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30
Anti-Inflammatory Properties of Cinnamon
Polyphenols and their Monomeric Precursors
Dhanushka Gunawardena*, Suresh Govindaraghavan*,† and Gerald
Münch*,‡,k
*Department of Pharmacology, School of Medicine, University of Western Sydney, Campbelltown, NSW, Australia
†
Network Nutrition Pty Limited, North Ryde, NSW, Australia ‡Molecular Medicine Research Group, University
of Western Sydney, Campbelltown, NSW, Australia kCompleMed, University of Western Sydney, Campbelltown,
NSW, Australia
(iNOS), with the formation of stoichiometric amounts are closely connected to other inflammatory pathways
of L-citrulline from L-arginine. Compounds able to including NF-κB, COX-2 expression, and pro-
reduce NO production by iNOS may thus be attractive inflammatory cytokines.
as anti-inflammatory agents and, for this reason, the
effects of polyphenols on iNOS activity have been
3.2.4 Nuclear Transcription Factor Kappa B
intensively studied. Current results suggest that poly-
phenols inhibit NO release by suppressing NOS NF-κB is a ubiquitous factor that resides in the cyto-
enzymes expression and/or NOS activity.45 plasm. When it becomes activated, it is translocated to
the nucleus, where it induces gene transcription. NF-
3.2.2 Cytokine System κB is activated by free radicals, inflammatory stimuli,
Cytokines are the major mediators of local, intercellu- carcinogens, tumor promoters, endotoxins, γ-radiation,
lar communications required for an integrated response ultraviolet (UV) light, and X-rays. Therefore, agents
to a variety of stimuli in immune and inflammatory pro- that can suppress NF-κB activation have the potential
cesses. Numerous cytokines have been identified in tis- to suppress cytokine expression and, therefore,
sues across a range of immuno-mediated inflammatory decrease inflammatory response. Recent data suggest
diseases.46 Also, a “balance” between the effects of pro- that dietary polyphenols can work as modifiers of sig-
inflammatory (e.g., IL-1β, IL-2, TNF-α, Il-6, IL-8 and IFN- nal transduction pathways to elicit beneficial effects.
γ) and anti-inflammatory cytokines (e.g., IL-10, IL-4, Polyphenols have been shown to exert their anti-
TGF-β) is thought to determine the outcome of disease, inflammatory activity by modulating NF-κB activation
whether in the short- or long-term. It has been observed and act on multiple steps of the activation process.26
that several flavonoids are able to decrease the expression The influence of EGCG on NF-κB pathway has been
of different pro-inflammatory cytokines/chemokines extensively studied demonstrating its inhibitory effects
such as TNF-α, IL-1β, IL-6, IL-8, MCP-1 in LPS-activated on NF-κB obtained by counteracting the activation of
mouse primary macrophages, PMA or phytohemaggluti- IKK and the degradation of IκBα.50,51 An interesting
nin (PHA) stimulated human peripheral blood mononu- in vivo study carried out on rats showed that EGCG
clear cells, activated human astrocytes, human synovial markedly attenuated the myocardial injury after ische-
cells, activated human mast cell line HMC-1, nasal muco- mia and reperfusion.37,5257
sal fibroblasts and A549 bronchial epithelial cells.47 In
fact, polyphenols, such as quercetin and catechins, cou-
pled their inhibitory action on TNF-α and IL-1β to the
enhancement of IL-10 release.47,48
4. ANTI-INFLAMMATORY ACTIVITY OF
CINNAMON EXTRACTS
3.2.3 Peroxisome Proliferator Activated Receptors
The expression of many inflammatory cytokines is
4.1 Cinnamomum zeylanicum
regulated at the transcriptional level, which can either C. zeylanicum polyphenol extract has been found to
enhance or inhibit the inflammation process. affect immune responses by regulating anti- and pro-
Peroxisome proliferator-activated receptors (PPARs) inflammatory and GLUT gene expression in mouse
are nuclear hormone receptors that are activated by macrophages.58 Another laboratory study found that
specific endogenous and exogenous ligands.49 Three the water-soluble C. zeylanicum extract reverses TNF-
isoforms (α, β/δ, and γ) have been identified, and are α-induced overproduction of intestinal apoB48 by
encoded by separate genes. Among these, PPARα acti- regulating gene expression involving inflammatory,
