Ginger : An Herbal Medicinal Product with Broad Anti-Inflammatory Actions

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J Med Food
8 (2) 2005, 125–132
© Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition

Ginger—An Herbal Medicinal Product with Broad Anti-Inflammatory Actions
Reinhard Grzanna,1 Lars Lindmark,2 and Carmelita G. Frondoza3
1RMG Biosciences, Inc.; 3Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine,
Baltimore, Maryland; and 2Ferrosan A/S, Soeborg, Denmark
The anti-inflammatory properties of ginger have been known and valued for centuries. During the past 25
years, many laboratories have provided scientific support for the long-held belief that ginger contains constituents with anti-
inflammatory properties. The original discovery of ginger’s inhibitory effects on prostaglandin biosynthesis in the early 1970s
has been repeatedly confirmed. This discovery identified ginger as an herbal medicinal product that shares pharmacological
properties with non-steroidal anti-inflammatory drugs. Ginger suppresses prostaglandin synthesis through inhibition of cy-
clooxygenase-1 and cyclooxygenase-2. An important extension of this early work was the observation that ginger also sup-
presses leukotriene biosynthesis by inhibiting 5-lipoxygenase. This pharmacological property distinguishes ginger from non-
steroidal anti-inflammatory drugs. This discovery preceded the observation that dual inhibitors of cyclooxygenase and
5-lipoxygenase may have a better therapeutic profile and have fewer side effects than non-steroidal anti-inflammatory drugs.
The characterization of the pharmacological properties of ginger entered a new phase with the discovery that a ginger extract
(EV.EXT.77) derived from Zingiber officinale (family Zingiberaceae) and Alpina galanga (family Zingiberaceae) inhibits the
induction of several genes involved in the inflammatory response. These include genes encoding cytokines, chemokines, and
the inducible enzyme cyclooxygenase-2. This discovery provided the first evidence that ginger modulates biochemical path-
ways activated in chronic inflammation. Identification of the molecular targets of individual ginger constituents provides an
opportunity to optimize and standardize ginger products with respect to their effects on specific biomarkers of inflammation.
Such preparations will be useful for studies in experimental animals and humans.
KEY WORDS: • chemokines • cyclooxygenase • cytokines • ginger • inflammation
thesis of prostaglandins (PGs).5 Soon thereafter, ginger was
found to contain constituents that inhibit PG synthesis, a
GINGER (Zingiber officinale Roscoe) has a long history finding that provided a sound scientific rationale for its anti-
of medicinal use.1,2 In traditional Chinese and Indian
inflammatory effects.6 Subsequent studies revealed that gin-
medicine, ginger has been used to treat a wide range of ail-
ger also contains constituents with pharmacological proper-
ments including stomachaches, diarrhea, nausea, asthma,
ties similar to the novel class of dual-acting NSAIDs.7
respiratory disorders, toothache, gingivitis, and arthritis.2,3
Compounds in this class inhibit arachidonic acid metabo-
Today, ginger and its extracts are recommended by herbal
lism via the cyclooxygenase (COX) and lipoxygenase
practitioners primarily for dyspepsia and the prevention of
(LOX) pathways. These compounds have notably fewer
motion sickness.4 A number of recent studies have renewed
side effects than conventional NSAIDs and now are being
interest in ginger for the treatment of chronic inflammatory
investigated as a novel class of anti-inflammatory com-
conditions. This interest can be traced to the discovery in
the early 1970s that non-steroidal anti-inflammatory drugs
Results of recent studies summarized in this review have
(NSAIDs) produce their effects by inhibiting the biosyn-
shown that ginger’s pharmacological effects on the inflam-
matory process extend well beyond the inhibition of PG syn-
thesis. These studies uncovered an effect of ginger on the
production of cytokines that are synthesized and secreted at
Manuscript received 12 August 2004. Revision accepted 11 November 2004.
sites of inflammation. These molecules have become highly
Address reprint requests to: Carmelita G. Frondoza, Ph.D., Department of Orthopaedic
promising targets for the treatment of chronic inflammatory
Surgery, Johns Hopkins University School of Medicine, Good Samaritan Hospital, 5601
Loch Raven Boulevard, Baltimore, MD 21239, E-mail:
[email protected]
disorders.11 The preclinical findings on mechanisms by

which ginger produces its effects are complemented by re-
compounds. HAPC include all constituents containing the
cent clinical trials that support the traditional view that gin-
3-methoxy-4-hydroxyphenyl moiety (mainly gingerols and
ger has analgesic and anti-inflammatory properties.12–15 Re-
shagaols). According to analytical certificates, each capsule
sults from clinical trials, observational studies, and case
of EV.EXT.77 contains a minimum of 30 mg of HAPC/ACA
reports on the medicinal use of ginger can be found on the
in 255 mg of mixed extract complex. Despite the success in
Internet.12 This review contains an account of the scientific
tracking the anti-inflammatory activities in chromatographic
data on ginger compiled over the past 25 years. These data
fractions of ginger extracts,6,21 no attempts have been made
strongly support the commonly held view that ginger is a
to standardize preparations based on bioactivity. This
valuable medicinal product for the treatment of chronic in-
method would have the advantage that it does not require
flammatory conditions.
