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applied
sciences
Review
Uncaria tomentosa (Willd. ex Schult.) DC.: A Review
on Chemical Constituents and Biological Activities
Gaber El-Saber Batiha 1, 2, *,†, Amany Magdy Beshbishy 1, †, Lamiaa Wasef 2,
Yaser H. A. Elewa 3,4, Mohamed E. Abd El-Hack 5, Ayman E. Taha 6,
Adham Abdullah Al-Sagheer 7, Hari Prasad Devkota 8and Vincenzo Tufarelli 9
1National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary
Medicine, Nishi 2-13, Inada-cho, Obihiro 080-8555, Hokkaido, Japan; amanimagdi2008@gmail.com
2Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University,
Damanhour 22511, Al Beheira, Egypt; lamiaawasef@vetmed.dmu.edu.eg
3Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University,
Zagazig 44511, Egypt; y-elewa@vetmed.hokudai.ac.jp
4Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine,
Hokkaido University, Sapporo 060-0818, Hokkaido, Japan
5Department of Poultry, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt;
dr.mohamed.e.abdalhaq@gmail.com
6Department of Animal Husbandry and Animal Wealth Development, Faculty of Veterinary Medicine,
Alexandria University, Edfina 22578, Egypt; Ayman.Taha@alexu.edu.eg
7Animal Production Department, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt;
adham_alsaht@zu.edu.eg
8Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku,
Kumamoto City, Kumamoto 862-0973, Japan; devkotah@kumamoto-u.ac.jp
9DETO—Section of Veterinary Science and Animal Production, University of Bari ‘Aldo Moro’ s.p.
Casamassima km 3, 70010 Valenzano, Italy; vincenzo.tufarelli@uniba.it
*Correspondence: dr_gaber_batiha@vetmed.dmu.edu.eg or gaberbatiha@gmail.com; Tel.: +20-45-271-6024;
Fax: +20-45-271-6024
†Equally contributed.
Received: 20 January 2020; Accepted: 11 March 2020; Published: 13 April 2020
Abstract:
Uncaria tomentosa (Willd. ex Schult.) DC. (Family: Rubiaceae), commonly known as
cat’s claw, is a tropical medicinal vine originating at the Amazon rainforest and other areas of
South and Central America. It has been traditionally used to treat asthma, abscesses, fever, urinary
tract infections, viral infections, and wounds and found to be effective as an immune system
rejuvenator, antioxidant, antimicrobial, and anti-inflammatory agent. U. tomentosa is rich in many
phytoconstituents such as oxindole and indole alkaloids, glycosides, organic acids, proanthocyanidins,
sterols, and triterpenes. Biological activities of U. tomentosa have been examined against various
microorganisms and parasites, including pathogenic bacteria, viruses, and Plasmodium,Babesia and
Theileria parasites. Several formulations of cat’s claw (e.g., tinctures, decoctions, capsules, extracts,
and teas) are recently available in the market. The current review covers the chemical constituents,
biological activities, pharmacokinetics, and toxic properties of U. tomentosa extracts.
Keywords: Uncaria tomentosa; cat’s claw; biological activities; pharmacokinetics; phytoconstituents
1. Introduction
Medicinal plants have been used for various therapeutic purposes from ancient times and they
have also served as an important source for drug discovery [
1
–
3
]. A large proportion of the population
living in developing countries in Asia and Africa depend on plant-based traditional medicines for
Appl. Sci. 2020,10, 2668; doi:10.3390/app10082668 www.mdpi.com/journal/applsci
Appl. Sci. 2020,10, 2668 2 of 12
primary healthcare [
4
,
5
]. One of the main reasons for the wide use of plants is due to their easy
accessibility and low-cost [
6
–
8
]. Essentially, herbal therapies contain parts of herbs or unpurified
herbal extracts that involve a variety of phytoconstituents that are usually thought to act synergistically
together and can be used as a lead compound to discover a huge number of compounds that can be
used recently in the treatment of several diseases [7,8].
Uncaria tomentosa (Willd. ex Schult.) DC is commonly known as cat’s claw that is derived from the
Spanish word Uña de Gato that identifies the small, curved-back thorns on the stem at the leaf junction.
It is a tropical medicinal vine of the Rubiaceae family that is widely distributed in the Amazon rainforest
and other areas of South and Central America [
9
,
10
]. Thirty-four Uncaria species have been reported
including U. guianensis and U. tomentosa that are found in South America. Traditionally, U. tomentosa
has been reported to be used to asthma, abscesses, fever, urinary tract infections, viral infections,
and wounds [
9
]. It is also reported to be effective as an immune system rejuvenator, antioxidant,
antimicrobial, and anti-inflammatory. U. tomentosa is a potent complimentary herb for treating most
parasites [
11
]. Various chemical constituents are reported from the extracts of U. tomentosa along with
their biological activities. The main objective of this review is to review the available scientific literature
regarding the chemical constituents, biological activities of U. tomentosa along with the reported side
effects and precautions related to drug-drug interactions.
