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Efficacy and safety of freeze-dried cat's claw in osteoarthritis of the knee: Mechanisms of action of the species Uncaria guianensis


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Aim: The purpose of this investigation was to evaluate the ability of cat's claw, an Amazonian medicinal plant, to treat osteoarthritis of the knee, collect safety and tolerance information and compare the antioxidant, and anti-inflammatory actions of Uncaria guianensis and Uncaria tomentosa in vitro. Materials and methods: Forty-five patients with osteoarthritis of the knee were recruited, 30 were treated with freeze-dried U guianensis, and 15 with placebo. Hematological parameters were assessed on entry and exit of the four-week trial. Pain, medical and subject assessment scores and adverse effects were collected at weeks 1, 2 and 4. The antioxidant and anti-inflammatory activity of the cat's claw species was determined by the alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) free radical scavenging method. Inhibition of TNFalpha and prostaglandin E2 (PGE2) production was determined in RAW 264.7 cells by ELISA. Results: Cat's claw had no deleterious effects on blood or liver function or other significant side-effects compared to placebo. Pain associated with activity, medical and patient assessment scores were all significantly reduced, with benefits occurring within the first week of therapy. Knee pain at rest or at night, and knee circumference were not significantly reduced by cat's claw during this brief trial. In vitro tests indicated that U guianensis and U. tomentosa were equivalent at quenching DPPH radicals (EC50, 13.6-21.7 microg/ml) as well as inhibiting TNFalpha production. However, the latter action was registered at much lower concentrations (EC50, 10.2-10.9 ng/ml). Cat's claw (10 microg/ml) had no effect on basal PGE2 production, but reduced LPS-induced PGE2 release (P < 0.05), but at higher concentrations than that required for TNFalpha inhibition. Conclusion: Cat's claw is an effective treatment for osteoarthritis. The species, U guianensis and U tomentosa are equiactive. They are effective antioxidants, but their anti-inflammatory properties may result from their ability to inhibit TNFalpha and to a lesser extent PGE2 production.
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Abstract. Aim: The purpose of this investigation was to eval-
uate the ability of cat’s claw, an Amazonian medicinal plant,
to treat osteoarthritis of the knee, collect safety and tolerance
information and compare the antioxidant, and anti-inflam-
matory actions of Uncaria guianensis and Uncaria tomen-
tosa in vitro.
Materials and methods: Forty-five patients with osteoarthri-
tis of the knee were recruited, 30 were treated with freeze-
dried U. guianensis, and 15 with placebo. Hematological
parameters were assessed on entry and exit of the four-week
trial. Pain, medical and subject assessment scores and
adverse effects were collected at weeks 1, 2 and 4. The
antioxidant and anti-inflammatory activity of the cat’s claw
species was determined by the
drazyl (DPPH) free radical scavenging method. Inhibition of
and prostaglandin E
) production was deter-
mined in RAW 264.7 cells by ELISA.
Results: Cat’s claw had no deleterious effects on blood or liv-
er function or other significant side-effects compared to
placebo. Pain associated with activity, medical and patient
assessment scores were all significantly reduced, with bene-
fits occurring within the first week of therapy. Knee pain at
rest or at night, and knee circumference were not significant-
ly reduced by cat’s claw during this brief trial. In vitro tests
indicated that U. guianensis and U. tomentosa were equiva-
lent at quenching DPPH radicals (EC
, 13.621.7 mg/ml) as
well as inhibiting TNF
production. However, the latter
action was registered at much lower concentrations (EC
10.210.9 ng/ml). Cat’s claw (10 mg/ml) had no effect on
basal PGE
production, but reduced LPS-induced PGE
release (P < 0.05), but at higher concentrations than that
required for TNF
Conclusion: Cat’s claw is an effective treatment for
osteoarthritis. The species, U. guianensis and U. tomentosa
Inflamm. res. 50 (2001) 442 448
1023-3830/01/090442-07 $ 1.50+0.20/0
are equiactive. They are effective antioxidants, but their anti-
inflammatory properties may result from their ability to
inhibit TNF
and to a lesser extent PGE
Key words: Inflammation – TNF
Antioxidant – Prosta-
glandin – Complimentary medicine
Cat’s claw is a medicinal plant from the Amazon River basin
that has been used for the treatment of chronic inflammation,
including arthritis, by indigenous cultures for centuries.
Despite its increasing popularity in the Western world, there
are no studies that have assessed its therapeutic potential for
arthritis in a placebo controlled trial. This present investiga-
tion was designed to assess this potential, and in addition,
compare the antioxidant and anti-inflammatory properties of
two species of cat’s claw. In the Western world Uncaria
tomentosa is better known than Uncaria guianensis, but both
species share the same traditional ethnomedical applications.
To date a direct comparison of these species in models of
inflammation is lacking.
Preclinical evaluation of cat’s claw has largely been
directed at Uncaria tomentosa. We have described that this
specie of cat’s claw protects against a multitude of oxidative
stresses, including peroxynitrite [1] which has been implicat-
ed as a mediator of arthritis [2] and other chronic inflamma-
tory disorders [3, 4], as well as UV radiation and free radical
-picrylhydrazyl, DPPH) induced cytotoxici-
ty [5]. Further, we have observed that cat’s claw prevents the
gastrointestinal damage from high dose NSAIDs, either as
acute gastritis [6] or chronic enteritis [5]. These observations
alone would suggest that cat’s claw be considered as an
adjunct therapy in the treatment of arthritis. However, as cat’s
claw may attenuate directly arthritic joint pain and dysfunc-
© Birkhäuser Verlag, Basel, 2001
Inflammation Research
Original Research Papers
Efficacy and safety of freeze-dried cat’s claw in osteoarthritis of the
knee: mechanisms of action of the species Uncaria guianensis
J. Piscoya
, Z. Rodriguez
, S. A. Bustamante
, N. N. Okuhama
, M. J.S. Miller
and M. Sandoval
Universidad Nacional Mayor de San Marcos, Facultad de Medicina, Lima, Peru
Rainforest Phytoceuticals, LLC, Delmar, NY, USA
Center for Cardiovascular Sciences, Albany Medical College, 47 New Scotland Avenue (MC8), Albany, NY, 12208, USA, Fax: ++518 262 5241,
Reveived 31 August 2000; returned for revision 10 November 2000; accepted by L.G. Letts 17 November 2000
Correspondence to: M. Sandoval
tion a detailed assessment in arthritis is warranted. Previous-
ly, many have erroneously considered cat’s claw as an
immune stimulant, a counter-intuitive concept for an anti-
inflammatory agent that arose from a patent on the oxindole
alkaloids present in Cat’s claw [79]. We have described that
cat’s claw is a remarkably potent inhibitor of NF-
B [1], a
critical transcription factor implicated in arthritis [10, 11].