knowledge of the identity of pharmacologically active con-
stituents.22 This approach would permit mixtures derived
from different sources to be standardized with respect to an
accepted biological readout such as inhibition of PG syn-
As is the case with many other herbal preparations, gin-
thesis. Such biological assay would be especially useful if
ger extracts are a complex, multicomponent mixture of bio-
active constituents of ginger exert their anti-inflammatory
logically active constituents. More than 400 chemical com-
effects via different pharmacological mechanisms and thus
pounds have been isolated and identified in extracts of
may act synergistically.
ginger rhizomes, and new ones are still being detected.16–19
At present, only a few of them have been evaluated for their
pharmacological properties. Current evidence suggests that
a subfraction containing the structurally related compounds
gingerols, shogaols, and paradols accounts for a major por-
tion of ginger’s anti-inflammatory properties. These com-
A major breakthrough in inflammation research was the
pounds share an aromatic ketone moiety but differ in the
discovery by Vane5 in 1971 that aspirin and related drugs
length of their alkyl side chain and the substitution pattern
produce their anti-inflammatory effects by inhibiting the
on the side chain. Structure–activity relationship analysis
synthesis of PGs. This seminal observation prompted sev-
suggests that the presence of the phenolic hydroxy group
eral laboratories to explore whether naturally occurring sub-
adjacent to the methoxy group is critical for the inhibition
stances with known anti-inflammatory properties also act as
of PG synthesis.20,21 The relative proportions of gingerols,
inhibitors of PG synthesis. Kiuchi et al.6 were the first to
shogaols, and paradols in ginger extracts are determined by
show that extracts of plants belonging to the Zingiberaceae
a number of factors, including the geographic origin, the ma-
family inhibit PG synthesis in vitro. These investigators sub-
turity of the rhizomes at the time of harvest, and the method
jected extracts of fresh ginger to chromatographic purifica-
by which the extracts are prepared. Shogaols, dehydrated
tion and analyzed the resulting fractions for their effect on
products of gingerols, are a major component of dried gin-
PG synthesis. They isolated and identified [6]-gingerol and
ger powder. Gingerols are thermally labile because of the
presence of a ?-hydroxy keto group, which readily undergoes
dehydration to form the corresponding shogaols (Fig. 1).
Shogaols may be further converted to paradols by hydro-
genation. Shogaols and zingerone are found only in small
quantities in fresh ginger, but are present in large amounts
in stored ginger, suggesting that this conversion takes place
during processing and storage. The extent of this conversion
is likely to have a significant impact on the health effects of
ginger preparations since the two classes of compounds are
likely to vary in their bioavailability, pharmacokinetics, and
pharmacological properties.
Differences in the methods by which ginger extracts are
prepared make it difficult to compare the results of studies
from various laboratories. Comparative studies of the phar-
macological properties of ginger would be greatly facilitated
if extracts would be standardized in reference to a univer-
sally accepted, internal constituent. Since the inhibitory ef-
fects of ginger on PG synthesis can be attributed to the pres-
ence of hydroxymethoxyphenyl compounds (HAPC), it is
reasonable to use these compounds as an internal standard.
The ginger preparation EV.EXT.77, which is derived from
Z. officinale Roscoe and Alpina galanga, is standardized in
reference to HAPC and acetoxychavicol acetate (ACA)
FIG. 1.
Chemical structures of some ginger constituents.

four structurally related compounds that inhibit PG synthe-
also leukotriene (LT) synthesis. LTs are derived from arachi-
sis in rabbit renal medulla homogenates with IC50 values
donic acid through the action of the enzyme 5-LOX (Fig.
ranging from 1.0 to 5.5 ?M. Under the same assay condi-
2). LTs are potent mediators of the inflammatory process
tions, indomethacin, one of the most potent inhibitors of PG
and are suspected of playing a key role in the development
synthesis, had an IC50 value of 4.9 ?M. These studies pro-
of gastrointestinal ulcers associated with long-term use of
vided the first direct experimental evidence that ginger con-
NSAIDs.29,30 Flynn and Rafferty7 were the first to show that
tains several constituents with anti-inflammatory activities
several ginger constituents are dual inhibitors of arachidonic
comparable in potency to NSAIDs.