2. Chemical Constituents of U. tomentosa
Previous studies reported the chemical constituents of several Uncaria species and recognized
the different molecules present in different parts of the plant. It is worth noting that more than 50
phytochemical molecules have been identified and isolated from U. tomentosa, some of them are
considered new to that species [
12
]. U. tomentosa leaves contain higher oxindole alkaloid content than
that present in stem bark and branches. This result is compatible with a study previously described
by Laus et al. [
13
], who documented the accumulation of speciophylline and uncarine F (the main
oxindole alkaloids) in leaves that can occur as tetracyclic oxindole alkaloid (TOA) or pentacyclic
oxindole alkaloid (POA) derivatives. Both TOA and POA are liable to isomerization that depends
mainly on medium polarity, pH, and temperature [13].
A recent study about the chemical variation of a wild population of cat’s claw from Peru reported the
existence of three specific chemotypes that producing different alkaloidal constituents [
14
]. Chemotype I
is mainly composed of the POA with the intersection of D/E ring, chemotype II consists primarily of POA
with trans D/E ring junction, while chemotype III consists primarily of TOA derivative. Uncarine C and
uncarine E are two POA stereoisomers, while mitraphylline, rhynchophylline, and isorhynchophylline
are TOAs found in cat’s claw. On the basis of these results, the U.S. Pharmacopeia revealed that dried raw
material of cat’s claw included 0.05% (w/w) of the TOA concerning the POA amount, whereas cat’s claw
powdered dried extract, tablets, and capsules contained up to 25% (w/w). Cat’s claw contains several
active compositions including ajmalicine, campesterol, carboxyl alkyl esters, akuammigine, sitosterols,
rutin, chlorogenic acid, speciophylline, catechin, cinchonain [
15
], corynoxeine, harman, daucosterol,
epicatechin, hirsuteine, corynantheine, hirsutine, loganic acid, mitraphylline, iso-pteropodine, oleanolic
acid, ursolic acid, lyaloside [
16
], rhynchophylline, palmitoleic acid, pteropodine quinovic acid
glycosides, procyanidins [
10
], stigmasterol, 3,4-dehydro-5-carboxystrictosidine, vaccenic acid, uncarine
A thru F, and strictosidines [
10
,
17
]. Moreover, other reports revealed that various compounds other
than oxindole alkaloids such as rotundifoline and isorotundifolune, coumarins, flavonoids, quinovic
acid glycosides, and triterpenes may be responsible for the cat’s claw medicinal effects [18,19].
3. Biological Activities of U. tomentosa Extracts and Compounds
3.1. Traditional Uses
U. tomentosa bark and root have been traditionally used as a therapy in tropical South America for
many conditions, like inflammations, cancer, gastric ulcers, arthritis, and infections. Moreover, it was
Appl. Sci. 2020,10, 2668 3 of 12
documented to be used for blood purifications, after child delivery as a wash for wounds to allow
skin healing, cleansing the kidneys, asthma, inhibition of several diseases, menstrual irregularity and
hemorrhages, fevers, and possess a normalizing activity on body systems [
20
]. It also was used for the
treatment of various ailments including abscesses, urinary tract infections, contraception, rheumatism,
and weakness. Additionally, it was used as a treatment option for mental disorders (e.g., anxiety).
Some indigenous people in America used the water stored in the stem to quench thirst, and as a
restorative drink [21]. Few pharmacological effects of U. tomentosa have shown in Figure 1.
Appl. Sci. 2020, 10, x FOR PEER REVIEW 3 of 12
3. Biological Activities of U. tomentosa Extracts and Compounds
3.1. Traditional Uses
U. tomentosa bark and root have been traditionally used as a therapy in tropical South America
for many conditions, like inflammations, cancer, gastric ulcers, arthritis, and infections. Moreover, it
was documented to be used for blood purifications, after child delivery as a wash for wounds to
allow skin healing, cleansing the kidneys, asthma, inhibition of several diseases, menstrual
irregularity and hemorrhages, fevers, and possess a normalizing activity on body systems [20]. It also
was used for the treatment of various ailments including abscesses, urinary tract infections,
contraception, rheumatism, and weakness. Additionally, it was used as a treatment option for mental
disorders (e.g., anxiety). Some indigenous people in America used the water stored in the stem to
quench thirst, and as a restorative drink [21]. Few pharmacological effects of U. tomentosa have shown
in Figure 1.
