridoid glycoside, syringopicroside (48), is the main
active constituent and has been shown to possess anti-
inflammatory, broad-spectrum antimicrobial, antiviral, and immune
enhancement effects [149-150].
Liu and Wang [150] investigated the anti-inflammatory effects
of the iridoid glycoside fraction of folium syringae leaves on
TNBS-induced colitis in rats. Ulcerative colitis was induced
through rectal administration of TNBS. The iridoid glycoside
fraction (80, 160, 240 mg/kg) was orally administered (10 ml/kg)
twice daily 24 h after colitis was established. Treatment with the
iridoid glycoside fraction (containing 55.74% syringopicroside)
suppressed pathological symptoms caused by TNBS and dose-
dependently inhibited the elevated level of NO, in fact, the 240
mg/kg dose exhibited better therapeutic effects compared to the
positive control salicylazosulfapyridine (SASP). Myeloperoxidase
(MPO) activity was reduced and malondialdehyde (MDA) levels
were suppressed indicating that this fraction successfully scavenges
oxidative free radicals. In addition, the fraction effectively inhibited
the protein and mRNA expressions of the pro-inflammatory
cytokines NF-κBp65, TNF-α and IL-6 in a dose-dependent manner
[150].
In a follow up study, Liu and Wang [157] determined that this
fraction dose-dependently depressed the levels of the pro-
inflammatory cytokines TNF-α and IL-8, the inflammatory protein
COX-2, and TGF-1β levels in the colon tissues. It significantly
blocked NF-κB signaling by inhibiting IκBα phosphorylation/
degradation and IKK-β (inhibitor of NF-κB) activity. In addition,
it down-regulated the protein and mRNA expressions of Fas/FasL,
Bax and caspase-3, and activated Bcl-2 in intestinal epithelial cells.
Administration of this syringopicroside-rich fraction resulted in
marked protective effects on dextran sulfate sodium (DSS)-induced
colitis through inhibition of intestinal epithelial cell (IEC) apoptosis
and blockade of the NF-κB signal pathway [151].
3.27. Verbascum species (Mullein)
Extracts, decoctions and infusions prepared from Verbascum
species (commonly known as “mullein”) have an illustrious history
of traditional use, especially for the treatment of respiratory
disorders. It is believed that the extracts exert their activity through
expectorant, mucolytic and demulcent properties. Verbascum
flowers are boiled in milk and are applied externally for pruritic
conditions affecting the urogenital organs. Several species are
specifically used in Turkey and said to be mildly diuretic and to
have a soothing and anti-inflammatory effect on the urinary tract, in
addition to acting as a mild sedative [152-153]. Oil prepared from
the flowers is used to soothe earache, and can be applied externally
to treat eczema and other types of inflammatory skin conditions
[154].
A methanolic extract of the flowers of Verbascum lasianthum
Boiss. (Scrophulariaceae) was shown to possess significant
inhibitory activity in the carrageenan-induced hind paw oedema
model and in p-benzoquinone-induced writhings in mice. Through
bioassay-guided fractionation several compounds, including
aucubin (14), catalpol (15), geniposidic acid (17) and ajugol (49)
were isolated which have been shown in previous studies to have
anti-inflammatory activity. Orally administered ucubin (14) was
found to possess significant antinociceptive and anti-inflammatory
activities without inducing any apparent acute toxicity or gastric
damage [155].
Verbascum mucronatum Lam. is used as haemostatic in Turkish
folk medicine and exhibits anti- inflammatory, antinociceptive and
wound healing properties [152]. The aqueous extract (200 mg/kg)
of V. mucronatum produced an anti-inflammatory effect
comparable to indomethacin (10 mg/kg) in the carrageenan-induced
hind paw oedema model [156]. Through assay-guided fractionation,
catalpol (15), ajugol (49), lasianthoside (50), picroside IV (51) and
two saponins, ilwensisaponin A and C verbascoside were isolated.
In the same study the in vivo wound-healing activity of V.
mucronatum was evaluated by linear incision and circular excision
experimental models and subsequent histopathological analysis.