acid metabolism. Compounds containing the 4-hydroxy-3-
The inhibition of PG synthesis by NSAIDs and ginger is
methoxyphenyl moiety, including [6]-gingerol, shagaol, gin-
due to inhibition of arachidonic acid metabolism by COX.23
gerdione, and dihydroparadol, inhibit PG and LT produc-
This enzyme exists in at least two distinct isoforms, desig-
tion in human neutrophils in the low micromolar range. This
nated COX-1 and COX-2.24 COX-1 is constitutively ex-
observation prompted Flynn and Rafferty7 to designate some
pressed in nearly all cells and tissues. It regulates important
ginger constituents as functional dual inhibitors of COX and
physiologic processes such as gastrointestinal cytoprotection
LOX. Kiuchi et al.21 found gingerols with long alkyl side
and electrolyte homeostasis in kidneys. In contrast, COX-2
chains (n ? 6; see Fig. 1) to be more potent inhibitors of LT
is almost undetectable in most tissues, but its expression is
synthesis than of PG synthesis. The significance of this ob-
greatly increased at sites of inflammation.24 It is generally
servation was not fully appreciated until the recent discov-
accepted that many of the toxic effects of NSAIDs are due
ery that dual inhibitors of COX and LOX are more effec-
to inhibition of COX-1, while the therapeutic effects reside
tive and have fewer gastrointestinal side effects than pure
in the inhibition of COX-2. These observations have led to
COX inhibitors.8,10 Nickerson-Nutter and Medvedoff31
major efforts by pharmaceutical companies to develop
showed that inhibitors of PG and LT synthesis in combina-
NSAIDs that preferentially inhibit COX-2.25 So far, only
tion are more effective in preventing collagen-induced
one study has attempted to determine the relative potency
arthritis in animals than inhibitors of either class of com-
of gingerols on COX enzyme activity in intact cells. A study
pounds alone. Unlike ginger, NSAIDs do not inhibit the syn-
by Tjendraputra et al.20 showed that gingerols are somewhat
thesis of LTs from arachidonic acid. Consequently, COX in-
more potent inhibitors of COX-1 than COX-2, thus identi-
hibition by NSAIDs shifts arachidonic acid metabolism to
fying them as non-selective COX inhibitors. This was a sur-
the LOX pathway, leading to an increased production of
prising finding since non-selective NSAIDs are known for
LTs.32 Compounds with this dual effect on COX and LOX
their gastrointestinal and renal side effects.26 In fact, ginger
are being evaluated as a new class of anti-inflammatory
extracts have anti-ulcer activity and are recommended for
drugs.8–10 The observation that constituents of ginger are
the treatment of gastrointestinal problems.26–28 The lack of
dual COX/LOX inhibitors may explain why even high doses
ginger’s gastrointestinal side effects suggested the presence
of ginger extract do not produce the side effects often ob-
of a yet unidentified pharmacological activity responsible
served with non-selective COX inhibitors.
for the protective effects against the toxicity associated with
COX-1 inhibition.
Several clinical studies support the value of ginger for the
treatment of arthritis. In addition to alleviating pain, ginger
An important advance in the characterization of the anti-
extract has been reported to decrease joint swelling.33,34 In
inflammatory properties of ginger was the discovery that
an exploratory trial of 57 osteoarthritic cases the ginger ex-
some of its constituents not only inhibit PG synthesis but
tract EV.EXT.33 prepared from the rhizomes of Z. offici-
FIG. 2.
Arachidonic acid is metabolized via two separate
pathways: Metabolism along the COX pathway leads to the
formation of PGs and thromboxanes, while metabolism along
the LOX pathway leads to the formation of LTs.

nale was reported to be better than placebo during the
ginger extract can inhibit the induction of pro-inflammatory
first period of treatment before cross-over with NSAIDs.14
cytokines, we have conducted a series of experiments in hu-
Altman and Marcussen13 using a similar ginger extract
man synovioctyes and chondrocytes.44,45 Synoviocytes ob-
(EV.EXT.77) conducted a 6-week, double-blind placebo-
tained during arthroplasty from osteoarthritic patients were
controlled parallel group study involving 247 patients with
activated with either TNF-? or IL-1?, the two key cytokines
osteoarthritis and demonstrated a statistically significant re-
involved in the inflammation and degradation of joints. Gin-
duction in knee pain. Their analysis of secondary efficacy
ger extract inhibited the expression of TNF-? in synovio-
variables also showed a consistently superior response in pa-
cytes activated by either IL-1? or TNF-? at the transcript
tients treated with ginger extract compared with the control
(Fig. 3) and protein levels.46 Similarly, ginger extract sup-
group. Another 6-month, double-blind placebo-controlled
pressed TNF-? expression in activated chondrocytes.45 The
study of 29 osteoarthritic patients evaluated the ginger ex-
ginger extract also inhibited the induction of genes encod-
tract Zintona EC derived from Z. officinale; this study also
ing chemokines: monocyte chemotactic protein-1 and inter-
observed significantly reduced knee pain compared with
feron-? inducible protein-10 (see Fig. 3).47
controls.15 These recent clinical studies confirm the benefi-
In addition to induction of cytokines and chemokines,
cial effects of ginger extracts in the treatment of arthritis and
COX-2 protein levels are also greatly increased in inflamed
joint tissue because of COX-2 gene induction.48 Overex-
pression of COX-2 is a characteristic feature of osteoarthri-
tis,49 rheumatoid arthritis,50 and a number of other patho-
logical conditions such as artherosclerosis, inflammatory
Genes encoding pro-inflammatory cytokines are up-reg-
ulated in chronic inflammatory conditions. Cytokines are a
class of small proteins that are secreted at sites of inflam-
mation principally by lymphocytes, macrophages, and fi-
broblasts. They function as chemical messengers between
cells involved in immune and inflammatory responses.
Chemokines are a subset of cytokines that act primarily as
chemoattractants by inducing the recruitment of effector
cells to sites of tissue damage. Inhibiting the production of
pro-inflammatory cytokines or blocking their actions is a
new and successful therapeutic approach for the treatment
of inflammatory disorders,11 most notably rheumatoid
arthritis.35 Several studies have shown that a number of nat-
ural products also contain constituents capable of inhibiting
cytokine induction in cells.36 For example, the flavonoid
wogonin inhibits inflammatory activation of microglial cells
in culture by diminishing lipopolysaccharide (LPS)-induced
tumor necrosis factor-? (TNF-?), interleukin (IL)-1?, and
nitric oxide induction.37 Chang et al.38 demonstrated that
wogonin inhibits monocyte chemotactic protein-1 gene ex-
pression in human endothelial cells. Some natural products
of the terpenoid family have been reported to suppress in-
flammatory processes via inhibition of the production of
TNF-? and IL-1?.39–41 Several products are available or are
currently under development for controlling the adverse ef-
fects of TNF-? and IL-1? overproduction in rheumatoid
FIG. 3.