Figure 1. Schematic representation of different pharmacological activities of Uncaria tomentosa (cat’s
claw).
3.2. Antioxidant Activity
The antioxidant activities of U. tomentosa have been attributed to the existence of alkaloids,
flavan-3-ol monomers, and polyphenols. The preclinical assessment revealed that the cat’s claw
defends toward various oxidative stresses, involving peroxynitrite that has been included in arthritis
and other chronic inflammatory diseases along with inhibiting acute or chronic gastritis caused by
high doses of nonsteroidal anti-inflammatory drugs (NSAIDs) [22,23].
U. tomentosa aqueous extract
was found to protect against oxidative stress in human erythrocytes and relieve chronic intestinal
inflammation in rats caused by indomethacin [24,25].
Another study documented that
hydroxybenzoic acids, proanthocyanidins acids hydroxycinnamic were responsible for potent radical
scavenging and anti-inflammatory activities of the cat’s claw [26,27]. In an in vitro experiment, U.
tomentosa bark showed high antioxidant efficacy manifested by trolox equivalent antioxidant
capacity, free radical diphenylpicrylhydrazyl capacity, superoxide radical scavenging activity, and
peroxyl radical-trapping capacity. Moreover, it protected membrane lipids from the peroxidation
caused by the iron/ascorbate system and was also evaluated by the formation of thiobarbituric acid-
reactive substances (TBARs) [26]. Another in vitro study revealed that the cat’s claw prevented the
inducible nitric oxide synthase (iNOS) gene expression caused by lipopolysaccharide, nitrite
Figure 1.
Schematic representation of different pharmacological activities of Uncaria tomentosa
(cat’s claw).
3.2. Antioxidant Activity
The antioxidant activities of U. tomentosa have been attributed to the existence of alkaloids,
flavan-3-ol monomers, and polyphenols. The preclinical assessment revealed that the cat’s claw
defends toward various oxidative stresses, involving peroxynitrite that has been included in arthritis
and other chronic inflammatory diseases along with inhibiting acute or chronic gastritis caused by
high doses of nonsteroidal anti-inflammatory drugs (NSAIDs) [
22
,
23
]. U. tomentosa aqueous extract
was found to protect against oxidative stress in human erythrocytes and relieve chronic intestinal
inflammation in rats caused by indomethacin [
24
,
25
]. Another study documented that hydroxybenzoic
acids, proanthocyanidins acids hydroxycinnamic were responsible for potent radical scavenging and
anti-inflammatory activities of the cat’s claw [
26
,
27
]. In an
in vitro
experiment, U. tomentosa bark
showed high antioxidant efficacy manifested by trolox equivalent antioxidant capacity, free radical
diphenylpicrylhydrazyl capacity, superoxide radical scavenging activity, and peroxyl radical-trapping
capacity. Moreover, it protected membrane lipids from the peroxidation caused by the iron/ascorbate
system and was also evaluated by the formation of thiobarbituric acid-reactive substances (TBARs) [
26
].
Another
in vitro
study revealed that the cat’s claw prevented the inducible nitric oxide synthase
(iNOS) gene expression caused by lipopolysaccharide, nitrite formation, cell death, and the NF-kappaB
activation. Cat’s claw possessed a cytoprotective effect due to its ability to interact with the injurious
oxidant, therefore, it may act on regulating cell death [22].
Appl. Sci. 2020,10, 2668 4 of 12
3.3. Anti-Neoplastic Activity
Cat’s claw was supposed to have antitumor and immunostimulatory effects because of its oxindole
alkaloids content [
10
,
23
,
28
]. U. tomentosa extracts were found to have antiproliferative efficacy against
SW620 colon adenocarcinoma, MCF7 breast cancer, and AGS gastric cells [
19
]. Interestingly, several
studies suggested the antiproliferative effect of U. tomentosa against several cancer cell lines, namely
cervical carcinoma, osteosarcoma, and breast cancer. For instance, an
in vitro
study reported that
U. tomentosa hot water extract prevents inflammatory responses as well as tumor cell proliferation by
inhibiting the transcriptional regulator nuclear factor kappa beta (NF-
κ
B) activation without interfering
with interleukin-2 (IL-2) production or IL-2 receptor signaling [29]. Cheng et al. [30] documented the
antiproliferative effect of cat’s claw extracts against several cell lines, including glioma, premyelocytic
leukemia, MCF7 breast cancer, acute lymphoblastic leukaemia, and neuroblastoma.