Inhibition of NF-
B is a highly prized mechanism in the
development of new anti-inflammatory agents. We have
determined that cat’s claw (Uncaria tomentosa) is an effec-
tive inhibitor of TNF
gene expression in vitro and in vivo.
production is regulated at the transcriptional level,
largely by NF-
B [11]. The effectiveness of TNF
therapies for arthritis is proof positive that NF-
B activation
and TNF
production are critical elements of the disease
process [12, 13]. Consequently, any therapeutic agent that
shares this action has the potential to offer benefit in arthritis
[14]. In addition, considering that osteoarthritis (OA) is the
most common form of arthritis in developing countries and
the United States [15], and causes pain and disability in old-
er people [1618], it is warranted to investigate the use of
this Amazonian medicinal plant for the treatment of OA. To
test this hypothesis, we set out to evaluate a cat’s claw specie,
Uncaria guianensis in osteoarthritis a specie low in oxindole
alkaloids, and to compare its in vitro actions with Uncaria
Materials and methods
Except where noted, all chemicals were at least reagent grade and were
obtained from Sigma Chemical Company (St. Louis, MO). Cat’s claw
(Uncaria tomentosa and Uncaria guianensis) was collected from the
Upper Tropical Region of Peru. The authenticity of the two species of
cat’s claw was confirmed by Ing. Warren Rios, Professor at Universidad
Nacional Agraria de la Selva, Tingo Maria, Peru.
Cat’s claw preparation
For the clinical trial, an aqueous extraction of cat’s claw bark (Uncaria
guianensis) was prepared by boiling in hot water for 30 minutes, decant-
ed and total solids separated by filtration with a Whatman N
4 filter
paper. The filtrate was then freeze-dried in the laboratories of Universi-
dad Nacional Mayor de San Marcos, Lima, Peru. Then tablets were pre-
pared with the freeze-dried (100 mg + excipient). For the in vitro exper-
iments, Rainforest Phytoceuticals, LLC (Delmar, NY,, supplied purified freeze-dried extracts of Uncaria
tomentosa and Uncaria guianensis.
Forty-five male patients, ages 45-75 years, with symptomatic
osteoarthritis (OA) of the knee (grades II-III of the Kellgren/Lawrence
(K/L) classification [19], fulfilling the American College of Rheuma-
tology criteria for the knee [20], and with pain present most days of the
prior month were recruited for the study. Radiographic evidence of knee
OA was defined by the presence of osteophytes in at least 1 tibiofemoral
compartment. Criteria for entry into the study were osteoarthritis of the
knee that required NSAID therapy for at least 3 months prior to the
study, and there had to be evidence of knee pain on movement scored by
the patient [21]. Before entering the trial, patients underwent washout
periods of 7 days for any NSAIDs or 12 hours for analgesics. During the
trial, acetaminophen intake (500-mg tablets) was permitted in cases of
persistent pain, and the dose and duration were recorded. Entry also
required a normal liver and hematological function assessment (alanine
aminotransferase – ALT; aspartate aminotransferase – AST; erythrocyte
sedimentation rate – ESR, hematocrit and hemoglobin) at baseline as
previously described [22].
Patients were not retained for the study if they had serious con-
comitant medical illness (pre-existing renal, cardiovascular, gastroin-
testinal, hepatic or hematological complications, and history of alco-
holism or drug abuse), secondary OA, radiographic grade IV by the K/L
classification, hypersensitivity reactions to salicylates nor patients tak-
ing oral anticoagulants, systemic or treated with intraarticular injection
of glucocorticoids for at least three months before the study.
Study design
This was a prospective, multicenter, randomized, double blind, placebo-
controlled, parallel trial of 4-week duration. This duration was chosen
according to personal communication from previous patients taking
freeze-dried cat’s claw, and also to gain more information about cat’s
claw safety profile. The study was conducted in accordance with the
Helsinki Declaration (1964) and its revision (1975). Patients entered the
study after fulfilling the inclusion and exclusion criteria and signing an
informed consent.
Cat’s claw administration
Patients were randomly assigned to two treatment groups. One group
(n = 15) received placebo (1 capsule daily), the second group (n = 30)
received 100 mg of freeze-dried cat’s claw (1 capsule of 100 mg daily).
Placebo tablets contained the same excipient but without cat’s claw.
Physicians and patients were blind to the treatment nature, and identical
procedures were also used in the laboratory analysis.
Evaluation of efficacy
Subjects were assessed at the commencement of the study for pain at
rest, at night and during exercise. Tenderness was scored on a 4-point
scale [21], (0 = no tenderness, 1 = patient complained of pain, 2 =
patient complained of pain and winced, 3 = patient complained of pain,
winced and withdrew the joint). The global tolerance to the study treat-
ment was assessed by the patient and the investigator at weeks 14 of
the trial, as described previously [23 25] with a scoring system using a
5-point scale (very good, good, moderate bad and very bad). Subjects
were also assessed at the conclusion of the study for ALT, AST, ESR,
hematocrit and hemoglobin. All adverse effects (AEs) reported by the
patients during the study treatment were recorded on the case report
form (CRF) and described their nature, frequency and severity.
Free radical scavenging assay.
The DPPH free radical scavenging method previously reported [26] was
modified as follows. The soluble solids content of the cat’s claw extracts
were standardized to give stock solutions containing 20 mg/ml water.
An aliquot of the freeze-dried cat’s claw extracts (U. tomentosa or U.
guianensis) were placed in a cuvette and a 60 mM ethanolic solution of
DPPH were added (final vol 1 ml). The decrease in absorbance at 515
nm was determined continuously with data capturing at 30-sec intervals
with a Beckman Coulter DU-640 spectrophotometer (Beckman Instru-
ments, Fullerton, CA). All determinations were performed in triplicate.
The DPPH scavenging capacity of cat’s claw was determined as previ-
ously described [5]. Ascorbic acid (10 100 mM) was used as a refer-
ence antioxidant-control to compare the efficacy of DPPH inhibition.