The healing potential was comparatively assessed with a reference
ointment Madecassol® which contains a 1% extract of Centella
asiatica. Verbascum mucronatum was found to accelerate the
wound-healing processes (inflammation, proliferation and re-
modeling), confirming the widespread use of this species in
traditional medicine [156].
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2115
Table 1. Summary of Iridoid-Containing Plant Species Investigated for Anti-Inflammatory Properties
Species Name
Plant
Part(s)
Used
Isolated Iridoid Glycoside
Common Uses /
Biological Activity
In vitro
Studies
In vivo
Studies
Proposed Mechanism of Action
References
Ajuga bracteosa Wall.
ex Benth. (Lamiaceae)
Whole
plant
6-deoxyharpagide (1);
raptoside (2)
Hepatitis; pneumonia;
bone disease
Yes
Yes
COX-2 inhibition.
[46-48]
Boschniakia rossica
(Cham. & Schltdl.)
Standl.
(Orobanchaceae)
Whole
plant
Boschnaloside (3); 8-
epideoxyloganic acid (4)
Antisenile agent
Yes
Yes
TNF-α, iNOS, COX-2 inhibtion.
[49-53]
Bouchea fluminensis
(Vell.) Moldence
(Verbenaceae)
Aerial
parts
Lamiide (5)
Bowel stimulator; anti-
inflammatory agent
Yes
Yes
Inhibition of phospholipid
peroxidation and free radical
scavenging activity.
[56-58]
Catalpa ovata G. Don.
(Bignoniaceae)
Stem
Catalposide (6)
Anti-inflammatory agent
Yes
Yes
Inhibition of the production of TNF-
α and NO with significant decreases
in mRNA levels of TNF-α and
inducible NO synthase.
Attenuates the induction of intestinal
epithelial pro-inflammatory gene
expression and reduces the severity
of trinitrobenzene sulfonic acid-
induced colitis in mice.
Inhibits the production of tumour
necrosis factor-α (TNF-α),
interleukin-1 (IL-1), and interleukin-
6 (IL-6), and the activation of
nuclear factor-В.
[64-67]
Cornus officinalis
Siebold et Zucc
(Cornaceae)
Fruit
Cornel iridoid glycoside
(CIG); morroniside (7);
loganin (8); cornuside (10);
7-O-cinnamoyl-
morroniside (11 )
Anti-inflammatory and
haemostasis-promoting
agent
Yes
Yes
Ihibition of IL-1, IL-6, TNF-α,
PGE2, iNOS and E-selectin
expression, NO production, NFκB
and COX-2.
Suppression of ICAM-1, VCAM-1
and MCP-1.
[68-76]
Enicostema axillare
(Lam.) A.Raynal
(Gentianaceae)
Whole
plant
Swertiamarin (12)
Diabetes mellitus;
rheumatism; ulcers;
hernia; swelling; itching
and anti-inflammatory
agent
Yes
Yes
Anti-oxidant and hepatoprotective.
Inhibits TBX2.
[45; 77-79]
Eucommia ulmoides
Oliv. (Eucommiaceae)
Bark
and
leaves
Aucubin (14); Genipin
(16);
Diabetes mellitus;
hypertension; anti-
oxidant and anti-
inflammatory agent
Yes
Yes
Concentration-dependent inhibition
on lipid peroxidation induced by
Fe2+/ascorbate.
Concentration-dependent inhibition
of NO production and iNOS
expression upon stimulation by
lipopolysaccharide / interferon-g.
Blockage of lipopolysaccharide
indicating that it exhibits inhibitory
effect on NO production through the
inhibition of NFK-B activation.
Promotes wound healing.
[80-83]
Gardenia jasminoides
J.Ellis (Rubiaceae)
Fruit
Geniposide (13); Genipin
(16)
Sedative; diuretic;
cholagogue;
antiphlogistic; anti-
inflammatory; anti-
oxidant and anti-
thrombotic agent
Yes
Yes
Inhibition of lipopolysaccharide-
stimulated iNOS expression or
COX-2 promoter activity.
[84-92]
Gentiana lutea L.
(Gentianaceae)
Roots
Gentiopicroside (18)
Gastric stimulation and
anti-inflammatory agent
No
Yes
Reversal of NR2B over-expression
during the chronic phases of
persistent inflammation caused by
hind paw administration of complete
Freund’s adjuvant.