3.4. Anti-Inflammatory Activity
Recently, POA isolated from U. tomentosa extract has been documented to enhance the lymphocyte
proliferation-regulating factor released from human endothelial cells; however, TOA was found to
reduce POA activity on these cells in a dose-related manner [
22
,
31
]. Additionally, U. tomentosa stem
bark extracts have been revealed to stimulate the
in vitro
production of IL-6 and IL-1 in rat alveolar and
lipopolysaccharide-stimulated macrophages in a dose-related manner and its suppressive activities on
cancer cell multiplication appear to be due to apoptosis induction [
18
,
32
]. Moreover, Xiao et al. [
33
]
examined the hypotensive efficacy of isorhynchophylline in rats and dogs, whereas Xiang et al. [
34
]
documented the ability of rhynchophylline to suppress rabbit and rat platelet accumulation ex vivo.
Additionally, the anti-inflammatory activity of the standardized aqueous extract of U. tomentosa (AC
11
of U. tomentosa extract) was attributed to NF-
κ
B inhibition [
35
]. Recently, several studies reported the
antioxidant, anti-neoplastic and immunomodulant activities of the alkaloids isolated from the cat’s
claw [
36
–
38
]. For instance, Lopes et al. [
39
] revealed that U. tomentosa extract encourages the myeloid
precursor’s proliferation by increasing serum colony-stimulating growth factors (CSFs). Moreover,
in vivo
studies demonstrated the effectiveness of aqueous U. tomentosa extract on leukocyte counts in
healthy animals and doxorubicin-induced neutropenia [
23
,
40
,
41
]. Interestingly, Cisneros et al. [
42
]
reported that lung inflammation was reduced in all mice treated with U. tomentosa bark extract.
Additionally, Dreifuss et al. [
19
] examined the
in vivo
anti-inflammatory efficacy of quinovic acid
glycoside separated from the aqueous cat’s claw extracts.
3.5. Antimicrobial, Antiprotozoal and Antiviral Activities
The previous study documented the antimicrobial effect of U. tomentosa bark extracts against
several morphological forms of Borrelia burgdorferi and respiratory pathogens namely Enterococcus
faecalis,Pseudomonas aeruginosa and Staphylococcus aureus and this activity were attributed to the presence
of proanthocyanidins, including dimers and oligomers up to undecamers [
43
]. U. tomentosa showed
remarkable antifungal efficacy against various anidulafungin, terbinafine and fluconazole-resistant
non-albicans species [
44
]. The antiprotozoal activity has been recently documented by Batiha et al. [
45
]
against Babesia and Theileria parasites and this efficacy was attributed to its ability to digest harmful
microorganisms. In addition to that, it has been documented to treat many parasites except Giardia.
Therefore, U. tomentosa could be a good complementary antiprotozoal herb [
11
,
45
]. The antiviral activity
of quinovic acid glycosides has been demonstrated
in vitro
against vesicular stomatitis, ribonucleic
acid (RNA), a minus-strand RNA virus, and rhinovirus 1B [
25
]. Caon et al. [
46
] assessed the
in vitro
antiherpetic activity of hydroethanolic U. tomentosa extract, as well as the purified fractions of oxindole
alkaloids and quinovic acid glycosides against herpes simplex virus (HSV) infections as well as the
protective activity of these preparations on UV-induced DNA damage.
Appl. Sci. 2020,10, 2668 5 of 12
3.6. Immunomodulatory Activity
Smith et al. [
47
] reported that the POA isolated from U. tomentosa extracts improved the cellular
immune system, while the TOA suppressed this immunostimulating effect of this POA
in vitro
. Another
in vitro
study showed the effect of different cat’s claw extracts and mixtures of alkaloids in modulating
the immunobiochemical pathways enhanced by interferon-gamma [
48
]. Notably,
in vivo
experiments
revealed that U. tomentosa extracts exhibited immunomodulatory activity indirectly and promoted a
higher provide of myeloid progenitors in the bone marrow as a result of the release of biologically
active cytokines (e.g., CSFs, IL-6, and IL-1) [
49
]. Moreover, Allen-Hall et al. [
50
] documented that
U. tomentosa extracts prevented the mitogen-activated protein kinases (MAPK) signaling pathway and
change cytokine expression in the human acute monocytic leukemia cell line THP-1.
3.7. Cardiovascular Activity
Hirsutine isolated from U. rhynchophylla extract was found to decrease intracellular calcium
concentrations in rat aortas by inhibiting the calcium channels and effecting calcium stores [
51
].
Moreover, it showed a vasodilated, negative chronotropic, and antiarrhythmic effect. TOA namely
corynoxeine, isocorynoxiene, rhynchophylline, and isorhynchophylline exhibited a Ca
2+
channel
blocking effect, which resulted in low blood pressure and may affect the central nervous system [52].