Vol. 50, 2001 Osteoarthritis and cat’s claw 443
Inhibition of TNF
The ability of cat’s claw to inhibit TNF
synthesis/release in vitro was
determined by stimulating TNF
production in RAW 264.7 cells
(1 ¥ 10
cells/well), a murine macrophage cell line, after administration
of lipopolysaccharide (LPS, 50 ng/ml). Cells were either pretreated with
cat’s claw (Uncaria tomentosa or Uncaria guianensis) with concentra-
tions ranging from 1 to 1000 ng/ml for two h and/or treated with LPS
(50 ng/ml) for 1 h. The media was then replaced and cells were incu-
bated at 37 °C for 16 h. Culture medium was collected for determination
of TNF
levels using the Quantikine M mouse TNF
Immunoassay kit
(R & D Systems Inc., Minneapolis, MN). Samples were processed for
ELISA determinations following the manufacturer’s recommendations.
Inhibition of PGE
RAW 264.7 cells (1 ¥ 10
cells/well) were used to determine the capac-
ity of cat’s claw (Uncaria tomentosa) to decrease the production of LPS-
induced prostaglandin E
). Cells were pretreated with cat’s claw
(10 mg/ml) for 1 h, then the media was replaced with medium contain-
ing LPS (50 ng/ml), and cells were incubated at 37 °C for 4 h. At the end
of the incubation period, medium was collected and PGE
was quanti-
fied using a Prostaglandin E
EIA kit-monoclonal (Cayman Chemical,
Ann Arbor, MI).
Data analysis
Clinical trial data was evaluated by one-way ANOVA followed by post
hoc analysis with the Kruskal-Wallis and Mann-Whitney test. Results
are expressed as the mean ± SE. Statistical analysis for the in vitro
experiments was performed using t-test and one-way ANOVA. Post hoc
comparison of means was done by Least Significant Difference test and
unpaired t-test. A probability value of < 0.05 was considered signifi-
Clinical Trial
At the commencement of the study there was no difference
between the treatment groups in all variables assessed –
hematological and disease activity scores, indicating effec-
tive randomization (Table 1). Compared to placebo, the cat’s
claw group had a significant improvement in the pain associ-
ated with activity (Fig. 1), patient and medical assessment
scores (Fig. 2). Importantly, all of these indices were found to
be improved significantly after one week of the trial, with the
exception of the medical assessment score which bordered
on significance (P = 0.0715) but improvement was highly
significant at weeks 2 and 4 (P < 0.001). In addition, there
was a significant improvement in these disease indices with
time of treatment (P < 0.05), with scores at week 4 lower than
baseline or week 1 values.
In contrast, pain at rest or at night, and knee circumfer-
ence (Table 2) were not significantly altered in either place-
bo or cat’s claw groups during the course of the study. No
change in hematological determinations was observed in
either group, over the course of the study (Table 3). There
was also no difference in the incidence and form of side
effects reported by the two groups. Specifically, at week one,
in the cat’s claw group one patient presented with vomiting
444 J. Piscoya et al. Inflamm. res.
Table 1. Patient demographics and baseline characteristics.
Placebo 100 mg/day
(n = 15) Freeze-dried
cat’s claw
(n = 30)
Age, years 60.9 ± 6.5 59.9 ± 8.4
Rest pain score 4.2 ± 2.9 4.4 ± 2.6
Activity pain score 6.8 ± 1.9 5.7 ± 2.6
Night pain score 4.6 ± 2.8 4.6 ± 2.3
Right knee perimeter 41.2 ± 8.4 39.0 ± 7.4
Left knee perimeter 40.0 ± 7.1 38.6 ± 8.4
Values are the mean ± SD. No statistical differences between the two
Fig. 1. Pain on activity scores in placebo (n = 15) and cat’s claw (n = 30)
treated groups at the commencement of the trial, as well as determina-
tions at week 1, 2 and 4. The single * indicates significant difference
from placebo (P < 0.01) and ** indicates significant difference from
placebo (P < 0.001).
Fig. 2. Physician (medical) and patient assessment scores of disease
activity in placebo (n = 15) and cat’s claw (n = 30) treated groups, as
determined at week 1, 2 and 4 of the trial. The * indicates a significant
difference from placebo (P < 0.05), and the † indicates significant dif-
ference from placebo (P < 0.001).
and another with dizziness. At week two, the cat’s claw group
had 5 patients reporting headache (P = 0.1526), and at week
four, three patients in the cat’s claw group and one patient in
the placebo group presented with headache; one patient in
the placebo group reported dizziness and another reported
ringing in the ears (P = 0.3842).
Free radical scavenging
DPPH gives a steady absorbance reading at 515 nm.
Absorbance declined in the presence of cat’s claw (Fig. 3),
indicating radical quenching. The effectiveness of Uncaria
guianensis and Uncaria tomentosa as DPPH scavengers is
shown in Figure 3. The EC
for both species were 13.6 vs
21.7 mg/ml, respectively (Table 4). While the rate of quench-
ing may have been marginally greater for Uncaria guianen-
sis at some concentrations this had no impact on total antiox-
idant activity. Thus, we regard their antioxidant activity in
this system to be comparable.
Inhibition of TNF
Murine macrophages (RAW 264.7 cells) when stimulated
with LPS release substantial quantities of TNF
into the
media. Inclusion of cat’s claw into the media prior to LPS
administration, resulted in a dose-dependent reduction in
levels (Fig. 4, P < 0.001). As observed with the DPPH
assay, the potency of Uncaria tomentosa and Uncaria guia-
nensis extracts as inhibitors of TNF
synthesis were equiva-
lent in this assay. It is important to note however that the con-
centrations required to inhibit TNF
production were con-
siderably lower than that needed to quench DPPH radicals
(Table 4).
Inhibition of PGE
Murine macrophages (RAW 264.7 cells) were also used to
assess PGE
release. Cat’s claw had no effect on basal
(unstimulated) PGE
production, indicating that cyclooxyge-
nase-1 (COX-1) activity was not influenced. However, the
marked increase in PGE
production induced by LPS
(0.5 mg/ml) was significantly reduced (P < 0.05) by cat’s claw
(Figure 5), suggestive of an inhibition of cyclooxygenase-2
(COX-2) expression. The dose of cat’s claw (10 mg/ml) was
greater than that required suppressing TNF
production but
less than concentrations required for antioxidant activity.
Vol. 50, 2001 Osteoarthritis and cat’s claw 445
Table 2. Effect of cat’s claw (Uncaria guianensis) on measures of pain
at rest and night.
Assessment Placebo Freeze-dried cat’s claw
of pain
Entry Week 4 Entry Week 4
Score at rest 4.15 ± 0.77 3.94 ± 0.69 4.41 ± 0.48 3.42 ± 0.33
Score at night 4.60 ± 0.74 4.17 ± 0.69 4.63 ± 0.42 3.06 ± 0.37
Values are mean ± SE from participants of the study.