[45; 93-95]
2116 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
(Table 1). Contd…..
Species Name
Plant
Part(s)
Used
Isolated Iridoid Glycoside
Common Uses /
Biological Activity
In vitro
Studies
In vivo
Studies
Proposed Mechanism of Action
References
Harpagophytum
procumbens (Burch.)
DC. ex Meisn. subsp.
procumbens
(Pedaliaceae)
Secondary
tubers
Harpagoside (19);
harpagide (20); 8-
coumaroyl-harpagide (21);
pagoside (22)
Rheumatism; arthritis;
sores; ulcers and boils
Yes
No
Inhibition of the biosynthesis of
cysteinyl-leukotrienes and TBX2.
Suppression PGE2 synthesis and NO
production by inhibiting LPS-
stimulated enhancement of the
COXe-2 and iNOS mRNAs
expressions.
[44; 96-
108]
Himatanthus sucuuba
(Spruce ex Müll. Arg.)
Woodson
(Apocynaceae)
Bark;
latex;
leaves
Plumericin (23);
isoplumericin (24)
Wound healing; laxative;
hallocinogen; tumours;
boils; oedema; arthritis;
gastritis; verminosis
No
Yes
-
[109-111]
Kigelia africana
(Lam.) Benth.
(Bignoniaceae)
Bark;
Fruit;
Flower
Verminoside (25)
Psoriasis; eczema;
venereal disease
Yes
Yes
Verminoside inhibits iNOS
expression and NO release in the
LPS induced J774.A1 macrophage
cell line.
[112-116]
Lamiophlomis rotate
(Benth. ex Hook. f)
(Lamiaceae)
Aerial
parts;
roots
Loganin (8) (and others)
Detumescence;
haemostasis; pain
alleviation; blood
circulation promotion
Yes
Yes
Lamiophlomis rotata injection
increased phagocytosis by mouse
peritoneal macrophages, and
decreased the LPS-induced
production of IL-1.
[117-118]
Mentzelia scabra
subsp. chilensis (Gay)
Weigend (Loasaceae)
Aerial
parts
Mentzeloside (syn.
deutzioside) (26)
Gastric ulcers; helminth
infections
No
Yes
Dose-dependent inhibitory activity
on carrageenan induced rat-paw
oedema.
[119-120]
Phillyrea latifolia L.
(Oleaceae)
Aerial
parts
Oleuropeoside (27);
ligustroside (28)
Oropharyngeal
inflammation; burns;
headaches
Yes
No
Inhibition of PGE2 release.
[121-123]
Picrorhiza kurroa
Royle ex Benth.
(Scrophulariaceae)
Root
Picroside II (29); picroside
III (30); picroside V (31);
6-feruloyl catalpol (32);
picroside I (34); kutkoside
(35)
Jaundice; indigestion;
common fever; acute
viral hepatitis and
bronchial asthma
Yes
Yes
Stimulation of the cell-mediated and
humoral components of the immune
system.
[43; 124-
129]
Plantago asiatica L.
(Plantaginaceae)
Seeds
Aucubin (14)
Bronchitis; diarrhoea;
constipation, wounds
No
Yes
Oral wound healing.
[83; 130-
131]
Rehmannia glutinosa
Steud.
(Scrophulariaceae)
Root
Catalpol (15)
Contact dermatis and
rhinitis; promotes blood
circulation; improves
kidney function
Yes
Yes
Inhibition of the secretion of both
TNF-α and IL-1.
Neuroprotective by attenuating LPS-
induced the expression of iNOS.
[132-133]
Russelia
equisetiformis
(Schltdl. & Cham.)
Whole
plant
10-O-cinnamoyl sinuatol
(36)
Diabetes; leukemia; pain
and inflammation
Yes
Yes
Inhibition of pro-inflammatory
mediators.
[134-136]
Scrophularia
auriculata ssp.
pseudoauriculata,
(Scrophulariaceae)
Aerial
parts
Scropolioside A (38);
scrovalentinoside (39)
Inflammatory skin
diseases
Yes
Yes
In vivo scropolioside A reduces both
oedema formation and cell
infiltration whereas in vitro it
reduces the proliferation of activated
T-lymphocytes.