3.8. Anti-Alzheimer’s Disease (AD) Activity
U. tomentosa is reported to act as a strong medicinal extract eliminator of A
β
plaques and
it is considered as a potential plant for Alzheimer’s Disease (AD) therapy. This activity was
attributed to the fact that U. tomentosa contains newly identified polyphenolic components namely
specific proanthocyanidins that possess both “plaque and tangle” reducing and inhibitory effects.
Proanthocyanidin B2 (epicatechin-4
β
-8-epicatechin) is one major cat’s claw-identified specific
polyphenol that markedly diminished the brain plaque load and enhanced short-term memory
in younger and older A
β
precursor protein (APP) transgenic mice “plaque-producing”. Moreover,
proanthocyanidin B2 has been shown to be a strong inhibitor of the brain inflammation as evidenced
by a decrease in astrocytosis and gliosis in TASD-41 transgenic mice [
53
]. List of some of POA and
TOA alkaloids along with their structures and biological activities are provided in Table 1.
Table 1. List of some of bioactive alkaloids isolated from Uncaria tomentosa.
Compounds Molecular Formula Structure Biological Activity References
Pentacyclic oxindole alkaloids (POA)
Uncarine F C21H24 N2O4
Appl. Sci. 2020, 10, x FOR PEER REVIEW 5 of 12
purified fractions of oxindole alkaloids and quinovic acid glycosides against herpes simplex virus
(HSV) infections as well as the protective activity of these preparations on UV-induced DNA damage.
3.6. Immunomodulatory Activity
Smith et al. [47] reported that the POA isolated from U. tomentosa extracts improved the cellular
immune system, while the TOA suppressed this immunostimulating effect of this POA in vitro.
Another in vitro study showed the effect of different cat’s claw extracts and mixtures of alkaloids in
modulating the immunobiochemical pathways enhanced by interferon-gamma [48]. Notably, in vivo
experiments revealed that U. tomentosa extracts exhibited immunomodulatory activity indirectly and
promoted a higher provide of myeloid progenitors in the bone marrow as a result of the release of
biologically active cytokines (e.g., CSFs, IL-6, and IL-1) [49]. Moreover, Allen-Hall et al. [50]
documented that U. tomentosa extracts prevented the mitogen-activated protein kinases (MAPK)
signaling pathway and change cytokine expression in the human acute monocytic leukemia cell line
THP-1.
3.7. Cardiovascular Activity
Hirsutine isolated from U. rhynchophylla extract was found to decrease intracellular calcium
concentrations in rat aortas by inhibiting the calcium channels and effecting calcium stores [51].
Moreover, it showed a vasodilated, negative chronotropic, and antiarrhythmic effect. TOA namely
corynoxeine, isocorynoxiene, rhynchophylline, and isorhynchophylline exhibited a Ca2+ channel
blocking effect, which resulted in low blood pressure and may affect the central nervous system [52].
3.8. Anti-Alzheimer’s Disease (AD) Activity
U. tomentosa is reported to act as a strong medicinal extract eliminator of Aβ plaques and it is
considered as a potential plant for Alzheimer’s Disease (AD) therapy. This activity was attributed to
the fact that U. tomentosa contains newly identified polyphenolic components namely specific
proanthocyanidins that possess both “plaque and tangle” reducing and inhibitory effects.
Proanthocyanidin B2 (epicatechin-4β-8-epicatechin) is one major cat’s claw-identified specific
polyphenol that markedly diminished the brain plaque load and enhanced short-term memory in
younger and older Aβ precursor protein (APP) transgenic mice “plaque-producing”. Moreover,
proanthocyanidin B2 has been shown to be a strong inhibitor of the brain inflammation as evidenced
by a decrease in astrocytosis and gliosis in TASD-41 transgenic mice [53]. List of some of POA and
TOA alkaloids along with their structures and biological activities are provided in Table 1.
Table 1. List of some of bioactive alkaloids isolated from Uncaria tomentosa.
Compounds Molecular
Formula Structure Biological Activity References
Pentacyclic oxindole alkaloids (POA)
Uncarine F C₂₁H₂₄N₂O₄
Anticancer activity [36]
Speciophylli
ne C21H24N2O4
Anti-neoplastic
activity [19]
Anticancer activity [36]
Speciophylline C21H24 N2O4
Appl. Sci. 2020, 10, x FOR PEER REVIEW 5 of 12
purified fractions of oxindole alkaloids and quinovic acid glycosides against herpes simplex virus
(HSV) infections as well as the protective activity of these preparations on UV-induced DNA damage.
3.6. Immunomodulatory Activity
Smith et al. [47] reported that the POA isolated from U. tomentosa extracts improved the cellular
immune system, while the TOA suppressed this immunostimulating effect of this POA in vitro.
