Curcumin: A Natural Herb Extract with Antiparasitic Properties

Abstract

This short review addresses the knowledge on curcumin use against parasite infections from traditional to modern medicine.
Curcumin is the active ingredient of turmeric (Curcuma longa). The extract of the rhizome of turmeric has been traditionally used against various diseases including parasitic infections.
Recently, the crude extract of turmeric and its active ingredient curcumin have been explored with respect to the biological
and molecular activity against many pathogens. The antioxidant, antitumor, and anti-inflammatory properties of curcumin make
it a promising natural drug to be used against bacterial, fungal, and viral agents. Antiparasitic effects of curcumin have
attracted considerable attention over the last decades. Curcumin has been found to display activity against various parasites
both in vitro and in vivo. However, the effects of curcumin become obvious in most cases at relatively high dose levels. The
bio-molecular and cellular processes involved in curcumin effects on parasites are not sufficiently understood at present
and more research in this area is inevitable to define the actual applicability of curcumin in parasite control measures and
therapy. We here review the available information on the therapeutic potential of curcumin against parasites obtained from
in vitro studies, animal models, and clinical trials.

Full text

Chapter 6
Curcumin: A Natural Herb Extract
with Antiparasitic Properties
Md. Shahiduzzaman and Arwid Daugschies
Abstract This short review addresses the knowledge on curcumin use against
parasite infections from traditional to modern medicine. Curcumin is the active
ingredient of turmeric (Curcuma longa). The extract of the rhizome of turmeric has
been traditionally used against various diseases including parasitic infections.
Recently, the crude extract of turmeric and its active ingredient curcumin have
been explored with respect to the biological and molecular activity against many
pathogens. The antioxidant, antitumor, and anti-inflammatory properties of curcu-
min make it a promising natural drug to be used against bacterial, fungal, and viral
agents. Antiparasitic effects of curcumin have attracted considerable attention over
the last decades. Curcumin has been found to display activity against various
parasites both in vitro and in vivo. However, the effects of curcumin become
obvious in most cases at relatively high dose levels. The bio-molecular and cellular
processes involved in curcumin effects on parasites are not sufficiently understood
at present and more research in this area is inevitable to define the actual applica-
bility of curcumin in parasite control measures and therapy. We here review the
available information on the therapeutic potential of curcumin against parasites
obtained from in vitro studies, animal models, and clinical trials.
6.1 Introduction
The plant turmeric, Curcuma longa L. (Zingiberaceae family), has a long history of
therapeutic use in Indian and Chinese medicines for the treatment of flatulence,
dyspepsia, liver disorder, jaundice, urinary tract diseases, wound, inflammation, and
Md. Shahiduzzaman
Department of Parasitology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
e-mail: szamanpara@yahoo.com
A. Daugschies (*)
Institute of Parasitology, University of Leipzig, An den Tierkliniken 35, 04103 Leipzig, Germany
e-mail: daugschies@vetmed.uni-leipzig.de
H. Mehlhorn (ed.), Nature Helps..., Parasitology Research Monographs 1,
DOI 10.1007/978-3-642-19382-8_6, #Springer-Verlag Berlin Heidelberg 2011
141