Inhibition of the production of PGE2,
leukotriene B4, NO, IL-1β, IL-2, IL-
4, TNF-α and interferon-γ.
[39-40]
Scrophularia deserti
Delile
(Scrophulariaceae),
Aerial
parts
Harpagoside (19);
scropolioside-D2 (40);
koelzioside (41)
Fever; kidney diseases;
diabetes mellitus;
inflammation of the
mouth, lungs, large
intestines, bladder and
heart
No
Yes
-
[137-139]
Scrophularia
frutescens L.
(Scrophulariaceae)
Aerial
parts
Harpagoside (19)
Joint and lower back
pain and inflammation
Yes
Yes
Hydrolysed products of harpagoside
with glucosidase treatment showed a
significant inhibitory effect on COX-
2 activity.
[44; 140-
141]
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2117
(Table 1). Contd…..
Species Name
Plant
Part(s)
Used
Isolated Iridoid Glycoside
Common Uses /
Biological Activity
In vitro
Studies
In vivo
Studies
Proposed Mechanism of Action
References
Scrophularia
scorodonia L.
(Scrophulariaceae)
Aerial
parts
Aucubin (14); harpagoside
(19); harpagide (20); 8-
acetylharpagide (42);
scorodioside (43);
scropolioside B (44);
bartsioside (45)
Inflammatory diseases
Yes
No
Inhibition of TXB2, PGE2 and LTC4
release.
[142-143]
Sideritis perfoliata L.
subsp. perfoliata
(Lamiaceae)
-
Ajugoside (46)
Rheumatism; ulcers;
digestive disorders
Yes
No
Lipoxygenase inhibition.
[144]
Stachytarpheta
cayennensis (L.C.
Rich) Vahl
(Verbenaceae)
Flower;
leaves;
roots
Ipolamiide (47)
Pain; inflammation;
fever; liver and gastric
disturbances
Yes
Yes
Inhibition of leukocyte accumulation
and influx.
Inhibitory effect on histamine and
bradykinin.
[56; 145-
148]
Syringa species
(Oleaceae)
Leaves
Iridoid glycoside-rich
fraction; Syringopicroside
(48)
Acute enteritis; icteric
hepatitis; acute mastitis;
bacillary dysentery;
upper respiratory tract
infections
Yes
Yes
Reduction of the activity of
myeloperoxidase, depression of
malondialdehyde and NO levels and
inhibition of the protein and mRNA
expressions of NFK-B and TNF-α
and IL-6.
[149-151]
Verbascum lasianthum
Boiss.
(Scrophulariaceae)
Aerial
parts
Aucubin (14); catalpol (15);
geniposidic acid (17);
ajugol (49)
Respiratory disorders;
urinary tract infections;
earache; inflammatory
skin disorders
No
Yes
-
[155]
Verbascum
mucronatum Lam
(Scrophulariaceae)
-
Catalpol (15); ajugol (49);
lasianthoside (50);
picroside IV (51)
Respiratory disorders;
urinary tract infections;
earache and
inflammatory skin
disorders
-
Yes
-
[152; 156]
Verbascum
pterocalycinum var.
mutense Hub.-Mor.
(Scrophulariaceae)
Flowers
Ajugol (49); picroside IV
(51)
Respiratory disorders;
urinary tract infections;
earache, inflammatory
skin disorders
No
Yes
-
[157-158]
Verbena officinalis L.
(Verbenaceae)
Whole
plant
Verbenalin (52)
Detoxing agent; diuretic;
expectorant and anti-
rheumatic
No
Yes
Topically and orally administered
extracts showed anti-inflammatory
activity in the TPA-induced ear
inflammation model and in
carrageenan-induced rat-paw
oedema.
[159-163]
Veronica anagallis-
aquatic L.
(Plantaginaceae)
Aerial
parts
Catalposide (6);
veronicoside (53);
verproside (54)
Influenza; pain;
haemoptysis;
laryngopharyngitis and
hernia
-
Yes
Catalposide significantly inhibited
the production of NO in LPS-
stimulated RAW 264.7 macrophages
in a dose-dependent manner. RT-
PCR and Western blot analyses
demonstrates that catalposide also
suppressed the expression of the
iNOS gene and protein and inhibited
the activation of LPS-induced NF-
κB.