Another in vitro study showed the effect of different cat’s claw extracts and mixtures of alkaloids in
modulating the immunobiochemical pathways enhanced by interferon-gamma [48]. Notably, in vivo
experiments revealed that U. tomentosa extracts exhibited immunomodulatory activity indirectly and
promoted a higher provide of myeloid progenitors in the bone marrow as a result of the release of
biologically active cytokines (e.g., CSFs, IL-6, and IL-1) [49]. Moreover, Allen-Hall et al. [50]
documented that U. tomentosa extracts prevented the mitogen-activated protein kinases (MAPK)
signaling pathway and change cytokine expression in the human acute monocytic leukemia cell line
THP-1.
3.7. Cardiovascular Activity
Hirsutine isolated from U. rhynchophylla extract was found to decrease intracellular calcium
concentrations in rat aortas by inhibiting the calcium channels and effecting calcium stores [51].
Moreover, it showed a vasodilated, negative chronotropic, and antiarrhythmic effect. TOA namely
corynoxeine, isocorynoxiene, rhynchophylline, and isorhynchophylline exhibited a Ca2+ channel
blocking effect, which resulted in low blood pressure and may affect the central nervous system [52].
3.8. Anti-Alzheimer’s Disease (AD) Activity
U. tomentosa is reported to act as a strong medicinal extract eliminator of Aβ plaques and it is
considered as a potential plant for Alzheimer’s Disease (AD) therapy. This activity was attributed to
the fact that U. tomentosa contains newly identified polyphenolic components namely specific
proanthocyanidins that possess both “plaque and tangle” reducing and inhibitory effects.
Proanthocyanidin B2 (epicatechin-4β-8-epicatechin) is one major cat’s claw-identified specific
polyphenol that markedly diminished the brain plaque load and enhanced short-term memory in
younger and older Aβ precursor protein (APP) transgenic mice “plaque-producing”. Moreover,
proanthocyanidin B2 has been shown to be a strong inhibitor of the brain inflammation as evidenced
by a decrease in astrocytosis and gliosis in TASD-41 transgenic mice [53]. List of some of POA and
TOA alkaloids along with their structures and biological activities are provided in Table 1.
Table 1. List of some of bioactive alkaloids isolated from Uncaria tomentosa.
Compounds Molecular
Formula Structure Biological Activity References
Pentacyclic oxindole alkaloids (POA)
Uncarine F C₂₁H₂₄N₂O₄
Anticancer activity [36]
Speciophylli
ne C21H24N2O4
Anti-neoplastic
activity [19]
Anti-neoplastic activity [19]
Mitraphylline C21H24 N2O4
Appl. Sci. 2020, 10, x FOR PEER REVIEW 6 of 12
Mitraphyllin
e C21H24N2O4
Anti-inflammatory,
antioxidant activities [54,55]
Isomitraphyl
line C21H24N2O4
Antioxidant activity [55]
Pteropodine C21H24N2O4
Immunomodulating
properties [48]
Isopteropodi
ne C21H24N2O4
Antimicrobial activity [37]
Tetracyclic oxindole alkaloid (TOA)
Corynoxeine C22H26N2O4
Antiproliferative
activity [56]
Rhynchophy
lline C22H28N2O4
Inhibit the platelet
aggregation and
thrombosis
[57]
Anti-inflammatory,
antioxidant activities [54,55]
Appl. Sci. 2020,10, 2668 6 of 12
Table 1. Cont.