Table 3. Effect of cat’s claw (Uncaria guianensis) on hematological
Assessment Placebo Freeze-dried Cat’s claw
Entry Week 4 Entry Week 4
Hemoglobin, 14.41 ± 2.01 12.67 ± 0.31 12.75 ± 0.23 13.89 ± 1.05
Hematocrit, 37.29 ± 2.41 39.15 ± 1.29 38.00 ± 0.67 36.87 ± 1.30
ESR, mm/h 20.97 ± 1.49 16.56 ± 0.98 17.80 ± 1.08 17.75 ± 1.18
AST, U/L 32.82 ± 8.59 25.31 ± 2.17 21.77 ± 1.37 29.69 ± 8.11
ALT, U/L 19.41 ± 2.65 21.12 ± 2.08 21.04 ± 1.51 19.38 ± 1.63
Values are mean ± SE from participants of the study as described in
materials and methods. Erythrocyte sedimentation rate (ESR), Aspar-
tate aminotransferase (AST), and Alanine aminotransferase (ALT).
Fig. 3. Antioxidant activity of cat’s claw assessed by DPPH free radical
method. The DPPH scavenging capacity of cat’s claw Uncaria guianen-
sis (solid bars) and Uncaria tomentosa (open bars) was quantified spec-
trophotometrically at 515 nm. In vitro reactions were carried out for
5 min and the degree of DPPH inhibition is expressed as absorbance
depletion as described in Materials and methods. Values are mean ± SE
of three experiments with three samples each. No significant difference
between the species was noted in their ability to quench DPPH. Inset:
DPPH inhibition by ascorbic acid as antioxidant of reference r = 0.9784
, 4.8 mM).
Table 4. Comparison of the antioxidant and anti-TNF
activities of
cat’s claw species.
Assay Freeze-dried cat’s claw
Uncaria tomentosa Uncaria guianensis
Max EC
Inhibition, % Inhibition, %
Antioxidant 21.7 mg/ml 85.5 13.6 mg/ml 90.5
10.2 ng/ml 79.0 10.9 ng/ml 73.0
Freeze-dried cat’s claw was used for these experiments. The antioxidant
activity was assayed by in vitro scavenging of the free radical DPPH
(60 mM), and quantified spectrophotometrically at 515 nm. The anti-
activity was determined using the Quantikine M mouse TNF
immunoassay as described in Materials and methods.
This placebo-controlled double blind study clearly defines
that cat’s claw (Uncaria guianensis) is an effective treatment
for osteoarthritis of the knee. Within the four-week study
protocol the major benefits of cat’s claw treatment were in
alleviating pain associated with exercise, patient and physi-
cian assessment scores. Improvement in knee circumference
and pain at rest or at night was not observed but this may
reflect the duration of treatment, as therapeutic trends were
evident with cat’s claw and treatment duration was a signifi-
cant factor in the disease assessment scores and pain with
exercise. Cat’s claw therapy was not associated with any
changes in liver or hematological function, and the incidence
and frequency of side effects was not different from placebo
control. In this limited study we confirm the ethnomedical
reputation of cat’s claw for being well tolerated and safe.
Whether the more popular specie of cat’s claw, Uncaria
tomentosa, is more effective in treating arthritis is unknown
and was not the goal of this study. However, we attempted to
address this issue in the laboratory setting. Uncaria tomen-
tosa and Uncaria guianensis displayed comparable antioxi-
dant activity using the DPPH free radical scavenging assay.
Certainly oxidative stress and free radical damage has been
implicated in arthritis [27 29] and other chronic inflamma-
tory diseases [3, 5]. The antioxidant function of cat’s claw
may explain its ability to offer benefit to patients with
osteoarthritis. On the other hand, the therapeutic benefits of
antioxidants alone can be questioned.
In the TNF
production assay, species were equivalent,
producing substantial reductions in TNF
synthesis. A criti-
cal finding was that suppression of TNF
production was
noted at concentrations that were far less than that required
for antioxidant activity (Table 4). The cytokine TNF
regarded as a critical mediator of chronic inflammation [30,
31], including arthritis [13, 14, 32]. The success of Inflix-
imab™, the TNF
antibody therapy in bringing active dis-
ease into quiescence is proof positive that TNF
is a legiti-
mate therapeutic target. Whether the benefits of cat’s claw are
solely due to inhibition of TNF
production is unknown.
Indeed, the use of TNF
antibody therapy is usually confined
to rheumatoid arthritis and here we have examined the effects
of cat’s claw in osteoarthritis. However, inflammatory medi-
ators are activated in both forms of joint inflammation
although differences in cellular source and etiology exist
[33]. We have demonstrated that cat’s claw inhibits TNF
gene expression in gastric mucosa in NSAID gastritis [6]: an
action that is the result of its ability to inhibit the activation
of NF-
B [1]. The transcription factor NF-
B, is a redox-sen-
sitive transcription factor that regulates the expression of
over 28 different genes involved in inflammation [12], coor-
dinating many aspects of the inflammatory process (adhesion
molecules, cytokines, chemokines, enzymes). Inducible
nitric oxide synthase is an example of a NF-
B regulated
gene, that has been implicated in osteoarthritis [28, 29],
whose expression can be reduced by either cat’s claw direct-
ly [1] or by anti-TNF
antibody [32]. Thus, suppression of
B activation is critical target for treating inflammation,
as has been demonstrated with antisense technology [34].
While NF-
B is activated by oxidants, there was a clear dis-
crepancy in the concentrations required for these two species,
Uncaria tomentosa and Uncaria guianensis to act either as
antioxidants or anti-TNF
agents. We interpret this to mean
that the different constituents in this decoction are responsi-
ble for antioxidant and anti-TNF
activities, or alternatively
these components are functionally more directed at tran-
scriptional inhibition than antioxidant activity.
The importance of this study is that it provides therapeu-
tic information as to the application of a medicinal plant in
446 J. Piscoya et al. Inflamm. res.
Fig. 4. Effect of cat’s claw (Uncaria tomentosa and Uncaria guianen-
sis) on LPS-induced TNF
production by macrophages (RAW 264.7).
Cells were seeded at 1 ¥ 10
cells/well. Freeze-dried concentrates from
both species of cat’s claw inhibited TNF
production in an equivalent
dose-dependent manner. Bars represent TNF
release into the media for
Uncaria tomentosa (horizontal) and Uncaria guianensis (cross). Cells
were treated with LPS (50 ng/ml) for 1 h or pretreated with freeze-dried
cat’s claw for 2 h then challenged with LPS for 1 h, and incubated for
16 h as described in Materials and methods. All data represent mean ±
SE for triplicate determinations. * significant decrease (P < 0.05) from
LPS alone for Uncaria guianensis. ** significant decrease (P < 0.01)
from LPS alone, for both species.