[43; 66;
163]
Vitex peduncularis
Wall. ex Schauer
(Verbenaceae)
Root
bark or
young
stem
bark
Pedunculariside (55);
agnuside (56)
Malaria type fever,
especially black water
fever
Yes
No
Selective inhibition of COX-2.
[164-165]
Tatli and Akdemir [157] isolated ajugol (49) and picroside IV
(51) and several other phenolic compounds from Verbascum
pterocalycinum var. mutense Hub.-Mor. These compounds together
with saponin glycosides were investigated for anti-inflammatory
and antinociceptive properties [158]. A dose-related anti-
inflammatory and antinociceptive response was obtained at 100 and
200 mg/kg. Although the activities of ajugol and picroside IV were
found to be insignificant, the saponins, ilwensisaponin A and C
showed notable activity without inducing any apparent acute
toxicity or gastric damage.
3.28. Verbena officinalis (Vervain)
Although native to Europe, Verbena officinalis L.
(Verbenaceae) has become naturalised in many countries and is
especially renowned in China as a medicine to treat fever and to
detoxify the body. The plant is said to promote blood circulation,
remove blood stasis and induce diuresis. It has also been used in
folk medicine as a diuretic, expectorant and anti-rheumatic. In
Navarra, Spain, it is used extensively in traditional medicine,
especially topically due to anti-inflammatory effects [159]. The
2118 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
O
OH
OH
OH
HO
O
O
OH
HO
O
O
OH
O
OH
OH
HO
OH
O
O
6-Deoxyharpagide (1)
Reptoside (2)
O
OO
OH
OH
HO
OH
HO
O
OO
OH
OH
HO
OH
OHO
Boschnaloside (3)
8-Epideoxyloganic acid (4)
O
OH
HO
HO
O
OH
OH
HO
OH
O
OO
O
O
O
O
OH
O
HO O
OH
OH
HO
OH
Lamiide (5)
Catalposide (6)
OO
HO
O
OO
O
OH
OH
HO
OH
O
OO
OH
OH
HO
OH
OO
HO
Morroniside (7)
Loganin (8)
O O
O
OH
OO
OH
OH
HO
OH
SR
O
O
HO
HO
OH
O
OH
OH
OH
HO
O
OO
O
Sweroside (9)
Cornuside (10)
O
OH
OH
HO
OH
O O
O
O
OO
O
O O
O
OH
OO
OH
OH
HO
OH
7-O-Cinnamoylmorroniside (11)
Swertiamarin (12)
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2119
(Fig. 2). Contd…..
O
O
OO
HO O
OH
OH
HO
OH
O
OO
OH
OH
HO
OH
HO
HO
Geniposide (13)
Aucubin (14)
O
O
HO
O
HO O
OH
OH
HO
OH
O
OH
OO
HO
Catalpol (15)
Genipin (16)
O
O
OHO
HO O
OH
OH
HO
OH
O O
OO
OH
OH
HO
OH
Geniposidic acid (17)
Gentiopicroside (18)
O
O
OH
O
O
OH
OH
HO
OH
O
HO
O
O
OH
O
OH
OH
HO
OH
HO
OH
O
Harpagoside (19)
Harpagide (20)
O
O
OH
O
O
O
OH
OH
HO
OH
HO
OH
OH
O
O
OH
HO
O
O
OH
OH
HO
O
8-Coumaroylharpagide (21)
Pagoside (22)
O
O
O
OO
O
H
O
O
O
OO
H
O
Plumericin (23)
Isoplumericin (24)
2120 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
(Fig. 2). Contd…..
O
O
HO
O
O
O
O
OH
OH
HO
OH
HO
HO
O
HO
O
OO
OH
OH
HO
OH
Verminoside (25)
Mentzeloside (26)
O
O
OH
O
O
HO
O
OH
OH
OH
HO
O
O
O
O
OHO
O
O
O
HO
HO OH
HO
O
Oleuropeoside (27)
Ligustroside (28)
O
O
O
O
O
O
OH
OH
HO
OH
O
HO
HO
HO
O
O
O
OH
OH
HO
O
O
OH
O
O
HO
Picroside II (29)
Picroside III (30)
O
O
O
O
O
O
OH
OH
HO
OH
O
HO
O
O
O
HO
O
O
OH
OH
HO
OH
O
HO
Picroside V (31)
6-Feruloylcatalpol (32)
O
O
O
HO
O
O
O
OH
OH
HO
OH
O
HO
O
O
HO
O
O
OH
O
HO O
OH
OH
HO
O
Minecoside (33)
Picroside 1 (34)
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2121
(Fig. 2). Contd…..