Compounds Molecular Formula Structure Biological Activity References
Isomitraphylline C21H24 N2O4
Appl. Sci. 2020, 10, x FOR PEER REVIEW 6 of 12
Mitraphyllin
e C21H24N2O4
Anti-inflammatory,
antioxidant activities [54,55]
Isomitraphyl
line C21H24N2O4
Antioxidant activity [55]
Pteropodine C21H24N2O4
Immunomodulating
properties [48]
Isopteropodi
ne C21H24N2O4
Antimicrobial activity [37]
Tetracyclic oxindole alkaloid (TOA)
Corynoxeine C22H26N2O4
Antiproliferative
activity [56]
Rhynchophy
lline C22H28N2O4
Inhibit the platelet
aggregation and
thrombosis
[57]
Antioxidant activity [55]
Pteropodine C21H24N2O4
Appl. Sci. 2020, 10, x FOR PEER REVIEW 6 of 12
Mitraphyllin
e C21H24N2O4
Anti-inflammatory,
antioxidant activities [54,55]
Isomitraphyl
line C21H24N2O4
Antioxidant activity [55]
Pteropodine C21H24N2O4
Immunomodulating
properties [48]
Isopteropodi
ne C21H24N2O4
Antimicrobial activity [37]
Tetracyclic oxindole alkaloid (TOA)
Corynoxeine C22H26N2O4
Antiproliferative
activity [56]
Rhynchophy
lline C22H28N2O4
Inhibit the platelet
aggregation and
thrombosis
[57]
Immunomodulating
properties [48]
Isopteropodine C21H24N2O4
Appl. Sci. 2020, 10, x FOR PEER REVIEW 6 of 12
Mitraphyllin
e C21H24N2O4
Anti-inflammatory,
antioxidant activities [54,55]
Isomitraphyl
line C21H24N2O4
Antioxidant activity [55]
Pteropodine C21H24N2O4
Immunomodulating
properties [48]
Isopteropodi
ne C21H24N2O4
Antimicrobial activity [37]
Tetracyclic oxindole alkaloid (TOA)
Corynoxeine C22H26N2O4
Antiproliferative
activity [56]
Rhynchophy
lline C22H28N2O4
Inhibit the platelet
aggregation and
thrombosis
[57]
Antimicrobial activity [37]
Tetracyclic oxindole alkaloid (TOA)
Corynoxeine C22H26 N2O4
Appl. Sci. 2020, 10, x FOR PEER REVIEW 6 of 12
Mitraphyllin
e C21H24N2O4
Anti-inflammatory,
antioxidant activities [54,55]
Isomitraphyl
line C21H24N2O4
Antioxidant activity [55]
Pteropodine C21H24N2O4
Immunomodulating
properties [48]
Isopteropodi
ne C21H24N2O4
Antimicrobial activity [37]
Tetracyclic oxindole alkaloid (TOA)
Corynoxeine C22H26N2O4
Antiproliferative
activity [56]
Rhynchophy
lline C22H28N2O4
Inhibit the platelet
aggregation and
thrombosis
[57]
Antiproliferative activity
[56]
Rhynchophylline C22H28 N2O4
Appl. Sci. 2020, 10, x FOR PEER REVIEW 6 of 12
Mitraphyllin
e C21H24N2O4
Anti-inflammatory,
antioxidant activities [54,55]
Isomitraphyl
line C21H24N2O4
Antioxidant activity [55]
Pteropodine C21H24N2O4
Immunomodulating
properties [48]
Isopteropodi
ne C21H24N2O4
Antimicrobial activity [37]
Tetracyclic oxindole alkaloid (TOA)
Corynoxeine C22H26N2O4
Antiproliferative
activity [56]
Rhynchophy
lline C22H28N2O4
Inhibit the platelet
aggregation and
thrombosis
[57]
Inhibit the platelet
aggregation and
thrombosis
[57]
4. Reported Side Effects
The American Herbal Products Association (AHPA) classified cat’s claw as a class-4 safety rating,
although, it was known traditionally to be safe and nontoxic, indicating the lack of scientific data for herb
safety consideration [
31
]. Previous reports noted several adverse effects after administration of high
doses of cat’s claw including nausea, acute renal failure, slow heart rate, stomach discomfort, hormonal
effects, diarrhea, hepatotoxicity, decrease progesterone and estrogen levels, neuropathy [
58
,
59
], and
increased risk of bleeding when administered with blood thinner agents such as warfarin, therefore,
patients may be recommended to stop cat’s claw administration before surgeries [
31
,
60
,
61
]. Signs of
allergic reactions including swelling of face, lips, tongue, or throat, difficulty breathing, and hives have
been observed [
62
]. Additionally, acute renal failure was noticed in systemic lupus erythematosus
patients after the daily administration of four capsules of the cat’s claw [31,63,64].
Appl. Sci. 2020,10, 2668 7 of 12
5. Precautions
5.1. Drug-Drug Interactions
5.1.1. Immunosuppressant Drugs
Theoretically, it was believed that POA isolated from cat’s claw possesses an immunostimulatory
effect, therefore, it is contraindicated to be used with immunosuppressant drugs including cyclosporine,
azathioprine, daclizumab, basiliximab, mycophenolate, muromonab-CD3, tacrolimus, sirolimus,
corticosteroids, prednisone, or other chemotherapeutic drugs recommended for autoimmune disease
treatment or after organ transplantation [39,62].
5.1.2. Anticoagulants
Cat’s claw contains TOA that increased risk of bleeding when administered with aspirin,
anticoagulant drugs such as warfarin or heparin, NSAIDs such as ibuprofen and naproxen, antiplatelet
drugs like clopidogrel due to rhynchophylline inhibitory efficacy on platelet aggregation, therefore,
patients may be recommended to stop cat’s claw administration before surgeries [31,61].