Fig. 5. Effect of cat’s claw (Uncaria tomentosa) on prostaglandin E
) production. Murine macrophages (RAW 264.7 cells) were
pretreated with cat’s claw (10 mg/ml) for 1 h and/or treated with LPS
(50 ng/ml) for 4 h. PGE
release into the media was assessed by ELISA
as described in Materials and methods. All data represent mean ± SE
for triplicate determinations. * significant decrease (P < 0.05) from
LPS alone.
the treatment of osteoarthritis. This type of information,
along with safety and tolerability data, will assist health care
professionals to make informed and educated decisions as to
the utility of cat’s claw. It should be noted that this freeze-
dried formulation was quite potent. Dosing at 100 mg once a
day reflects a potency that one normally associates with a
pharmaceutical rather than a medicinal plant preparation. On
the other hand, we have determined that the micropulveriza-
tion preparative method, which is the standard formulation in
the Western world, is approximately 20-fold less potent [5],
in which case gram quantities will be needed to achieve the
same effects.
Cat’s claw has had enjoyed a remarkable clinical experi-
ence in South America, and it is highly regarded for the treat-
ment of chronic inflammation [35]. This study as well as our
previous investigations [1, 5, 6], supports this ideology. Of
particular interest in the treatment of arthritis is the ability of
cat’s claw to not only confer benefit to the joints but also
negate the side effects of NSAIDs on the stomach and intes-
tine [5, 6]. With the observation that cat’s claw significantly
lowered PGE
production by macrophages, presumably due
to an inhibition of COX-2 expression, concomitant with in
vivo benefits on pain, it is likely that cat’s claw administra-
tion may lower the need for arthritic patients to consume
NSAIDs. Thus, this Amazonian botanical not only treats the
arthritic disease process but also reduces the toxic side
effects of the current standard pharmaceuticals used in the
management of arthritis. The concept that botanicals can be
used to reduce the toxicity of pharmaceuticals is an intrigu-
ing and greatly under-explored area of investigation.
Another complimentary medicine approach to osteo-
arthritis that is more commonly appreciated is the use of glu-
cosamine and chondroitin sulfate [36]. While the mecha-
nisms of action of these nutraceuticals have not been com-
pletely elucidated [37], their actions appear to be quite dis-
tinct from cat’s claw. Glucosamine and chondroitin are sub-
strates for cartilage and as such, assist in replacing chondro-
cyte material that is lost during the inflammatory process.
There is no evidence for a direct action on gene expression or
antioxidant activity, in contrast to the present observations
with cat’s claw. Thus, it is clear that this disease can be
approached therapeutically from different perspectives.
However, we believe that an approach that directly interrupts
the disease process has a better chance for therapeutic bene-
fits in a large proportion of the population than an approach
that is designed to arithmetically replace substrates lost as a
result of ongoing inflammation. In that regards, cat’s claw is
also distinct from NSAIDs as they only treat the symptoms
of the condition (pain, swelling) and not the underlying dis-
ease process. Given the ability of cat’s claw to negate the side
effects of NSAIDs, it is possible that a combination of cat’s
claw and NSAID would be a significant improvement in the
management of arthritis, and a cost-effective alternative to
COX-2 inhibitors.
We conclude that cat’s claw is a medicinal plant that
deserves further consideration in the treatment of arthritis
and other chronic inflammatory disorders.
Acknowledgements. We gratefully acknowledge the assistance of: Drs.
Herman Silva, Raúl Díaz, Inés Segami, César Ugarte, Felipe Becerra,
Pedro Mendoza, José Escalante, Graciela Alonso, Raúl Marañón, Jorge
Zapata and Dennis Elera for providing advice, and active participation
during the course of the study. The clinical trial was performed under
the sponsorship of Seguro Social del Peru (ESSALUD). The in vitro
experiments were supported by grants RO1 HD 31885 and PO1 CA
28842 from the National Institutes of Health, Bethesda, MD (to
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... Además, se ha observado que es capaz de regular la activación de las interlucinas IL-1 y IL-6 y la muerte celular. 124,[126][127][128][129][130] La función de la uña de gato como inhibidor del factor nuclear NF-kB es fundamental para considerarla en el tratamiento de la OA, ya que dos de los agentes antinflamatorios -ampliamente utilizados en esta enfermedad (salicilatos y glucocorticoides)-, ejercen su acción terapéutica mediante este mecanismo. 128,129 Existen escasos estudios clínicos acerca del uso de la Uncaria en el tratamiento específico de la OA. ...
... No obstante, la información documentada muestra resultados alentadores, ya que la administración de esta planta (sola o en combinación con otras hierbas) ha mostrado reducción significativa del dolor y mejoría en la función de las articulaciones de pacientes con este padecimiento. 127,128,130,131 Por lo tanto, la uña de gato tiene potencial para ser usada en el tratamiento de la OA. Sin embargo, se requiere de más investigación para determinar su eficacia y seguridad. ...
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La osteoartrosis (OA) es la enfermedad reumática más frecuente y suele resultar en discapa-cidad. Su tratamiento debe ser integral y contemplar diversos aspectos. Sin embargo, el uso crónico de medi-camentos antinflamatorios se asocia con reacciones adversas graves de tipo gastrointestinal, cardiovascular, hematológico y renal. Hace siglos que las plantas medicinales se utilizan en el manejo de esta enfermedad. Ob-jetivo. El objetivo de este estudio fue realizar una revisión sistemática de la evidencia publicada de 13 plantas, cuyo uso en OA está reportado. Material y métodos. La estrategia de búsqueda incluyó los siguientes criterios: documentos en inglés y español, textos completos, estudios en humanos, guías clínicas, revisiones sistemáticas, metanálisis, estudios clínicos aleatorizados, estudios observacionales/ epidemiológicos/ económicos, revisiones, consensos. Se enfatizó especialmente en el mecanismo de acción farmacológico que pudiera justificar el uso, así como fundamentar la eficacia clínica. La evidencia obtenida se seleccionó mediante preguntas de trabajo y nivel de evidencia. Resultados. Se encontraron 734 artículos; se seleccionaron 346 artículos para su análisis; de éstos, 131 tuvieron utilidad por su nivel de evidencia. Entre los mecanismos de acción encontrados de las plantas investigadas se encuentra la inhibición de citocinas proinflamatorias, disminución de la señalización de TNF-α y NF-κB, reducción de la osteoclastogénesis, incremento de la diferenciación de los osteoclastos, descenso de la actividad de ciclooxigenasa 2 y de la síntesis de prostaglandinas. Conclusiones. Se concluye que las diversas plantas estudiadas tienen mecanismos de acción que apoyan su uso en el tratamiento de la OA y poseen diversos grados de efectividad demostrada.