other diseases. It has also been used in the treatment of intestinal parasites and of
parasitic skin infection. The scientific backgrounds for the curcumin effects have
been discovered gradually. A crude extract of turmeric contains curcumin and
curcuminoids (Rasmussen et al. 2000) where curcumin is the major constituent.
Curcumin is a polyphenolic orange–yellow compound and the main coloring prin-
ciple of curcumin is 1,7-bis-(4-hydroxy-3-methoxy-phenyl)-hepta-1,6-diene-3,5-
dione (diferuloylmethane). Curcumin has attracted considerable attention in recent
years due to its remarkable pharmacological activities, including antioxidant, anti-
tumor, and anti-inflammatory activities (Surh 2002; Aggarwal et al. 2003; Choi
et al. 2006; Shen and Ji 2007; Goel et al. 2008). It exerts influence on a variety of
biological and cellular processes. Curcumin has been suggested to be useful in
antidiabetic (Srinivasan and Menon 2003), anti-HIV (Jordan and Drew 1996;
Barthelemy et al. 1998), antibacterial (Negi et al. 1999; Mahady et al. 2002), and
antifungal treatment (Kim et al. 2003). In addition to inhibiting the growth of a
variety of pathogens, curcumin has been shown to have anthelmintic and antipro-
tozoal activities (Nose et al. 1998; Araujo et al. 1998, 1999; Koide et al. 2002). The
current experience regarding curcumin effects in various scenarios rewards more
research into the drug targets that might be suitable for therapeutic invention. The
purpose of this review is to provide a brief summary of the current published
knowledge of curcumin as a potential antiparasitic drug.
6.2 Curcumin Effects on Parasites
6.2.1 Helminths
Juice of turmeric traditionally has long been used to cure worm infections in south
and south-east Asia (Nadkarni 1976). Recently, it has been reported that the extract of
C. longa is active against Schistosoma mansoni (El-Ansary et al. 2007; El-Banhawey
et al. 2007) and Caenorhabditis elegans (Atjanasuppat et al. 2009). Curcumin
treatment modulates cellular and humoral immune responses of infected mice
and leads to a significant reduction of parasite burden and liver pathology in acute
murine schistosomiasis. It also possesses in vitro activity against adult S. mansoni
worms (Magalhaes et al. 2009) and is suspected to have therapeutic potential in the
treatment and prevention of schistosomiasis (Allam 2009). Antifibrogenic and anti-
inflammatory properties of curcumin may reduce Opisthorchis viverrini-induced
fibrosis and prevent cholangiocarcinoma development that may be associated with
opisthorchiasis (Boonjaraspinyo et al. 2009; Pinlaor et al. 2010). Thus, curcumin may
be useful as a chemopreventive drug by reducing the severity of O. viverrini-
associated disease and the risk of cholangiocarcinoma. It has been suggested that
this property of curcumin can be explained by reduction of the oxidative and nitro-
genic DNA damage that may be due to suppression of oxidant-generating genes and
enhancement of antioxidant genes in the nucleus of bile duct epithelial and inflamma-
tory cells (Pinlaor et al. 2009). Although particularly trematode infections have been
142 Md. Shahiduzzaman and A. Daugschies

studied, curcumin seems also to have a positive effect in nematode infections such
as Toxocara canis in dogs (Kiuchi et al. 1993). T. canis is a zoonotic parasite and,
like other ascarid infections, is very prevalent worldwide and particularly in
many developing countries. It would be of considerable benefit if curcumin effects
would also be seen in human infections with Ascaris lumbricoides or A. suum in
swine, however, no scientific data has been published in this respect so far.
6.2.2 Protozoa
Antiprotozoal activities of curcumin have been reported extensively over the last
decade. The spice rhizome of turmeric (1% crude extract), as well as its main
medicinal component, curcumin (0.05%), appear effective in reducing upper- and
mid-small-intestinal infections caused by Eimeria acervulina and Eimeria maxima
but they do not act beneficially in Eimeria tenella infections (Allen et al. 1998).
However, in vitro incubation of E. tenella sporozoites with curcumin showed
considerable effects on sporozoite morphology and viability and resulted in
decreased invasion of MDBK cells (Khalafalla et al. 2010). Curcumin, as an
alcoholic extract, was found to have antiprotozoal activity against Entamoeba
histolytica (Dhar et al. 1968). Antiprotozoal activities of curcumin were also
described for Plasmodium (Reddy et al. 2005; Cui et al. 2007), Leishmania (Araujo
et al. 1998; Rasmussen et al. 2000; Koide et al. 2002; Saleheen et al. 2002; Das et al.
2008), Trypanosoma (Nose et al. 1998), and Giardia lamblia (Pe
´rez-Arriaga et al.
2006), both in vitro and in vivo. Curcumin was able to reduce parasitemia by
80–90% in Plasmodium berghei-infected mice (Reddy et al. 2005). Recently,
curcumin was found to be effective against Cryptosporidium parvum in cell culture.
C. parvum appears to be more sensitive to curcumin than Plasmodium,Giardia, and
Leishmania (Shahiduzzaman et al. 2009). Synergistic antiprotozoal effects were
shown when curcumin was applied in combination with other drugs. For instance,
the combination of artemisinin and curcumin shows additive activity in killing
Plasmodium falciparum in culture and enabled experimentally P. berghei-infected
mice to survive (Nandakumar et al. 2006). Drug resistance of Plasmodium strains is
a major threat to malaria control. However, chloroquine-resistant P. falciparum
(Reddy et al. 2005) and artemisinin-resistant Plasmodium chabaudi (Martinelli
et al. 2008) were found to be sensitive to curcumin in culture and in mice,
respectively. These are promising data that may open alternative options for
malaria control, particularly where drug resistance has become a relevant issue.
6.3 Mode of Action and Perspectives
It appears that curcumin acts against parasites through unique biomolecular
mechanisms which would explain its activity on both drug-sensitive and drug-
resistant parasite strains. Various studies have shown that curcumin has antioxidant
6 Curcumin: A Natural Herb Extract with Antiparasitic Properties 143