Inhibition of cytokine and chemokine induction by ginger
arthritis. These include diacerein, a drug with IL-1 inhibitory
extract (GE) in human synoviocytes. Synoviocytes were incubated for
activity in vitro,42 etanercept, a TNF-? receptor fusion pro-
1 hour with media in the absence (lane 1) or presence of 100 ?g/mL
tein that competitively inhibits the binding of TNF-? to its
of GE (lane 2). Non-activated human synoviocytes express moderate
receptor, and infliximab, a monoclonal antibody that blocks
levels of TNF-? and low levels of IL-1?. When treated with TNF-?
(1 ng/mL) for 1 hour, synoviocytes in media alone showed increased
human TNF-? receptors.11,35
levels of TNF-? and IL-1? mRNA (lane 3). These increases were not
Osteoarthritis is associated with a variable degree of in-
observed in cultures of synoviocytes pretreated with GE (lane 4).
flammation. Activation of synovial cells in joints leads to
GAPDH, glyceraldehyde phosphate dehydrogenase; IP-10, interferon-?
the release of TNF-? and IL-1?.43 To determine whether a
inducible protein-10; MCP-1, monocyte chemotactic protein-1.

bowel disease, and certain types of tumors.51,52 The obser-
ropathology or signs of neurological deficits.61–63 Activa-
vation that COX-2 is up-regulated in pathological conditions
tion of microglial cells is usually a transient event designed
make suppression of COX-2 induction an obvious target. As
to allow tissue repair. Chronically activated microglial cells
illustrated in Figure 3, the ginger extract used in this study
are suspected to contribute significantly to the neuron loss
also prevents the induction of COX-2 in human synovio-
in neurodegenerative diseases. This conclusion is supported
cytes. Thus, ginger extracts inhibit COX-2 not only at the
by epidemiological studies documenting that long-term
enzyme level as described above but also at the transcrip-
use of NSAIDs significantly reduces the incidence of
tional level.46 The identity of the constituents responsible
Alzheimer’s disease.64,65 Currently, the National Institute
for these newly described effects remains to be determined.
on Aging is sponsoring a prospective clinical trial (The
Preliminary experiments with [6]-gingerol indicate that this
Alzheimer’s Disease Anti-Inflammatory Prevention Trial)
compound is not a likely candidate since it is only a weak
to determine whether the NSAIDs can delay or prevent the
inhibitor of LPS-induced cytokine induction in monocytic
onset of Alzheimer’s disease. Patients enrolled in this clin-
THP-1 cells (C.G. Frondoza et al., unpublished data). This
ical trial are cognitively normal individuals with a family
is in line with the finding of an approximately 1,000-fold
history of the disease or age-related memory loss (Study ID
difference in the concentrations of sodium salicylate and
Numbers IA0026 and U01-AG15477; NML identifier
aspirin needed to inhibit COX-2 enzyme activity and to
NCT 00007189).
inhibit COX-2 induction by LPS.53,54 If this initial obser-
In a pilot study, Grzanna et al.66 tested the effects of
vation can be confirmed, it would indicate that the anti-
the ginger extract EV.EXT.77 on THP-1 cells to deter-
cytokine effects of ginger might not be due to the presence
mine whether it can block the induction of pro-inflam-
of gingerols.
matory cytokines in these cells. THP-1 cells, a human
monocytic cell line that is widely used as a surrogate for
microglial cells, were exposed to an activator, TNF-?, IL-
1?, or LPS, in the presence or absence of ginger extract.
Figure 4 depicts the increase in mRNA in these cells in
A common pathological feature of neurodegenerative dis-
response to pro-inflammatory stimuli. Pretreatment of
eases is the concomitant inflammatory response in the cen-
THP-1 cells with ginger extract reduced or completely
tral nervous system.55–58 This inflammatory response is an
prevented gene induction (Fig. 4). Message levels of the
intrinsic defense mechanism mediated primarily by mi-
housekeeping gene glyceraldehyde phosphate dehydroge-
croglial cells. In healthy brains, these cells reside in a rest-
nase remained unchanged. The results of this study sug-
ing state. In pathological conditions, microglial cells un-
gest that the anti-inflammatory properties of the ginger ex-
dergo transformation into a cell type endowed with cytotoxic
tract are not restricted to synoviocytes and chondrocytes
and phagocytic capabilities. This transformation is charac-
but can also be observed in other cell types. In view of
terized by changes in the expression of the genes encoding
the suspected beneficial effects of anti-inflammatory
TNF-? and IL-1?. Activated microglial cells have been ob-
agents regarding the onset and progression of Alzheimer’s
served in Alzheimer’s disease59 and Parkinsons’s disease60
disease,67 ginger may provide beneficial effects similar to
and in brains of elderly individuals without apparent neu-
those of currently used COX inhibitors.
FIG. 4.