... Published safety data have shown minimal side effects in both animal and human models [173]. Human studies reflected a side effect profile comparable to a placebo in studies ranging from four weeks [174] to 52 weeks [175]. There are reports that Uncaria can have an impact on estrogen binding [176], with potential implications on contraceptive effects [177]. ...
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The primary objective of this paper is to provide an evidence-based update of the literature on the use of bioactive phytochemicals, nutraceuticals, and micronutrients (dietary supplements that provide health benefits beyond their nutritional value) in the management of persistent cases of Borrelia burgdorferi infection (Lyme disease) and two other tick-borne pathogens, Babesia and Bartonella species. Recent studies have advanced our understanding of the pathophysiology and mechanisms of persistent infections. These advances have increasingly enabled clinicians and patients to utilize a wider set of options to manage these frequently disabling conditions. This broader toolkit holds the promise of simultaneously improving treatment outcomes and helping to decrease our reliance on the long-term use of pharmaceutical antimicrobials and antibiotics in the treatment of tick-borne pathogens such as Borrelia burgdorferi, Babesia, and Bartonella.
... ex Schult.) DC (Cat's Claw) Family: Rubiaceae Traditionally, it is used to treat asthma, abscesses, fever, urinary tract infections, viral infections, and wounds [69] Alkaloids, sterols, glycosides, organic acids, and triterpenes [69] Osteoarthritis of the knee remiss after 4 weeks by inhibiting TNF-and diminishing PGE2 production [70] 15. ...
... Uncaria tomentosa improved fipronil-induced hepatotoxicity and oxidative stress in rats through suppression of NF-κB [14] . It reduced inflammation associated with osteoarthritis through inhibition of TNFα [15] . Moreover, it might inhibit neurodegenerative changes and improve human Alzheimer's disease and physiological aging [16] . ...
... Rhynchophylline (Figure 3b) is an indole alkaloid found in U. tomentosa extract that has been shown in studies to have substantial antioxidant and anti-inflammatory effects. [2,27,28] Ashwagandha, a member of the Solanaceae family, is a popular name for Withania somnifera. Among the active phytochemicals in Ashwagandha include withanolide A, withanone, withanolide D, as well as alkaloids, flavonoids, steroids, and zingerone. ...
Objective To test the null hypothesis that oral intake of the dietary supplement carboxy alkyl ester (CAE) would have no effect on attention as revealed by mean rapid visual information processing (RVIP) scores. Methods In a randomized double‐blind cross‐over placebo‐controlled trial, healthy participants (age 19–66 years) of both sexes were randomly assigned to consume 700 mg of CAE or 700 mg of placebo. They received baseline attention testing via the RVIP task. Then they consumed CAE or placebo followed by RVIP testing. Participants were then given a washout period where they did not consume CAE or placebo. Afterward, individuals who initially consumed CAE were given the placebo and those who initially consumed the placebo were given CAE. Finally, all participants were tested again via RVIP. Results A priori statistical computation revealed that 30‐day oral intake of CAE improved mean RVIP test scores ( t = 2.4, p < .05) relative to that at baseline, which resulted in a rejection of the null hypothesis. Conclusions Daily oral intake of the CAE dietary supplement may boost attention and further research is now needed to confirm this observation.
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Context: Anti-inflammatory drugs and biologics can effectively treat inflammatory conditions and diseases but can also cause burdensome side effects. Many patients prefer to use time-tested, traditional medicinal products and dietary supplements, but such products seldom receive the rigorous testing required for regulatory approvals of drugs and biologics. Thus, it is advantageous to demonstrate by experimentation the pharmacological and toxicological properties of unapproved natural products and compared to benchmark approved drugs or biologics. Objective: The studies intended to evaluate Samento®, a commercial hydro-alcoholic extract of the pentacyclic chemotype of Uncaria Tomentosa (Willd.) DC, for the prophylactic and treatment effects of irritant-induced inflammation and antigen-induced arthritic inflammation in two rat models. The studies were also intended to create a clinical bridge rationale for the use of Samento® in the treatment of inflammation in humans, with a suggested allometrically scaled starting dose. Design: The research team performed two in vivo animal model studies of induced inflammation in rats. Setting: The studies took place at the Universidad Peruana Cayetano Heredia in Lima, Peru. Prophylaxis model of irritant-induced inflammation: Holtzman rats in five groups (five each per group) were administered 14 daily doses of Samento® at 250, 500, and 1000 mg/kg of wet weight, or 40 mg/kg of naproxen sodium as a positive control, or nothing as a negative control. At 14 days the right legs of the rats were challenged by injection into the connective tissue by the chemical irritant carrageenan. Two hours thereafter the weight of the irritant-injected right leg was compared to the non-injected left leg of each rat, to determine the level of irritant-induced inflammation. Treatment model of antigen-induced arthritic inflammation: Arthritic inflammation was induced in five groups of Lewis rats (five each per group) by intradermal injection of the tail with non-allogeneic, bovine type II collagen in incomplete Freund's adjuvant. A sixth group was not injected with collagen antigen as a non-induced control. Ten days after the induction of arthritic inflammation in the five injected groups, individual groups were treated with Samento® at 250, 500, and 1000 mg/kg of wet weight daily for 21 days, or 0.2 mg/kg of methotrexate twice per week as a positive control, or nothing as a negative control. At 21 days the animals were assessed for antigen-induced arthritic inflammation and assigned an analog score ranging from 0 to 4. Results: The research team confirmed the presence of pentacyclic oxindoles and the absence of tetracyclic oxindoles within Samento®. In the prophylactic model, 14 days of pretreatment with oral Samento® produced dose-dependent, statistically significant reductions in inflammation in the rats' leg weights between the carrageenan induction and postintervention, for the 250, 500, and 1000 mg/kg Samento® groups (P < .05 for all groups). The 1000 mg/kg group had a 74% anti-inflammatory effect versus 97% with the 40 mg/kg of naproxen sodium in the positive control group. In the treatment model, 21 days of oral administration of Samento® produced dose-dependent, statistically significant reductions in arthritic inflammation postintervention, for the 250, 500, and 1000 mg/kg Samento® groups (P < .05 for all groups). Treatment with the highest tested dose of the extract (1000 mg/kg) yielded an 85% anti-inflammatory effect versus 90% with 0.2 mg/kg of methotrexate in the positive control group. Conclusions: The two rat models revealed that the Uncaria phytotherapy Samento® was an effective prophylactic as well as a treatment for induced inflammation in rats. The highest dose of the pentacyclic chemotype of Uncaria approached the anti-inflammatory activities of the established benchmark pharmaceutical positive controls. The results in the two rat models suggest an allometrically scaled starting dose of Samento® of 4 g daily in humans.