and anti-inflammatory properties and that it modulates numerous targets and cell
signaling pathways. These include growth factors, growth factor receptors, tran-
scription factors, cytokines, enzymes, and genes regulating apoptosis.
The discovery of the antioxidant properties of curcumin explains many of its
wide-ranging pharmacological activities. Curcumin is an effective antioxidant and
scavenges superoxide radicals, hydrogen peroxide, and nitric oxide (NO) from
activated macrophages (Joe and Lokesh 1994). Curcumin is associated with the
maintenance of reactive oxygen species (ROS) and activity of NO in a dose-
depending manner. High doses (20–50 mM) of curcumin induce formation of
ROS (Balasubramanyam et al. 2003) by elevation of cytosolic calcium through
the release of calcium ions from intracellular stores. Moreover, influx of extracel-
lular calcium leads to depolarization of mitochondrial membrane potential, release
of cytochrome c into the cytosol and concomitant nuclear alterations. For instance,
deoxynucleotidyltransferase-mediated dUTP end labeling and DNA fragmentation
in P. falciparum (Cui et al. 2007) and Giardia (Pe
´rez-Arriaga et al. 2006) were
observed and promising antileishmanial activity (Das et al. 2008) was supposed to
be related to this molecular mechanism. In leishmaniasis inducible nitric oxide
synthase (iNOS) is correlated with increasing doses of curcumin leading to intra-
cellular killing of Leishmania major (Liew et al. 1990, 1991; Green et al. 1990).
Leitch and Qing (1999) reported that both reactive nitrogen species (RNS) and ROS
play protective roles in experimental cryptosporidiosis in mice. Cryptosporidium
has a poor capacity to scavenge ROS (Entrala et al. 1997), making it potentially
more susceptible to killing by such oxygenic compounds. Certain ROS, especially
hydroxyl radicals and hydrogen peroxide, produced as a result of parasite exposure
to ultraviolet irradiation, resulted in inactivation (photo-toxicity) of C. parvum
oocysts (Gerrity et al. 2008; Ryu et al. 2008). Conversely, low doses (1–15 mM)
of curcumin activate peroxisome proliferator-activated receptor gamma, deactivate
type 1 response, inhibit iNOS, and interferes with adaptive immunity thus exacer-
bating the pathogenic effects of Leishmania donovani infection (Adapala and Chan
2008). Curcumin in low doses also is capable of blocking the action of both NO and
NO congeners on intracellular Leishmania or scavenges ROS produced as a result
of activation of macrophages in leishmaniasis infection. This contributes to protec-
tion of promastigotes and amastigotes of the visceral species, L. donovani, and
promastigotes of the cutaneous species, L. major (Chan et al. 2005) from host attack
after phagocytosis by for example macrophages. Despite the wide evidence that NO
can be regarded as a natural antiprotozoal weapon, little efforts have been made to
develop and test NO-based drugs. This is mainly due to the difficulty in designing
suitable chemical carriers that are able to release the right amount of NO, in the
right place and at the right time, to avoid toxic effects against nontarget host cells.
The curcumin diphasic effect against parasites that depends on applied dose and
exposure time may be advantageous for development of such an antiparasitic drug.
Antiparasitic activities of curcumin are achieved through effects on transcription
of genes. Recent studies find that histone acetylation plays an important role in
eukaryotic gene transcription, carcinogenesis, and the therapy of cancer. Generally,
histone acetylation contributes to the formation of a transcriptionally competent
144 Md. Shahiduzzaman and A. Daugschies