vation is responsible for the pleiotropic effects of per- insulin, and lipoprotein signaling pathways,59 and con-
oxisome proliferators, such as enzyme induction, cluded that the water-soluble extract improves inflam-
peroxisome proliferation and amelioration of inflam- mation related intestinal dyslipidemia. Of interest is a
mation. PPARα also plays a critical role in the regula- recent study that found that an aqueous extract of
tion of cellular uptake and β-oxidation of fatty acids. C. zeylanicum inhibited tau aggregation and filament
Furthermore, PPARδ (also known as PPARβ) is widely formation, hallmarks of AD.60
expressed with relatively higher levels in the brain, The anti-inflammatory effect of Cinnamomum zeyla-
colon, and skin. Although there have been extensive nicum was also investigated using ethanol extract
studies on PPARα and inflammation, very little is obtained from bark. In vitro and in vivo experiments
known about the effect of PPARδ on inflammation.27 were performed targeting TNF-α using flow cytome-
Few studies have regarded polyphenols as PPAR try. Ethanol extract of C. zeylanicum showed suppres-
ligands, but it is probable that polyphenols may also sion of intracellular release of TNF-α in murine
affect PPAR protein expression, which results in the neutrophils as well as leukocytes in pleural fluid. The
activation of the PPAR pathway, as PPAR pathways extract was found to inhibit TNF-α gene expression in
broccoli, olives, onions, green and black tea, cinnamon, acid derivatives. The common flavan-3-ols in
parsley, grapefruit, oranges and their juices, dark choc- proanthocyanidins are shown in Figure 30.3. The
olate, cocoa, and red wine.73 proanthocyanidins that consist exclusively of (epi)cate-
Proanthocyanidins are mixtures of oligomers and chin are procyanidins. Proanthocyanidins containing
polymers composed of flavan-3-ol units, linked mainly (epi)afzelechin or (epi)gallocatechin as subunits are
through C4C8 bonds; however, C4C6 bonds also called propelargonidin or prodelphinidin, respectively.
exist. The flavan-3-ol units can also be doubly linked Propelargonidin or prodelphinidin are mostly hetero-
by an additional ether bond between C2 and O7 (e.g., geneous in their constituent units and co-exist with the
cinnamtannin B1). Proanthocyanidins containing the procyanidins.76
single interflavan linkage are known as B-type,
whereas those containing double interflavan linkages
are known as A-type (Figure 30.1). The size of the 5.3 Other Cinnamon Phenolics
proanthocyanidin molecule is determined by the Anti-inflammatory cinnamon monophenolic com-
degree of polymerization (DP). 52,74 They are divided pounds include protocatechuic acid, urolignoside,
into three major classes (procyanidins, propelargoni- quercetin, rutin, kaempferol, isorhamnetin, cinnamald-
dins, and prodelphinidins) according to the type of hyde, 2-hydroxycinnamaldehyde, and eugenol.
their monomeric precursors. One laboratory study investigated the proximate
Cinnamomum zeylanicum bark contains dimeric, tri- composition, minerals, amino acids, polyphenolic com-
meric, and oligomeric proanthocyandins with doubly pounds, and presence of some anti-nutritional factors
linked bis-flavan-3-ol units (A-type procyanidins) in Sri Lankan cinnamon (C. zeylanicum) and Chinese
(Figure 30.2). Among the several cinnamon species, cinnamon (C. cassia) barks. The results showed that the
only the bark of C. zeylanicum contained, as major phe- tannins levels (0.652.18 %) were high in these two
nolic metabolites, a series of proanthocyanidins with bark samples, compared to other plant sources and
the doubly linked (A-type) unit, while the barks of C. there were no significant differences observed in the
burmanni and C. cassia, and the root bark of C. camphora amounts of catechin and isorhamentin between the
consisted of linearly linked proanthocyanidins (B- two barks; whereas rutin, quercetin and kaempferol
type).75 were significantly higher in Sri Lankan cinnamon than
that in Chinese cinnamon (Table 30.1).77
Water extracts of cinnamon fruits have been
5.2 Monomeric Precursors reported to contain high levels of phenolics, i.e., proto-
catechuic acid, urolignoside, rutin, and quercetin-3-O-
The cinnamon monomeric precursors are the pheno-
α-L-rhamnopyranoside78 (Figure 30.4).
lic subunits that produce the condensed polyphenols.