O
O
O
O
O
HO
O
O
OH
OH
HO
OH
O
OO
OH
OH
HO
OH
O
O
O
HO
O
HO
OH
Kutkoside (35)
10-O-Cinnamoyl sinuatol (36)
HO
O
O
HO
Cl
OH
O
O
O
O
O
O
O
O
O
O
O
OH
OH
HO
OH
O
O
HO
Rehmaglutin B (37)
Scropolioside A (38)
O
O
O
O
O
O
O
H3C
O
O
OH
OH
HO
OH
O
O
O
O
HO
O
O
O
O
O
O
O
O
O
OH
OH
HO
O
O
O
O
O
HO
Scrovalentinoside (39)
Scropolioside-D2 (40 )
O
O
O
O
OO
OH
OH
HO
OH
O
O
O
O
O
O
HO
O
OH
OH
OH
HO
O
O
OH
O
HO
O
Koelzioside (41)
8-Acetylharpagide (42)
2122 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
(Fig. 2). Contd…..
O
O
O
O
O
H
H
HO
O
HO
C
O
O
OH
OH
HO
OH
O
O
O
O
O
O
O
O
OO
O
O
OH
OH
HO
OH
O
HO
Scorodioside (43)
Scropolioside B (44)
O
OO
OH
OH
HO
OH
HO
O
OO
OH
OH
HO
OH
O
O
HO
Bartsioside (45)
Ajugoside (46)
O
O
OO
O
OH
OH
HO
OH
HO
OH
O
O
OO
O
O
OH
OH
HO
OH
Ipolamiide (47)
Syringopicroside (48)
O
HO
OO
OH
OH
HO
OH
HO
O
O
O
OH
HO
O
OH
O
HO OO
OH
OH
HO
OH
Ajugol (49)
Lasianthoside (50)
O
O
HO O
O
O
O
OH
OH
HO
OH
O
HO
O
O
O
O
O
OOH
HO
HO
OH
Picroside IV (51)
Verbenalin (52)
Anti-Inflammatory Iridoids of Bota nical Origin Current Medicinal Chemistry, 201 2 Vol. 19, No. 14 2123
(Fig. 2). Contd…..
O
O
O
O
OH
OH
HO
OH
O
O
HO
O
O
O
HO
HO
O
OH
OH
HO
OH
O
O
HO
Veronicoside (53)
Verproside (54)
O
O
OH
O
O
OHO
O
OH
OH
HO
OH
O
HO
O
HO
O
OO
OH
OH
HO
OH
Pedunculariside (55)
Agnuside (56)
Fig. (2). Chemical structures of selected isolated iridoid glycosides.
main components of V. officinalis are iridoids, phenylpropanoids,
flavonoids, and terpenoids [160].
The effects of a cream containing a 50% methanolic extract of
V. officinalis, incorporated in various concentrations (1%, 1.5%,
2%, 2.5%, 3%), was tested on a carrageenan-induced oedema and
formalin testing animal model. Piroxicam gel and methyl salicylate
ointment were used as positive controls for anti-inflammatory and
analgesic activity respectively. The cream formulation reduced
inflammatory oedema dose-dependently, with the 3% formulation
possessing activity similar to piroxicam gel. In the analgesia test the
cream dose-dependently exerted topically induced analgesia,
although not to the same extent as methyl salicylate. The active
constituents believed to be responsible for the antinociceptive and
anti-inflammatory activity are the iridoids, caffeoyl derivatives and
flavonoids [161]. Using a mouse model, Calvo and co-workers
[162] administered a 50% methnolic extract prepared from the
leaves of V. officinalis and the isolated iridoid glucoside verbenalin
(52) topically and orally to assess anti-inflammatory activity. In the
TPA-induced ear inflammation assay the extract and verbenalin
showed superior activity over oral administration in the
carrageenan-induced rat-paw oedema model [162].