environment by “opening” chromatin and permits access of transcription factors to
DNA (Fry and Peterson 2002; Lehrmann et al. 2002) whereas histone deacetylation
contributes to a “closed” chromatin state and transcriptional repression. The histone
acetylation–deacetylation balance is accurately maintained through a balance of
histone acetyltransferase (HAT) and histone deacetylase. Curcumin induces histone
hypoacetylation in vivo mainly through inhibition of HAT and concomitant genera-
tion of ROS by curcumin effects also contribute to inhibition of HAT activity (Kang
et al. 2005). Histone deacetylase is a novel therapeutic target for fungal-derived
antiprotozoal agents (like acipidin). Such drugs may alter proliferation of apicom-
plexan parasites (Darkin-Rattray et al. 1996). In vitro, curcumin effects on recom-
binant P. falciparum have been attributed to inhibition of histone deacetylation (Cui
et al. 2007) and inhibition of HAT activity (Balasubramanyam et al. 2004). A new
member of the apicomlexan histone deacetylase family has been recently described
in C. parvum (Rider and Zhu 2009), and it seems to be possible that a respective
mechanism is involved in inhibition of growth of Cryptosporidium by curcumin.
Curcumin induces hypoacetylation of histone H3 at K9 and K14, but not of H4 at
K5, K8, K12, and K16. The specific inhibition of the PfGCN5 HAT and generation
of ROS have been supposed to be responsible for curcumin-related cytotoxicity for
malaria parasites (Cui et al. 2007). Curcumin inhibits the intracellular adhesion
molecules that contribute to sequestration and establishment of Toxoplasma
(Barragan et al. 2005) and Plasmodium (Chakravorty and Craig 2005). The ortho-
logue of mammalian sarcoplasmic–endoplasmic reticulum Ca
2+
–ATPase in
P. falciparum, PfATP6, is the molecular target of artemisinins, which are the most
potent antimalarials available (Eckstein-Ludwig et al. 2003). It has been demon-
strated by docking simulation that curcumin can efficiently inhibit PfATP6, which
provides some deeper insights into the antimalarial mechanism of curcumin (Ji and
Shen 2009).
Curcumin is found to significantly increase adhesion but remarkably reduce
viability of Giardia trophozoites (Pe
´rez-Arriaga et al. 2006). It has been found
that biomolecular discharge from apical organelles of C. parvum and Toxoplasma
gondii is essential for host cell invasion and this depends on parasite intracellular
calcium levels (Chen et al. 2004; Lovett et al. 2002; Lovett and Sibley 2003).
Reduced intracellular calcium levels in free sporozoites decrease secretion from the
apical complex, thus reducing invasion and infection by the zoites. Curcumin
mechanistically interferes with protein kinase C (PKC) and calcium regulation
through increased ROS generation (Balasubramanyam et al. 2003). PKC-like
enzymes play a critical role in attachment and in internalization of Leishmania
mexicana (Varez-Rueda et al. 2009). Hypocalcimic action and inhibition of PKC by
curcumin therefore should be taken into account to develop suitable and novel
drugs for control of infection of parasite into host cells.
A significant inhibition of C. parvum sporozoite invasion of HCT cells by curcu-
min was reported in vitro (Shahiduzzaman et al. 2009). Infectivity of sporozoites is
mediated by interaction of molecules secreted from sporozoites with matching recep-
tors present on both parasite and host cell (Nesterenko et al. 1999). Phospholipase A2
(PLA2), a secretory mammalian host cell enzyme involved in arachidonic acid
6 Curcumin: A Natural Herb Extract with Antiparasitic Properties 145

metabolism, has been supposed to be associated with infectivity of Toxoplasma
(Saffer et al. 1989; Saffer and Schwartzman 1991) and Cryptosporidium (Pollok
et al. 2003). Curcumin was found to inhibit mammalian phospholipase (Huang et al.
1991; Rao et al. 1995) and it appears possible that similar effects on parasite PLA2
may reduce infectivity of sporozoites. However, other enzymes are also thought to
play a pivotal role in apicomplexan host cell invasion. Inhibition of C. parvum serine
protease (Forne et al. 1996) and arginine aminopeptidase (Okhuysen et al. 1994, 1996)
was reported to reduce the ability of sporozoites to infect host cells. Blocking of T.
gondii serineprotease (Conseil et al. 1999) significantly reduced the level of infection.
Curcumin is able to suppress both serine protease and aminopetidase activity in a
variety of tissues and cells (Shim et al. 2003; Ukil et al. 2003) and thus it may well be
that curcumin acts as an inhibitor of host cell invasion by impairing the function of
respectively relevant parasite enzymes. Curcumin has been proposed as a HIV-1 or
HIV-2 protease inhibitor (Sui et al. 1993). Parasite infections like cryptosporidiosis
and toxoplasmosis are known to be opportunistic pathogens that cause severe disease
in immunocompromised individuals. Thus, a protease inhibitor such as curcumin
could be of double benefit by directly acting on HIV and on opportunistic protozoa.
A glutathione transferase (PfGST) isolated from P. falciparum has been asso-
ciated with chloroquine resistance. Curcumin is a potent inhibitor of PfGST which
may open alternative perspectives for management of drug resistance in malaria
(Mangoyi et al. 2010).
Curcumin inhibits metalloproteinase activity including classical matrix metallo-
proteinase inhibitors such as EDTA, EGTA, phenantroline, and also tetracycline in
Trypanosoma brucei infection (de Sousa et al. 2010). It is suspected to inhibit the
matrix metalloproteinase-9-like molecules in Trypanosoma cruzi (Nogueira de Melo
et al. 2010) and Theileria annulata-infected bovine leukocytes (Baylis et al. 1995).
Metalloproteinases mediate the metastatic phenotype of T. annulata-transformed
cells (Adamson and Hall 1996). This property of curcumin has not been extensively
studied in terms of antiparasitic potential but deserves further research.
The apoptotic response of infected intestinal epithelial cells is actively sup-
pressed by C. parvum via up regulation of survivin, favoring parasite replication
(Liu et al. 2008). Curcumin-mediated down regulation of survivin induces apoptosis
in tumor cells and similarly may enhance apoptosis of C. parvum-infected cells.
Caspase-dependent apoptosis during infection with C. parvum raises the possibility
that therapeutic interference with host cell death could alter the course of the
pathology in vivo (Ojcius et al. 1999). In T. gondii-infected cells, the termination
of NF-
kappa
B(
k
B) signaling is associated with reduced phosphorylation of p65/RelA,
an event involved in the ability of NF-
k
B to translocate to the nucleus and to bind to
DNA. The phosphorylation of p65/RelA represents an event downstream of IaB
degradation that may be targeted by pathogens to subvert NF-
k
B signaling (Shapira
et al. 2005). Curcumin can effectively down-regulate NF-
k
B, thus inhibiting Ikap-
paBalpha kinase and reducing IkappaBalpha phosphorylation, leading to cell cycle
arrest, apoptosis, and suppression of proliferation (Shishodia et al. 2005) of parasite-
infected cells. Thioredoxin reductases (TrxRs) are essential for cell growth and
survival and they appear good targets for antitumor therapy. The parasitic nematode
146 Md. Shahiduzzaman and A. Daugschies