Ginger extract (GE) inhibits THP-1 cell
activation by TNF-?, IL-1?, or LPS. Cells were
preincubated with GE (10 ?g/mL) or medium alone
for1 hour. Thereafter, TNF-? (1 ng/mL), IL-1? (10
ng/mL), or LPS (20 ng/mL) was added, and cells
were incubated for an additional hour. Cell pellets
were assayed for cytokine, chemokine, and COX-
2 mRNA. Unstimulated THP-1 cells showed mod-
erate levels of TNF-? mRNA, while message lev-
els for IL-1? and COX-2 were undetectable (lane
1). Incubation of unstimulated THP-1 cells with GE
produced a slight decrease in the levels of TNF-?
(lane 2). Exposure of THP-1 cells to TNF-? (lane
3), IL-1? (lane 5), or LPS (lane 7) resulted in an
increase in mRNA levels of TNF-?, IL-1?, and
COX-2. These increases were blocked when THP-
1 cells were pretreated with GE before addition of
the stimulating agents (lanes 4, 6, and 8, respec-
tively). The housekeeping gene glyceraldehyde
phosphate dehydrogenase (GAPDH) served as a

A considerable body of scientific data supports the long-
NF-?B is a principal regulator of pro-inflammatory gene
held view that ginger has a broad spectrum of anti-inflam-
expression.68 These include genes encoding cytokines,
matory activities. The scientific data reviewed here show
chemokines, and the enzyme COX-2.69 Activated NF-?B
that ginger produces its anti-inflammatory effects through
can be detected at sites of inflammation, and a link among
multiple mechanisms. Ginger shares with NSAIDs the prop-
NF-?B activation, cytokine production, and inflammation is
erty of inhibiting PG synthesis. Some ginger constituents are
now generally accepted.70 Aberrant NF-?B activation has
dual inhibitors of COX and LOX, and thereby reduce the
been observed in synovial tissues of both osteoarthritis and
biosynthesis of both PGs and LTs. This remarkable prop-
rheumatoid arthritis71 and in several other chronic inflam-
erty distinguishes ginger from conventional NSAIDs and
matory diseases.72 NF-?B-directed therapies have been
may account for its lack of gastrointestinal and renal side
shown to be effective in several animal model of inflam-
effects. The recently discovered anti-cytokine effects of gin-
matory diseases.70 A number of natural products known for
ger show that the anti-inflammatory properties of this com-
their anti-inflammatory properties are now suspected to pro-
monly used herb are far from being fully characterized. The
duce their effects through inhibition of the NF-?B path-
identity of the constituents accounting for ginger’s anti-cy-
way.36 Several naturally occurring phenolic compounds in-
tokine effects remains to be determined. Future studies will
cluding curcumin and flavonoids have already been shown
need to address the question whether the anti-inflammatory
to inhibit NF-?B. Based on the observation that ginger ex-
effects of ginger so well documented in in vitro experiments
tract inhibits pro-inflammatory gene expression, Frondoza
can be verified in animals and humans. The results of clin-
et al.46 tested the effect of the ginger extract EV.EXT.77 on
ical studies conducted so far have been encouraging. Con-
NF-?B expression in vitro. The results show that this gin-
sidering the broad spectrum of ginger’s anti-inflammatory
ger extract significantly inhibits NF-?B expression in acti-
actions and its safety record, this herbal product is likely to
vated synoviocytes at 100 ?g/mL. Such a mechanism would
be a valuable dietary supplement in the treatment of in-
offer an explanation for the broad effect of ginger on in-
flammatory disorders.
flammatory processes in various cell types and tissues.
Some of the experiments reviewed here were supported
by a grant from the National Cancer Institute, National In-
stitutes of Health and by Ferrosan A/S.
The chemical mediators released by local or recruited
cells stimulate nociceptive primary afferents at sites of in-
flammation resulting in pain.73,74 Joint inflammation in
1. Afzal M, Al-Hadidi D, Menon M, Pesek M, Dhami MSI: Ginger:
chronic arthritis leads to hyperalgesia, a state characterized
An ethnomedical, chemical and pharmacological review. Drug
by an excessive response to noxious stimuli. PGs, TNF-?,
Metab Drug Interact 2001;18:159–190.
IL-1?, IL-6, and IL-8 all contribute to acute and chronic
2. Awang DVC: Ginger. Can Pharmaceut J 1992;125:309–311.
pain associated with inflammation. NSAIDs are effective
3. Leung AY: Encyclopedia of Common Natural Ingredients Used
in the management of inflammation-related pain. Similarly,
in Food, Drugs and Cosmetics, John Wiley and Sons, New York,
the effects of ginger in reducing joint pain are also likely
to be mediated through its effect on PG synthesis and other
4. Blumenthal M: The Complete German Commission E Mono-
inflammatory mediators. Recently, a novel molecular tar-
graphs, Americal Botanical Council, Boston, 1998.
get of ginger constituents was identified, suggesting an ad-
5. Vane JR: Inhibition of prostaglandin synthesis as a mechanism of
ditional mechanism by which ginger may reduce inflam-
action for aspirin-like drugs. Nature New Biol 1971;231:232–235.