C. verum is interesting in that it yields three types of
The common monomeric precursors (flavan-3-ols) of
oils from the leaf, stem bark and root bark. The major
the cinnamon proanthocyanidins are afzelechin,
constituent in the leaf oil is eugenol, in the stem bark
epiafzelechin, catechin, epicatechin, and their gallic
oil it is cinnamaldehyde, while camphor is the major
constituent in the root bark oil. C. cassia produces only
one type of oil, usually called bark oil, obtained by dis-
HO OH tilling leaves and bark together. Almost 95% of the oil
HO O
HO O
consists of cinnamaldehyde.7981
C. osmophloeum twigs and leaf essential oils contains
O
HO O OH trans-cinnamaldehyde and eugenol, which are reported
HO
HO
O
O O to possess excellent anti-inflammatory activities.67
OH
HO
HO OH OH
OH
OH OH
OH
OH HO O
OH
6. ANTI-INFLAMMATORY ACTIVITY OF
O
CINNAMON POLYPHENOLS
B-type Iinkage OH
OH
A-type Iinkage 6.1 Proanthocyanidins
O OH
6.1.1 Proanthocyanidins and COX Inhibition
OH In vitro studies of prodelphinidins (the proanthocya-
HO
OH nidins that consists of (epi)gallocatechin as subunits)
showed a decrease in the secretion of prostaglandin E2
FIGURE 30.1 Structure of cinnamon polymeric polyphenols. (PGE2) from human chondrocytes as well as their
OH
OH
OH
OH OH
O O OH
OH HO O OH
HO
HO
1 O
HO O OH OH
OH OH
HO
OH O O
OH OH
OH OH OH
O
OH OH 2 OH
HO OH
HO O
HO F OH
OH
HO O OH
OH OH HO O
E
OH
OH
OH OH OH
OH OH
HO O OH
OH OH
OH
OH
D O OH H
O OH 1
HO
HO
OH OH
OH OH
OH O O
OH OH
O O 2
OH OH
O
OH G OH
OH
O
OH
OH OH
HO
HO O OH I OH
O OH
OH HO O
3
HO
HO OH
HO O O
OH HO OH
OH OH
OH
OH OH
OH OH
HO O
OH
OH O OH
OH OH HO O
OH O OH
O OH HO O
HO O OH HO O O
OH OH
OH OH HO OH
OH HO OH
OH HO O OH OH OH
OH
HO O
HO O
OH K OH
OH OH
OH
HO O
O
O
OH
L OH
O OH O
OH OH
HO O OH OH
O
HO O
O OH
OH
O
OH
OH OH
O HO OH
O OH
HO O
OH
OH
OH
HO
J O
OH
HO O
OH HO O O
OH
OH OH
O OH HO
OH OH
HO O OH HO O
OH OH
O OH OH
HO O OH
HO O O
OH N
HO OH OH
OH OH OH
OH HO O
OH
M OH
OH
inhibition potential on COX-1 and COX-2 in vitro.82 This selectivity was enhanced by a reduction of the
The synthesis of PGE2 was significantly reduced concentration tested (1025 M). The same pattern was
by gallocatechin dimer (GCGC), gallocatechin- observed with the dimer.
epigallocatechin (GCEGC) and GCGCGC at
10 and 100 μg/mL. Moreover, these compounds inhib- 6.1.2 Proanthocyanidins and LOX-1 [Lectin-like
ited purified cyclooxygenase-1 (COX-1) and Oxidized LDL Receptor-1] Inhibition
cyclooxygenase-2 (COX-2).82 GC showed a preferential Procyanidin is one of the components that inhibits
inhibition of COX-2 compared to COX-1 at 1024 M. oxidized LDL (oxLDL) uptake since nearly half of the
OH OH
OH
HO O HO O
HO O
OH
OH OH
OH
OH OH
OH
OH OH
OH
HO O HO O
OH OH
HO O
O O
OH OH
OH O
O OH
OH OH
OH OH OH
Epiafzelechin OH
Catechingallate Epicatechingallate
OH OH
OH OH
OH OH
HO O HO O
OH OH
Gallocatechin
OH Epigallocatechin OH
TABLE 30.1 Polyphenol Content of Sri Lankan and Chinese procyanidins significantly differ among foods.52 Out of
Cinnamon Barks (mg/100 g)77 more than 400 foodstuff extracts derived from various
Sri Lankan Cinnamon Chinese Cinnamon sources, more than half of those displaying potent LOX-1
inhibition are known to contain a large amount of
Rutin 0.896 6 0.028 0.672 6 0.057 procyanidin.84
Quercetin 0.550 6 0.095 0.172 6 0.019
Kaempferol 0.492 6 0.134 0.016 6 0.000 6.1.3 Proanthocyanidins, NOS and Cytokines
Isorhamentin 0.113 6 0.015 0.103 6 0.000 The anti-inflammatory effects of a grape seed extract
Catechin 2.30 6 0.049a 1.90 6 0.141 containing a rich amount of dimeric and oligomeric
procyanidins were demonstrated by the decreasing
NO and prostaglandin E2 levels, avoidance of translo-
potent hit extracts. Purified procyanidins inhibited cation of NF-κB p65 to the nucleus, and by the
oxLDL binding in LOX-1-CHO (Chinese hamster downregulation of the expression of iNos and IκBα in
ovary) cells. Furthermore, oligomeric procyanidins RAW264.7 macrophages (mouse leukemic monocyte
(OPC) suppressed lipid accumulation in the vascular macrophage cell line) stimulated with LPS and