3.29. Veronica anagallis-aquatica (Water speedwell; Brook
pimpernel)
Veronica anagallis-aquatica L. (Plantaginaceae) grows
naturally in the Batiste Springs in the state of Idaho, USA. Veronica
anagallis-aquatica is used for the treatment of influenza,
haemoptysis, laryngopharyngitis and hernia. Traditionally, the
aerial parts of the plant are boiled in milk to obtain a poultice which
is applied to the abdomen to treat pain or in Anatolian regions the
warm aqueous extract is used as a bath remedy to alleviate
rheumatic pain [163]. Through bioassay-guided fractionation
procedures, the major compounds isolated from the aerial parts of
V. anagallis-aquatica were isolated. They include the calpol-
derived catalposide (16) veronicoside (53) and verproside (54).
These compounds were found to have a significant inhibitory effect
on carrageenan-induced mouse-paw oedema. Doses were estimated
according to the molar ratios of the iridoid glycosides in the
biologically active fraction, as well as in standard doses of 250 and
500 mg/kg [163]. Catalposide (16) significantly inhibited the
production of NO in LPS-stimulated RAW 264.7 macrophages in a
dose-dependent manner. RT-PCR and Western blot analyses
demonstrates that catalposide also suppressed the expression of the
iNOS gene and protein and inhibited the activation of LPS-induced
NF-κB [66]. Recio et a l. [43] suggested a structure-activity
relationship for topical anti-inflammatory activity of iridoid
glycosides. OH-substitution at C5, unsaturation at C7 - C8, methyl
substitution of carbonyl C11 and the integrity of the cyclopentane
ring were essential for higher activity. In their study, Küpeli et al.
[163] reported that esterification from C6 with benzoic acid (as in
veronicoside) or phenolic acids (p-hydroxybenzoic acid in
catalposide and protocatechic acid in verproside) provided a
significant increase in anti-inflammatory activity in higher doses.
3.30. Vitex peduncularis (Boruna; goda)
Vitex peduncularis Wall. ex Schauer (Verbenaceae) is found in
India and Khasia Terai. The bark is used for making an external
application for chest pains. An infusion of the leaves, root bark or
young stem bark is indicated for malarial type fever, especially in
black water fever [164]. In 1921 the British Medical Journal
reported an observational study where patients were given infusions
of the leaves prepared from V. peduncularis to alleviate malaria
associated fever. This lead was taken from ethnomedicinal uses of
Aboriginal tribes. In all cases the infusion alleviated seized the
fever.
A new iridoid, pedunculariside (55), together with agnuside
(56) were isolated from the butanol extract of V. peduncularis stem
bark. In a murine cell-based assay both pedunculariside and
agnuside showed selective inhibition of COX-2, with IC50 values of
0.15 mg/ml and 0.026 mg/ml, respectively. This selectivity to
COX-2 receptors is essential in order to circumvent the notorious
side-effects commonly associated with NSAIDs. Neither of the
compounds exhibited cytotoxicity against vero cells [165].
CONCLUSIONS
Inflammation is a complex process involving numerous
mediators affecting the majority of organs in the body. An article
referring to inflammation as “The Secret Killer” published in the
popular Time Magazine, eloquently describes the link between
2124 Current Medicinal Chemistry, 2012 Vol. 19, No. 14 Viljoen et al.
inflammation and various disease conditions: “It destabilises
cholesterol deposits in the coronary arteries, leading to heart attacks
and potentially even strokes. It chews up nerve cells in the brains of
Alzheimer's victims. It may even foster the proliferation of
abnormal cells and facilitate their transformation into cancer. In
other words, chronic inflammation may be the engine that drives
many of the most feared illnesses of middle and old age.” [166].
Certainly, research has shown that this is indeed the case, which
boldly emphasises the urgent and relevant need which exists to
discover novel anti-inflammatory agents to treat the various disease
conditions which manifest themselves through the inflammatory
process.