matory pain. Dedov et al.75 reported that gingerols act as
6. Kiuchi F, Shibuya M, Sankawa U: Inhibitors of prostaglandin
biosynthesis from ginger. Chem Pharm Bull (Tokyo) 1982;30:
agonists at vanilloid receptors. These receptors had previ-
ously been identified as receptors activated by capsaicin
7. Flynn DL, Rafferty MF: Inhibition of human neurotrophil 5-
and are suspected to be present on pain afferents mediat-
lipoxygenase activity by gingerdione, shagaol, capsaicin and re-
ing joint pain.76 Vallinoid receptor agonists are potent anal-
lated pungent compounds. Prostaglandins Leukot Med 1986;24:
gesics, and the finding by Dedov et al.75 has added gin-
gerols and zingerone to the list of vanilloid receptor
8. Celotti F, Laufer S: Anti-inflammatory drugs: New multitarget
agonists. The discovery that ginger constituents function as
compounds to face an old problem. The dual inhibition concept.
agonists at vanilloid receptors provides a new mechanistic
Pharmacol Res 2001;43:429–436.
explanation for the well-documented analgesic effect of
9. Fiorucci S, Meli R, Bucci M, Cirino G: Dual inhibitors of cy-
ginger in the treatment of pain in rheumatic and inflam-
clooxygenase and 5-lipoxygenase. A new avenue to anti-inflam-
matory conditions.
matory therapy? Biochem Pharmacol 2001;62:1433–1438.

10. Martel-Pelletier J, Lajeunesse D, Reboul P, Pelletier J-P: Thera-
29. Hudson N, Balsitis M, Everitt S, Hawkey CJ: Enhanced gastric
peutic role of dual inhibitors of 5-LOX and COX, selective and
mucosal leukotriene B4synthesis in patients taking non-steroidal
non-selective non-steroidal anti-inflammatory drugs. Ann Rheum
antiinflammatory drugs. Gut 1993;34:742–747.
Dis 2003;62:501–509.
30. Asako H, Kubes P, Wallace J, Wolf RE, Granger DN: In-
11. Dinarello CA: Anti-cytokine therapeutics and infections. Vaccine
domethacin-induced leukocyte adhesion in mesenteric venules:
Role of lipoxygenase products. Am J Physiol 1992;262:G903–
12. (accessed 18 April
31. Nickerson-Nutter CL, Medvedeff ED: The effect of leukotriene
13. Altman RD, Marcussen KC: Effects of a ginger extract on knee
synthesis inhibitors in models of acute and chronic inflammation.
pain in patients with osteoarthritis. Arthritis Rheum 2001;44:
Arthritis Rheum 1996;39:515–521.
32. Laufer S: Role of eicosanoids in structural degradation in os-
14. Bliddal H, Rosetzky A, Schlichting P, Weidner MS, Andersen
teoarthritis. Curr Opin Rheumatol 2003;15:623–627.
LA, Ibfelt H-H, Christensen K, Jensen ON, Barsley J: A ran-
33. Srivastava KC, Mustafa T: Ginger (Zingiber officinale) and
domized, placebo-controlled, cross-over study of ginger extracts
rheumatic disorders. Med Hypotheses 1989;29:25–28.
and ibuprofen in osteoarthritis. Osteoarthritis Cartilage 2000;8:9–
34. Srivastava K, Mustafa T: Ginger (Zingiber officinale) in rheuma-
tism and musculoskeletal disorders. Med Hypotheses 1992;39:
15. Wigler I, Grotto I, Caspi D, Yaron M: The effects of Zintona EC
(a ginger extract) on symptomatic gonarthritis. Osteoarthritis Car-
35. Choy EHS, Panayi GS: Cytokine pathways and joint inflamma-
tilage 2003;11:783–789.
tion in rheumatoid arthritis. N Engl J Med 2001;344:907–916.
16. Duke JA: Handbook of Medicinal Herbs, CRC Press, Boca Ra-
36. Bremner P, Heinrich M: Natural products as targeted modulators
ton, FL, 2002.
of the nuclear factor-?B pathway. J Pharm Pharmacol 2001;54:
17. Ma J, Jin XJ, Yang L, Liu Z-L: Diarylheptanoids from the rhi-
zomes of Zingiber officinale. Phytochemistry 2004;65:1137–
37. Lee H, Kim YO, Kim H, Kim SY, Noh HS, Kang SS, Cho GJ,
Choi WS, Suk K: Flavonoid wogonin from medicinal herb is neu-
18. Jolad SD, Lantz RC, Solyom AM, Chen GJ, Bates RB, Timmer-
roprotective by inhibiting inflammatory activation of microglia.
mann BN: Fresh organically grown ginger (Zingiber officinale):
FASEB J 2003;17:1943–1944.
Composition and effects on LPS-induced PGE2 production. Phy-
38. Chang Y-L, Shen J-J, Wung B-S, Cheng J-J, Wang DL: Chinese
tochemistry 2004;65:1937–1954.
herbal remedy wogonin inhibits monocyte chemotactic protein-1
19. Charles R, Garg SN, Kumar S: New gingerdione from the rhi-
gene expression in human endothelial cells. Mol Pharmacol
zomes of Zingiber officinale. Fitoterapia 2000;71:716–718.