Alzheimer's disease (AD), also called senile dementia, is the most common neurological disorder. Around 50 million people, mostly of advanced age, are suffering from dementia worldwide and this is expected to reach 100-130 million between 2040 and 2050. AD is characterized by impaired glutamatergic and cholinergic neurotransmission, which is associated with clinical and pathological symptoms. AD is characterized clinically by loss of cognition and memory impairment and pathologically by senile plaques formed by Amyloid β deposits or neurofibrillary tangles (NFT) consisting of aggregated tau proteins. Amyloid β deposits are responsible for glutamatergic dysfunction that develops NMDA dependent Ca2+ influx into postsynaptic neurons generating slow excitotoxicity process leading to oxidative stress and finally impaired cognition and neuronal loss. Amyloid decreases acetylcholine release, synthesis and neuronal transport. The decreased levels of neurotransmitter acetylcholine, neuronal loss, tau aggregation, amyloid β plaques, increased oxidative stress, neuroinflammation, bio-metal dyshomeostasis, autophagy, cell cycle dysregulation, mitochondrial dysfunction, and endoplasmic reticulum dysfunction are the factors responsible for the pathogenesis of AD. Acetylcholinesterase, NMDA, Glutamate, BACE1, 5HT6, and RAGE (Receptors for Advanced Glycation End products) are receptors targeted in treatment of AD. The FDA approved acetylcholinesterase inhibitors Donepezil, Galantamine and Rivastigmine and N-methyl-D-aspartate antagonist Memantine provide symptomatic relief. Different therapies such as amyloid β therapies, tau-based therapies, neurotransmitter-based therapies, autophagy-based therapies, multi-target therapeutic strategies, and gene therapy modify the natural course of the disease. Herbal and food intake is also important as preventive strategy and recently focus has also been placed on herbal drugs for treatment. This review focuses on the molecular aspects, pathogenesis and recent studies that signifies the potential of medicinal plants and their extracts or chemical constituents for the treatment of degenerative symptoms related to AD.
Context: Lyme disease is the most common, tick-borne disease in the USA. While most patients successfully recover with antibiotics, some patients experience persistent symptoms for months to years. Patients who attribute chronic symptoms to Lyme disease commonly use herbal supplements. The complexity, variability in dose and formulation, and lack of data for these herbal compounds make it difficult to assess their efficacy and safety. Objective: This review examines the evidence for the antimicrobial activity, safety, and drug-drug interactions of 18 herbal supplements that patients commonly use for treatment of persistent symptoms attributed to Lyme disease. Design: The research team performed a narrative review by searching the PubMed, Embase, Scopus, Natural Medicines databases, and NCCIH website. The search used the keywords for 18 herbal compounds: (1) andrographis (Andrographis paniculate), (2) astragalus (Astragalus propinquus), (3) berberine, (4) cat's claw bark (Uncaria tomentosa), (5) cordyceps (Cordyceps sinensis), (6) cryptolepis (Cryptolepis sanguinolenta), (7) Chinese skullcap (Scutellaria baicalensis), (8) garlic (Allium sativum), (9) Japanese knotwood (Polygonum cuspidatum), (10) reishi mushrooms (Ganoderma lucidum), (11) sarsaparilla (Smilax medica), (12) Siberian ginseng (Eleutherococcus senticosus), (13) sweet wormwood (Artemisia annua), (14) teasle root (Dipsacus fullonum), (15) lemon balm (Melissa officinalis), (16) oil of oregano (Origanum vulgare), (17) peppermint (Mentha x piperita), and (18) thyme (Thymus vulgaris). The team also searched for terms related to protocols, including Dr. Rawls' protocol and the Buhner protocol. Setting: University of Maryland Medical Center, Baltimore MD. Results: Seven of the 18 herbs reviewed had evidence for in-vitro activity against B. burgdorferi. These compounds included: (1) cat's claw (2) cryptolepis, (3) Chinese skullcap, (4) Japanese knotweed, (5) sweet wormwood, (6) thyme, and (7) oil of oregano. With the exception of oil of oregano these compounds also have anti-inflammatory activity. In vivo data and clinical trials are lacking. Clinicians should be cautious as many of the identified compounds have drug interactions and additive effects that could lead to increased risks for bleeding, hypotension, and hypoglycemia. Conclusions: Many of the herbs that alternative and integrative practitioners use to treat Lyme disease have anti-inflammatory effects that may contribute to patients' perceptions of symptomatic improvement. Some herbs have limited demonstrated anti-borrelial activity in vitro, but in-vivo data and clinical trial data is lacking. Further research is required to determine the efficacy, safety and appropriate use of these herbs for this patient population.
Thirty patients with osteoarthritis took part in a double-blind cross-over study involving two matched placebo periods. The comparative drugs were piroxicam (Feldene) 20 mg given as a once-daily dose, and diclofenac 50 mg three times daily. With the exception of the variable physicians' assessments of pain which were significantly lower on piroxicam than diclofenac (P < 0.05), no significant differences between the two active agents were demonstrated. The results showed that both drugs were effective in relieving symptoms associated with arthritis. Patients and physicians indicated a marked preference for piroxicam and diclofenac in comparison with placebo. Few side-effects were reported and in no instance was withdrawal of treatment necessary. There was variation in patient response to the different placebo treatment periods.