wall of stroke-prone spontaneously hypertensive rats interferon-γ.85
(SHR-SP) in which an anti-LOX-1 antibody was also Proanthocyanidins isolated from Ribes nigrum leaves
effective.83,84 interfered with the accumulation of circulating leuko-
LOX-1-inhibiting properties were almost identical cytes, associated with a reduction of pro-inflammatory
among procyanidins $ trimer and the dimer also potently factors such as TNF-α, IL-1β and CINC-1, a decrease of
inhibited LOX-1. Moreover, four different isomers of tri- NOx level, and a decrease in plasma exudation.86
mer procyanidins almost equally inhibited oxLDL bind- In a recent study, it was shown that proanthocyani-
ing to LOX-1. These results implicate that intake of dines (PA) significantly suppressed the content of lipo-
procyanidin-rich foods potentially inhibits LOX-1; regard- peroxidation product malondialdehyde (MDA) in
less of food source since the polymerization levels of carrageenan-induced inflamed paws of rats and
OCH3
OH OH
OH
OH
HO O
HO O
HO O
OH OH
OH O OH
OH O
OH O
Kaempferol
Quercetin Isorhamnetin
markedly lessened the activity of NOS and the content inflammatory cytokines (PSE at 100 μg/mL), tumor
of NO in exudates of carrageenan-induced paw edema necrosis factor-α and interleukin-6, in cultured human
in rats. These results demonstrated that inhibition of monocytic THP-1 cells in response to lipopolysaccha-
lipoperoxidation and NO formation was one of the ride. The isolated compounds from PSE also showed
anti-inflammatory mechanisms of PA.76 anti-inflammatory activities. They showed suppressive
Pro-inflammatory cytokines TNF-α, IL-1β and IL-6 activities against melanogenesis and cytokine produc-
are sequentially released in the pleural exudates tion at concentrations ranging from 0.110 μg/mL.
induced by carrageenin in rats.87 These cytokines cause Among the tested compounds, suppressive activities
chemotaxis to attract granulocytes and monocytes and of proanthocyanidin dimers or trimers in two assay
then, migrating leukocytes produce, in turn, further systems were stronger than those obtained with mono-
cytokines, such as TNF-α and IL-1β, and other pro- mer or tetramers. These data indicate that proantho-
inflammatory mediators. IL-6 has been proposed as a cyanidin oligomers have the potential to reduce
crucial mediator for the development of carrageenin- dermatological conditions such as inflammation and
induced pleurisy and for the accumulation of leuko- melanogenesis.89
cytes in the inflammatory site. Indeed, in carrageenin- Recent studies have demonstrated that proanthocya-
induced pleurisy in IL-6 knock-out mice, the degree of nidins reduce the expression of soluble adhesion mole-
plasma exudation, leukocyte migration and the release cules, intercellular adhesion molecule-1 (ICAM-1),
of TNF-α and IL-1β were greatly reduced. Moreover, a vascular cell adhesion molecule-1 (VCAM-1), and E-
positive feedback plays an important part in the devel- selectin in the plasma of systemic sclerosis patients.90
opment of the oedema as levels of TNF-α and IL-1β The same compounds have been shown to inhibit
are attenuated in IL-6 knock-out mice.88 TNF-α-induced VCAM-1 expression in human umbili-
Inhibitory activity of proanthocyanidins isolated cal vein endothelial cells cultures.91 A possible mecha-
from peanut skin tested on inflammatory cytokine pro- nism of the anti-inflammatory effect of PACs would be
duction and melanin synthesis in cultured cell lines an interference with the expression or the effect of
and administration of peanut skin extract (PSE, adhesion molecules. This interference would result in
200 μg/mL) decreased melanogenesis in cultured a reduction of polymorphonuclear cell migration and
human melanoma HMV-II co-stimulated with phorbol- subsequently in a reduction of the release of pro-
12-myristate-13-acetate. It also decreased production of inflammatory factors such as TNF-α and IL-1β.86
efficient RS scavenging capacity and modulated pro- inflammatory effects143 in RAW264.7 macrophage
inflammatory NF-κB activation via the NIK/IKK and cells.