20. Tjendraputra E, Tran VH, Liu-Brennan D, Roufogalis BD, Duke
39. Suh N, Honda T, Finlay HJ, Barchowsky A, Williams C, Benoit
CC: Effect of ginger constituents and synthetic analogues on cy-
NE, Xie Q-W, Nathan C, Gribble GW, Sporn MB: Novel triter-
clooxygenase-2 enzyme in intact cells. Bioorg Chem 2001;29:
penoids suppress inducible nitric oxide synthase (iNOS) and in-
ducible cyclooxygenases (COX-2) in mouse macrophages. Can-
21. Kiuchi F, Iwakami S, Shibuya M, Hanaoka F, Sankawa U: Inhi-
cer Res 1998;58:717–723.
bition of prostaglandin and leukotriene biosynthesis by gingerols
40. Lam T, Ling T, Chowdhury C, Chao T-H, Bahjat FR, Lloyd GK,
and diaryl heptanoids. Chem Pharm Bull (Tokyo) 1992;40:387–
Moldawer LL, Palladino MA, Theodorakis EA: Synthesis of a
novel family of diterpenes and their evaluation as anti-inflamma-
22. McLaughlin JL, Rogers LL, Anderson JE: The use of biological
tory agents. Bioorg Med Chem Lett 2003;13:3217–3221.
assays to evaluate botanicals. Drug Inform J 1998;32:513–524.
41. Murakami A, Takahashi D, Kinoshita T, Koshima K, Kim HW,
23. Srivastava K: Isolation and effects of some ginger compounds on
Yoshihiro A, Nakamura Y, Jiwajinda S, Ohigashi H: Zerumbone,
platelet aggregation and eicosanoid biosynthesis. Prostaglandins
a Southeast Asian ginger sequiterpene, markedly suppresses free
Leukot Med 1986;25:187–198.
radical generation, proinflammatory protein production, and can-
24. Vane JR, Bakhele YS, Botting RM: Cyclooxygenases I and 2.
cer cell proliferation accompanied by apoptosis: The ?,?-unsatu-
Annu Rev Pharmacol Toxicol 1998;38:97–120.
rated carbonyl group is a prerequisite. Carcinogenesis 2002;23:
25. Warner TD, Mitchell JA: Cyclooxygenases: New forms, new in-
hibitors, and lessons from the clinic. FASEB J 2004;18:790–804.
42. Pelletier J-P, Yaron M, Haraoui B, Cohen P, Nahir MA, Cho-
26. Sertie JAA, Basile AC, Oshiro TT, Silva FD, Mazella AAG: Pre-
quette D, Wigler I, Rosner IA, Beaulieu AD: Efficacy and safety
ventive anti-ulcer activity of the rhizome extract of Zingiber of-
of diacerein in osteoarthritis of the knee: A double-blind, placebo-
ficinale. Fitoterapia 1992;63:55–59.
controlled trial. The Diacerein Study Group. Arthritis Rheum
27. Yoshikawa M, Yamagashi S, Kumini K, Matsuda H, Okuno Y,
Yamashara J, Murakami A: Stomachic principles in ginger. An
43. Martel-Pelletier J: Pathophysiology of osteoarthritis. Osteoarthri-
anti-ulcer principle 6-gingesulfonic acid, and three monoacyl-
tis Cartilage 2003;11:1–3.
digalactosylglycerols gingerglycolipids A, B, and C, from Zin-
44. Frondoza CG, Frazier C, Polotsky A, Lahiji K, Hungerford DS:
giber rhizome originating in Taiwan. Chem Pharm Bull (Tokyo)
TNF-alpha expression of synoviocyte cultures is inhibited by hy-
droxy-alkoxy-phenyl compounds (HAPC) from ginger. Trans Or-
28. Yamahara J, Mochizuki M, Rong HQ, MAtsuda H, Fujimura H:
thop Res Soc 2000;46:1038.
The anti-ulcer effect in rats of ginger constituents. J Ethnophar-
45. Frondoza CG, Frazier C, Polotsky A, Lahiji K, Hungerford DS,
macol 1988;23:299–304.
Weidner M: Inhibition of chondrocyte and synoviocyte TNF-?

expression by hydroxy-alkoxy-phenyl compounds (HAPC) [ab-
60. Orr CF, Rowe DB, Halliday GM: An inflammatory review of
stract]. In: 3rd Symposium, International Cartilage Repair Soci-
Parkinson’s disease. Prog Neurobiol 2002;68:325–340.
ety, Gothenburg, Sweden, 2000, p. 35.
61. Benveniste EN: Role of macrophage/microglia in multiple scle-
46. Frondoza CG, Sohrabi A, Polotsky A, Phan PV, Hungerford DS,
rosis and experimental allergic encephalomyelitis. J Mol Med
Lindmark L: An in vitro screening assay for inhibitors of proin-
flammatory mediators in herbal extracts using human synoviocyte
62. Lue LF, Rydell R, Brigham EF, Yang L-B, Hampel H, Murphy
cultures. In Vitro 2004;30:95–101.
GM Jr, Brachova L, Yan S-D, Waker DG, Shen Y, Roger J: In-
47. Phan P, Sohrabi A, Polotsky A, Lindmark L, Hungerford DS,
flammatory repertoire of Alzheimer’s disease and nondemented
Lindmark L, Frondoza CG: Ginger extract components suppress
elderly microglia in vitro. Glia 2001;35:72–79.
induction of chemokine expression in human synoviocytes. J Al-
63. Rozovsky I, Finch CE, Morgan TE: Age-related activation of mi-
tern Complement Med 2005;11:149–154.
croglia and astrocytes: In vitro studies show persistent phenotypes
48. Stack E, DuBois RN: Regulation of cyclo-oxygenase-2. Best
of aging, increased proliferation, and resistance to down-regula-
Pract Res Clin Gastroenterol 2001;15:787–800.
tion. Neurobiol Aging 1998;19:97–103.