SUMMARY Background: Uncaria tomentosa is a vine commonly known as cat's claw or 'una de gato' (UG) and is used in traditional Peruvian medicine for the treatment of a wide range of health problems, particularly digestive complaints and arthritis. Purpose: The aim of this study was to determine the proposed anti-inflammatory properties of cat's claw. Specifically: (i) does a bark extract of cat's claw protect against oxidant-induced stress in vitro, and (ii) to determine if UG modifies transcriptionally regulated events. Methods: Cell death was determined in two cell lines, RAW 264.7 and HT29 in response to peroxynitrite (PN, 300 lM). Gene expression of inducible nitric oxide synthase (iNOS) in HT29 cells, direct effects on nitric oxide and peroxynitrite levels, and activation of NF-jB in RAW 264.7 cells as influenced by UG were assessed. Chronic intestinal inflammation was induced in rats with indomethacin (7.5 mg/kg), with UG administered orally in the drinking water (5 mg/mL). Results: The administration of UG (100 lg/mL) atten- uated (P < 0.05) peroxynitrite-induced apoptosis in HT29 (epithelial) and RAW 264.7 cells (macrophage). Cat's claw inhibited lipopolysaccharide-induced iNOS gene expression, nitrite formation, cell death and inhibited the activation of NF-jB. Cat's claw markedly attenuated indomethacin-enteritis as evident by reduced myeloperoxidase activity, morphometric damage and liver metallothionein expression. Conclusions: Cat's claw protects cells against oxidative stress and negated the activation of NF-jB. These studies provide a mechanistic evidence for the widely held belief that cat's claw is an effective anti-inflamma- tory agent.
Peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA) have increased expression of nitric oxide synthase type 2 (NOS2) protein and enhanced formation of nitric oxide (NO) that correlate with disease activity. NO may play a role in the inflammation of RA. Treatment of RA patients with a chimeric monoclonal antibody against tumor necrosis factor alpha (TNFalpha; cA2) results in clinical improvement in the majority of patients. The present study was designed to determine if cA2 therapy decreases PBMC NOS2 protein expression and NOS enzyme activity in RA patients. RA patients receiving background oral methotrexate participated in a double-blind, placebo-controlled clinical trial in which they were randomly assigned to receive a single infusion of either placebo or cA2 at 5, 10, or 20 mg/kg. NOS2 protein and NOS enzyme activity were measured in PBMC at baseline and 4 weeks following cA2 therapy. These results were compared with the degree of clinical change in disease activity. At baseline, elevated levels of NOS2 protein and NOS enzyme activity were more frequently detected in PBMC from RA patients than in those from healthy controls. Treatment of the RA patients with cA2 significantly reduced NOS2 protein expression and NOS enzyme activity. Changes in NOS activity following treatment correlated significantly with changes in the number of tender joints. These results indicate that TNFalpha likely plays an important role in enhancing NOS2 expression in RA, and that the antiinflammatory effects of cA2 treatment may be mediated by a reduction of NO overproduction.
Objective To evaluate the efficacy and safety of diacerein, a drug with interleukin-1β–inhibitory activity in vitro, in patients with knee osteoarthritis (OA).MethodsA total of 484 patients fulfilling the American College of Rheumatology criteria for knee OA were enrolled in this 16-week, randomized, double-blind, placebo-controlled, parallel study group with 3 diacerein dosages of 50 mg/day, 100 mg/day, and 150 mg/day (administered twice daily).ResultsIn the intent-to-treat population, 100 mg/day diacerein (50 mg twice daily) was significantly superior (P < 0.05) to placebo using the primary criterion (visual analog scale [VAS] assessment of pain on movement). Significant improvement (P < 0.05) was also observed for the secondary criteria, which included the Western Ontario and McMaster Universities OA Index (WOMAC), the WOMAC subscores, and the VAS assessment of handicap. In patients treated with diacerein dosages of 50 mg/day and 150 mg/day, favorable but not significant results were observed for the primary criterion. The best daily dosage of diacerein, calculated from the effect on the VAS assessment of pain on movement, was 90.1 mg. In the per-protocol population, the analysis of the primary criterion showed significant dose-dependent differences (P < 0.05) between each of the 3 diacerein dosages and the placebo. No differences were observed among the 3 diacerein groups. A significantly higher incidence (P < 0.05) of adverse events (AEs), as well as a higher rate of dropoout due to AEs, was observed in patients treated with 150 mg/day diacerein versus those treated with placebo, 50 mg/day diacerein, or 100 mg/day diacerein. Mild-to-moderate transient changes in bowel habits were the most frequent AEs, increasing with the dosage.Conclusion Diacerein, a drug for the treatment of OA, was shown to be an effective treatment for symptoms in patients with knee OA. Taking into account both efficacy and safety, the optimal daily dosage of diacerein for patients with knee OA is 100 mg/day (50 mg twice daily).
Objective To explore the signaling pathways by which the proinflammatory cytokine interleukin-17 (IL-17) may contribute to cartilage catabolism in osteoarthritis (OA) by inducing inducible nitric oxide synthase (iNOS) expression in chondrocytes.Methods We examined the IL-17–induced NO production in human OA chondrocytes, in combination with the proinflammatory cytokines IL-1β, tumor necrosis factor α (TNFα), and leukemia inhibitory factor (LIF); the antiinflammatory cytokines IL-4, IL-10, and IL-13; and IL-1 receptor antagonist (IL-1Ra). Further, we explored the major intracellular signaling pathways through which IL-17 induced iNOS expression and NO production.ResultsTreatment with IL-17 induced a dose-dependent increase in the level of NO. When IL-17 was combined with the above factors, it resulted in a synergistic effect with TNFα, an additive effect with LIF, and no further effect than when used alone with IL-1β. IL-4, IL-10, IL-13, and IL-1Ra had no true effect on IL-17–induced NO production. The cAMP mimetics, 3-isobutyl-1-methyl xanthine plus forskolin, completely blocked IL-17–induced NO production. KT-5720, genistein, and Calphostin C, inhibitors of protein kinase A (PKA), tyrosine kinase, and protein kinase C, respectively, reduced the IL-17–induced NO production by 72%, 56%, and 42%, respectively. Within minutes, IL-17 induced the phosphorylation of mitogen-activated protein kinase kinase-1/2 (MEK-1/2), -3/6 (MKK-3/6), p44/42, p38, and inhibitor of nuclear factor κB (IκB)-α, as well as the activation of mitogen-activated protein kinase–activated protein kinase-1 and -2 (MAPKAPK-1 and -2). Interestingly, IL-17 induced phosphorylation of the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) (p54/46) only when PKA was inhibited. Specific protein kinase inhibitors for MEK-1/2 (PD98059), p38 (SB202190), and nuclear factor κB (NF-κB) (pyrrolidine dithiocarbamate) each markedly decreased the IL-17–increased iNOS level and NO production. Inhibiting MAPK, including MEK-1/2 and p38, had no effect on the IL-17–induced activation of IκB-α, but reversed the IL-17 activation of MAPKAPK-1 and -2, respectively.Conclusion These findings show that the stimulation of NO production by IL-17 is mediated mainly by a complex activation of kinases, especially PKA, NF-κB, and MAPK. NF-κB appears to require MAPK activation, with downstream activation of MAPKAPK probably acting as a transactivating factor, to induce iNOS expression.