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

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

Review
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
ABSTRACT
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
INTRODUCTION
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
pounds.8–10
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:
cgfrondo@jhmi.edu
disorders.11 The preclinical findings on mechanisms by
125

126
GRZANNA ET AL.
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
CONSTITUENTS OF GINGER
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
GINGER INHIBITS PG BIOSYNTHESIS
pharmacological properties. Current evidence suggests that
THROUGH INHIBITION OF COX-1 AND
a subfraction containing the structurally related compounds
COX-2 ENZYME ACTIVITY
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.

ANTI-INFLAMMATORY EFFECTS OF GINGER
127
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.
GINGER HAS A HISTORY OF USE FOR
THE TREATMENT OF RHEUMATISM
GINGER CONSTITUENTS ARE DUAL
INHIBITORS OF COX AND 5-LOX
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.

128
GRZANNA ET AL.
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
inflammation.
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-
GINGER EXTRACT INHIBITS CYTOKINE AND
logical conditions such as artherosclerosis, inflammatory
CHEMOKINE INDUCTION IN SYNOVIOCYTES
AND CHONDROCYTES—IMPLICATIONS FOR
THE TREATMENT OF ARTHRITIS
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.

ANTI-INFLAMMATORY EFFECTS OF GINGER
129
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
GINGER AND HUMAN MONOCYTIC
microglial cells, were exposed to an activator, TNF-?, IL-
CELL ACTIVITY
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
control.

130
GRZANNA ET AL.
GINGER INHIBITS THE TRANSCRIPTION
CONCLUSION
FACTOR NUCLEAR FACTOR-?B (NF-?B)
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.
ACKNOWLEDGMENTS
GINGEROLS AS VANILLOID RECEPTOR
Some of the experiments reviewed here were supported
AGONISTS—A NOVEL MECHANISM FOR
by a grant from the National Cancer Institute, National In-
GINGER’S EFFECT ON PAIN
stitutes of Health and by Ferrosan A/S.
The chemical mediators released by local or recruited
REFERENCES
cells stimulate nociceptive primary afferents at sites of in-
flammation resulting in pain.73,74 Joint inflammation in
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