MAPK pathways in aging. These studies demonstrated A potential anti-inflammatory effect of HCA/BCA
that kaempferol as an efficient anti-inflammatory com- was assessed in LPS-stimulated microglial cultures
pound with the ability to attenuate oxidative stress- and microglia/neuroblastoma co-cultures. HCA/BCA
induced inflammation in aged rat kidney.138 significantly decreased the production of NO and
TNF-α in microglial cells. HCA/BCA also attenuated
the expression of iNOS and pro-inflammatory cyto-
8.5 Isorhamnetin kines such as interleukin-1β (IL-1β) and TNF-α at
30 -Methoxy-3,40 ,5,7-tetrahydroxyflavone (isorhamne- mRNA level via blockade of ERK, JNK, p38 MAPK,
tin) is an abundant flavonoid found in many dietary and NF-κB activation. Moreover, HCA/BCA was
plants.139 Isorhamnetin inhibits NO production and neuroprotective by reducing microglia-mediated neu-
iNOS protein and mRNA expression; it also reduces roblastoma cell death in a microglia-neuroblastoma co-
iNOS expression, and that effect may well be mediated culture. Affinity chromatography and LC-MS/MS
by inhibition of NF-κB activation.56 The IC50 value of analysis identified low-density lipoprotein receptor-
isorhamnetin and other flavonols on NO production related protein 1 (LRP1) as a potential molecular target
inhibitory activity in LPS-activated mouse peritoneal of HCA in microglial cells. Studies using the receptor-
macrophages124 is provided in Table 30.2. associated protein (RAP) that blocks a ligand binding
to LRP1 and the siRNA-mediated LRP1 gene silencing,
showed that HCA inhibited LPS-induced microglial
8.6 Cinnamaldehyde activation via LRP1 suggesting that HCA/BCA is anti-
inflammatory and neuroprotective in the CNS by
Cinnamaldehyde suppressed NF-B activation within
targeting LRP1, and may have a therapeutic potential
macrophage-like RAW264.7 cells.140 It has been dem-
against neuroinflammatory diseases.144
onstrated that CA is capable of blocking inducible
nitric oxide synthase (iNOS) and NO production by
mediation of NF-B activation blockade in LPS-
stimulated RAW264.7 cells.141 Cinnamaldehyde, iso-
8.8 Eugenol (4-Allyl-2-Methoxyphenol)
lated from the leaves of C. osmophloeum, was reported Eugenol is a major component of cinnamon leaves
to inhibit the secretion of IL-1β and TNF-α within LPS and has been reported to show potent antioxidant and
or lipoteichoic acid (LTA) stimulated murine J774A.1 anti-inflammatory actions,145147 and it effectively
macrophages. Cinnamaldehyde also suppressed the improved functional and structural pulmonary
production of these cytokines from LPS-stimulated changes induced by LPS, modulating lung inflamma-
human blood monocytes derived primary macro- tion and remodeling in an in vivo model of acute lung
phages and human THP-1 monocytes.142 These find- injury (ALI), through a mechanism involving inhibi-
ings demonstrated the anti-inflammatory (Table 30.3) tion of TNF-α release and NF-κB activation. This may
potential of cinnamaldehyde. lead to potential new therapies for ALI as well as other
chronic lung inflammatory diseases.148
Effect of eugenol on the production of NO by
8.7 20 -Hydroxycinnamaldehyde (HCA) and 20 - RAW264.7 macrophages showed anti-inflammatory
Benzoyloxycinnamaldehyde (BCA) effect; both eugenol and isoeugenol inhibited LPS-
20 -Hydroxycinnamaldehyde (HCA) from the stem dependent production of NO, through the inhibition of
bark of C. cassia and its derivative 20 -benzoyloxycinna- protein synthesis of iNOS. Isoeugenol was shown to be
maldehyde (BCA) were reported to show anti- the more effective than eugenol (Table 39.3) by inhibit-
ing LPS-dependent expression of cyclooxygenase-2
TABLE 30.3 Effects of Cinnamaldehyde and 2-hydroxycinnamalde- (COX-2).149
hyde on NO Production Inhibitory Activity in LPS-activated
RAW264.7 Macrophages5,149,150
Compound IC50 µM 9. CONCLUSION
Cinnamaldehyde 45.56
Dietary polyphenols comprise a vast array of biolog-
2-Hydroxycinnamaldehyde 8 ically active compounds that are ubiquitous in plants,
Eugenol 100 many of which have been used in traditional Oriental
medicine for thousands of years. In this review, we
Isoeugenol 10
summarized the current findings of the molecular
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