49. Amin AR, Attur M, Patel RN, Thakker GD, Marshall PJ, Rediske
64. in t’ Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn
J, Stuchin SA, Patel IR, Abramson SB: Superinduction of cy-
CM, Stijnen T, Breteler MMB, Stricker BHC: Nonsteroidal anti-
clcooxygenase-2 activity in human osteoarthritis-affected carti-
inflammatory drugs and the risk of Alzheimer’s disease. N Engl
lage. Influence of nitric oxide. J Clin Invest 1997;99:1231–1237.
J Med 2001;345:1515–1521.
50. Kang RY, Freire-Moar J, Sigal E, Chu CQ: Expression of cy-
65. Stewart WT, Kawas C, Corrada M, Metter EJ: Risk of
clooxygenase-2 in human and animal model of rheumatoid arthri-
Alzheimer’s disease and duration of NSAID use. Neurology
tis. Br J Rheumatol 1996;35:711–718.
51. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Hahn
66. Grzanna R, Phan PV, Polotsky A, Lindmark L, Frondoza CG:
KB: Molecular mechanisms underlying chemopreventive activi-
Ginger extract inhibits ?-amyloid peptide-induced cytokine and
ties of anti-inflammatory phytochemicals: Down-regulation of
chemokine expression in cultured THP-1 monocytes. J Altern
COX-2 and iNOS through suppression of NF-?B activation. Mu-
Complement Med 2004;10:1009–1013.
tat Res 2001;480–481:243–268.
67. Helmuth L: Protecting the brain while killing pain? Science
52. Lipsky PE: Specific COX-2 inhibitors in arthritis, oncology, and
beyond: Where is the science headed? J Rheumatol 1999;26:
68. Baeuerle PA, Baichwal VR: NF-?B as a frequent target for im-
munosuppressive and anti-inflammatory molecules. Adv Immunol
53. Kopp E, Ghosh S: Inhibition of NF-?B by sodium salicylate and
aspirin. Science 1994;265:956–959.
69. Christman JW, Lancaster LH, Blackwell TS: Nuclear factor ?B:
54. Housby JN, Cahill CM, Chu B, Prevelige R, Bickford K, Seven-
A pivotal role in the systemic inflammatory response syndrome
son MA, Calderwood SK: Non-steroidal anti-inflammatory drugs
and new target for therapy. Intensive Care Med 1998;24:1131–
inhibit the expression of cytokines and induce HSP70 in human
monocytes. Cytokine 1998;11:347–358.
70. Tak PP, Firestein GS: NF-?B: A key role in inflammatory dis-
55. Carty TJ, Sweeney FJ, Griffiths RJ, Ernest MJ, Pillar JS, Cheng
eases. J Clin Invest 2001;107:7–11.
JS, Loose LD, Joseph PA, Pazoles PP, Moore PF, Nagahisa A,
71. Marok R, Winyard PG, Coumbe A, Kus ML, Gaffney K, Blades
Kadin SB: Tenidap inhibits 5-lipoxygenase product formation in
S, Mapp PI, Morris CJ, Blake DR, Kaltschmidt C, Baeuerle PA:
vitro, but this activity is not observed in vivo. Inflamm Res
Activation transcription factor NF-?B in human inflamed synovial
tissue. Arthritis Rheum 1996;39:583–591.
56. Gonzalez-Scarano F, Baltuch G: Microglia as mediators of in-
72. Yamamoto Y, Gaynor RB: Therapeutic potential of inhibition of
flammatory and degenerative diseases. Annu Rev Neurosci 1999;
the NF-?B pathway in the treatment of inflammation and cancer.
J Clin Invest 2001;107:135–142.
57. Kreutzberg GW: Microglia: A sensor for pathological events in
73. Fakata KL: Anti-inflammatory agents for the treatment of mus-
the CNS. Trends Neurosci 1996;19:312–318.
culoskeletal pain and arthritis. Curr Pain Headache Rep 2004;8:
58. Stoll G, Jander S: The role of microglia and macrophages in the
pathophysiology of the CNS. Prog Neurobiol 1999;58:233–247.
74. Schaible HG, Ebersberger A, von Banchet GS: Mechanisms of
59. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM,
pain in arthritis. Ann NY Acad Sci 2002;966:343–354.
Cooper NR, Eikelboom P, Emmerling M, Fiebich BL, Finch CE,
75. Dedov VN, Tran VH, Duke CC, Connor M, Christie MJ, Man-
Frautschy SA, Griffin WST, Hampel H, Hull M, Landreth G, Lue
dadi S, Roufogalis BD: Gingerols: A novel class of vanilloid re-
L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J,
ceptor (VR1) agonists. Br J Pharmacol 2002;137:793–798.
Pasinetti G, Plata-Salaman C, Rogers J, Rydell R, Shen Y, Streit W,
76. He X, Schepelmann K, Schaible HG, Schmidt RF: Capsaicin
Strohmeyer R, Tooyoma I, van Muiswinkel FL, Veerhuis R, Walker
inhibits responses of fine afferents from the knee joint of the
D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T: Inflamma-
cat to mechanical and chemical stimuli. Brain Res 1990;530:
tion and Alzheimer’s disease. Neurobiol Aging 2000;21:383–421.

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