5.1.3. Diuretics
Cat’s claw has a diuretic effect, so it is contraindicated to be used with other diuretics, as they act
by the same mechanism and thus increases the risk of electrolyte imbalance. Moreover, it may interact
with hormonal drugs, cholesterol-lowering drugs, and drugs that affect the kidney [65].
5.1.4. Antihypertensive Drugs
Hirsutine extracted from cat’s claw was reported to have a hypotensive effect, therefore it is
not recommended to be used to hypotensive people or those administering antihypertensive drugs
(e.g., casein protein, coenzyme Q-10 (ubiquinone), fish oil, L-arginine, Lycium, or stinging nettle) due
to rhynchophylline and isorhynchophylline hypotensive effects as it may reduce the blood pressure to
be too low [33].
5.1.5. Cytochrome P450 Substrates
Cat’s claw prevents the microsomal CYP 3A4 activity, and thus, increased the serum levels of drugs
that are metabolized by CYP 3A4 suchlike nonnucleoside reverse-transcriptase inhibitors, cyclosporine,
and some benzodiazepines and increased the serious adverse effects of these drugs [
66
]. Moreover,
the cat’s claw may interact with allergic drugs like fexofenadine, anti-cancer agents as paclitaxel,
antifungals like ketoconazole, antiviral drugs, and oral contraceptives [67].
5.2. Drug Safety
Based on the possible safety data, U. tomentosa extracts appears to be safe when administered
to several cases of inflammation. Cat’s claw safety has not been documented in breastfeeding and
pregnant women, or children under three years of age because of insufficient safety research [31,64].
6. Recommended Doses
The typical and recommended dose of U. tomentosa is one gram given two to three times daily.
A standardized extract attributed to specific chemotype of this species consisting of less than 0.5%
oxindole alkaloids and 8% to 10% carboxy alkyl esters has been used in doses of 250 to 300 mg in
several clinical studies [
68
,
69
]. In rats, it was determined that the average lethal dose for a single dose
of water extract from U. tomentosa is higher than 8 g/kg. In humans, no toxic symptoms were noticed
with frequent administration of 350 mg/day for 6 successive weeks [
18
,
70
,
71
]. Tinctures, decoctions,
capsules, extracts, and teas are recently prepared from the cat’s claw. For instance, 250–1000 mg capsule
Appl. Sci. 2020,10, 2668 8 of 12
is taken orally in divided doses per day [
31
], while in a decoction, up to 25 g of raw bark has been
used, although this based on traditional management practices. Although U. tomentosa is commercially
applicable in skin formulation, its typical dose has not yet been documented [31].
7. Conclusions
The existing review investigates the medicinal activities and all phytochemical molecules extracted
from U. tomentosa.U. tomentosa (cat’s claw) is used in the tradition medicine as a treatment option against
wide range of health problems, including immune system deficiencies, neurodegenerative disorders,
cancer, chronic fatigue syndrome, Crohn’s disease, digestive complaints, parasitic and microbial
infections, kidney cleanser, inflammatory problems, irritable and leaky bowel syndrome. Moreover,
U. tomentosa has many phytochemical molecules that are attributed to its therapeutic activities and exist
in different degrees in the herb. U. tomentosa acts as an effective natural herbal extract eliminator of A
β
protein “plaques”. Thence, U. tomentosa could be a potential herb for AD treatment. Although these
medicinal properties, the cat’s claw shows several adverse effects such as nausea, acute renal failure,
stomach discomfort, hormonal effects, diarrhea, hepatotoxicity, neuropathy and it is contraindicated to
be used with anticoagulants, antihypertensive, and immunosuppressant drugs.
Author Contributions:
G.E.-S.B., A.M.B., L.W., Y.H.A.E., M.E.A.E.-H., A.E.T., A.A.A.-S., and H.P.D. wrote the
paper. G.E.-S.B., A.M.B. and V.T. revised the paper. All authors have read and agreed to the published version of
the manuscript.
Funding: This research not receive external fund.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
HIV human immunodeficiency viruses
TOA tetracyclic oxindole alkaloid
POA pentacyclic oxindole alkaloid
IUPAC International Union of Pure and Applied Chemistry
NSAIDs nonsteroidal anti-inflammatory drugs
TBARs thiobarbituric acid-reactive substances
iNOS inducible nitric oxide synthase
IL-2 interleukin-2
AC11 of U. tomentosa extract standardized aqueous extract of U. tomentosa
CSFs colony-stimulating growth factors
RNA ribonucleic acid
HSV herpes simplex virus
MAPK mitogen-activated protein kinases
AD Alzheimer’s disease
Aβbeta-amyloid
AHPA The American Herbal Products Association
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