The data presented in this review has highlighted the following
concepts;
1. Almost all of the species discussed in this review have a
rich history of traditional use in treating inflammatory
conditions, whether acute or chronic. Ethnobotanical leads
have provided mankind with many new medicines and this
is also true in the case of inflammation as highlighted in this
review. The data presented here for several species lends
credence and value to indigenous knowledge systems, a
healing modality, which has been in existence far longer
than any pharmaceutical company. The challenge however
remains to generate sufficient scientific data which will
allow this indigenous knowledge to be transformed into
consumer products.
2. In order to provide both focus and structure to the review
only iridoids have been discussed. Convincing
pharmacological data is presented for several iridoids which
provides evidence that this group of phytochemicals is
active in treating inflammation-related disorders. However,
several examples have been documented suggesting that the
iridoids do not act in isolation but may exert their activity
when acting in synergy with other molecules e.g. acteoside,
which often co-occurs with iridoids. Despite the fact that
many leads are taken from traditional healing practices
scientists still give preference to a reductionist approach in
the drug discovery process. Phytosynergy studies on
iridoids (and other compounds) may present an exciting and
rewarding research opportunity to better understand and
unravel the complex interactions which may exist in
treating inflammation.
3. The inflammation process is complex and numerous
mechanisms of action are possible. Therefore it is important
to note that if an extract or compound is not active in one
assay, it does not imply that it possesses no anti-
inflammatory activity. It may still exert anti-inflammatory
activity at another level in the inflammation cascade such as
through suppressing the expression of pro-inflammatory
mediators like TNF-α. It may also be beneficial for a
compound to selectively inhibit inflammation through
action on COX-2 which would then negate the infamous
gastric side-effects commonly associated with NSAIDs
through COX-1 inhibition. Two iridoids isolated from V.
peduncularis namely pedunculariside and agnuside showed
selective inhibition of COX-2. In addition, S. cayennensis
was shown to protect the gastric mucosa against damage
caused by the classic NSAID diclofenac in addition to
exhibiting anti-inflammatory activity. Exploring the
possible interaction between natural products and
conventional medicine could certainly be of scientific and
therapeutic interest.
4. Though in vitro data contributes greatly towards elucidating
the mechanism of action of any compound / extract, in vivo
data remains crucial. For some species discussed only in
vitro data is available. Even where in vivo studies have been
done in animals, the process of developing anti-
inflammatory drugs from botanical origin seems to
terminate at this point, as literature on clinical data (in vivo
human) remains scarce. Harpagophytum procumbens has
been tested in humans, as highlighted in this review, with
great success. Several in vitro studies have shown that the
hydrolysed products of various iridoids showed better
activity. In the case of harpagide and harpagoside,
hydrolysis of the glycosidic bonds by β-glucosidase is a
pre-requisite for activity. Therefore, it is important to
investigate this clinically as well as oral administration
would cause this necessary conversion. The prodrug effects
will clearly not be detected in vitro. Although various acute
toxicity and histopathology studies have shown that many
of the extracts and/or iridoids mentioned in the review are
seemingly well tolerated even in high doses, toxicity data is
still lacking for many species discussed.
5. Elucidating structure-activity relationships presents a
challenging, yet potentially rewarding opportunity for
producing more active compounds derived from the iridoid
scaffold. There are several examples where substitutions
resulted in superior anti-inflammatory activity. Minor
changes in chemical structure such as introducing a
hydroxyl group resulted in an increase in topical anti-
inflammatory activity in some cases. As already mentioned,
the activity of iridoid glycosides increased after hydrolysis.
Esterification from C6 with benzoic acid or p-
hydroxybenzoic caused a significant increase in anti-
inflammatory activity in higher doses in the case of
veronicoside and catalposide, respectively. Not only with
these modification optimise the activity of the molecule but
may also influence the pharmacokinetics of the molecules.
This group of natural products presents the medicinal
chemists with a plethora of opportunities which hitherto
remains largely neglected.
It is evident that this class of compounds presents a fascinating
opportunity for further research. There are numerous species from
which iridoids have been isolated that has as yet not been tested for
anti-inflammatory activity. In addition, the general increase in
lifestyle-related conditions in the population that is caused by
inflammation provides endless research opportunities as yet
unexplored.
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Received: November 22, 2011 Revised: January 07, 2012 Accepted: January 08, 2012