Haemonchus contortus contains two TrxRs, a cytoplasmic enzyme HcTrxR1 with a
selenocysteine in the active site (Gly–Cys–SeCys–Gly), similar to the mammalian
TrxR, and a mitochondrial enzyme HcTrxR2 with a Gly–Cyc–Cys–Gly active site
which is unique to nematodes. Curcumin inhibition of TrxRs (Hudson et al. 2010)
may reduce parasite proliferation which is attractive for control strategies. It has
been shown that curcuminoids strongly bind to P. falciparum thioredoxin (PfTrxR)
and glutathione (PfGR) reductases which has allowed the development of automated
high-throughput screening to rapidly determine the binding affinity of respective
enzyme ligands (Mulabagal and Calderon 2010).
6.4 Curcumin Analogs
Synthetic curcumin analogs exhibit more potent antiparasitic effects than curcumin
extracted from turmeric. The natural curcuminoids (curcumin, demethoxycurcumin,
bisdemethoxycurcumin) exhibit low antitrypanosomal and antileishmanial activity. In
contrast, curcumin derivatives (methylcurcumin) with des-O-methylcentrolobine are
very active against the extracellular form (promastigotes) and intracellular form (amas-
tigotes) of Leishmania amazonensis (Araujo et al. 1999). Curcuminoids synthesized by
the condensation of 2,4-pentanedione with differently substituted benzaldehydes and
the compound 1,7-bis-(2-hydroxy-4-methoxyphenyl)-1,6-heptadiene-3,5-dione are
highly effective in vitro against L. amazonensis promastigotes (Gomes et al. 2002b).
Chemically modified curcumin for example 1,7-bis-(4-propargyl-3-methoxyphenyl)-
1,6-heptadiene-3,5-dione, is about ten times more efficient against L. amazonensis
promastigotes than the original curcumin (Gomes et al. 2002a). The highly active
analog 1,7-bis(4-hydroxy-3-methoxyphenyl) hept-4-en-3-one (40) is particularly active
against kinetoplastid parasites. The diminazene-resistant strain of Trypanosoma brucei
brucei (TbAT1-KO) B48 is susceptible to curcuminoids carrying a conjugated keto
(enone) motif. The enone motif 40 was found to exert particularly high trypanocidal
activity against all Trypanosoma species and strains tested (Changtam et al. 2010).
6.5 Conclusions
In recent years, the molecular basis for curcumin efficacy has been extensively
investigated. Understanding of curcumin effects on the biomolecular or cellular
level will hopefully help to identify and develop new therapeutic options. Curcumin
is nontoxic to mammals at even high doses which makes it attractive as a potential
antiparasitic drug, however, synthetic analogs of curcumin are superior in effi-
ciency as compared to natural curcumin. In any case, curcumin extracted from
turmeric represents an accessible and low-cost alternative for control of parasites in
populations living in risk areas and thus further research into the potential of this
natural plant product appears very rewarding.
6 Curcumin: A Natural Herb Extract with Antiparasitic Properties 147

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