Journal of Ethnopharmacology 155 (2014) 1011–1028
Contents lists available at ScienceDirect
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep
Review
From arrow poison to herbal medicine – The ethnobotanical,
phytochemical and pharmacological significance
of Cissampelos (Menispermaceae)
Deepak Kumar Semwal, Ruchi Badoni Semwal, Ilze Vermaak, Alvaro Viljoen n
Department of Pharmaceutical Sciences, Faculty of Science, Tshwane University of Technology, Private Bag X680, Pretoria 0001, South Africa
art ic l e i nf o
a b s t r a c t
Article history:
Received 31 March 2014
Received in revised form
22 May 2014
Accepted 24 June 2014
Available online 2 July 2014
Ethnopharmacological relevance: Cissampelos species have a rich history of traditional use, being used for
both therapeutic and toxic properties. It is traditionally applied therapeutically in a diverse range of
conditions and diseases including asthma, cough, fever, arthritis, obesity, dysentery, snakebite, jaundice
and heart, blood pressure and skin-related problems. Conversely, it was traditionally included in
preparations of curare applied as arrow poison during hunting to cause death of animals by asphyxiation.
This review unites the ethnobotanical knowledge on Cissampelos with the phytochemistry and
pharmacological activity which has been explored thus far. In addition, it identifies knowledge gaps
and suggests further research opportunities.
Methods: The available electronic literature on the genus Cissampelos was collected using database
searches including Scopus, Google Scholar, Pubmed, Web of Science, etc. The searches were limited to
peer-reviewed English journals with the exception of books and a few articles in foreign languages which
were included.
Results: The literature revealed that pharmacological activity including analgesic and antipyretic, antiinflammatory, anti-allergic, bronchodilator, immunomodulatory, memory-enhancing, antidepressant,
neuroprotective, antimicrobial, antimalarial, antiparasitic, anti-ulcer, anticancer, anti-oxidant, cardiovascular, muscle-relaxant, hepatoprotective, antidiabetic, antidiarrhoeal, antifertility, and antivenom activity
have been confirmed in vitro and/or in vivo for various Cissampelos species. Cissampelos pareira L. and
Cissampelos sympodialis Eichl. are the most explored species of this genus and the smallest number of
studies have been conducted on Cissampelos laxiflora Moldenke and Cissampelos tenuipes Engl. Many
alkaloids isolated from Cissampelos such as warifteine, methylwarifteine, berberine, hayatin and
hayatidin showed promising anti-allergic, immunosuppressive, antidepressant, anticancer, vasodilatory
and muscle-relaxant activities.
Conclusion: The plants of this genus are used in traditional medicine for the treatment of various
ailments. These plants are a rich source of bioactive bisbenzylisoquinoline and aporphine alkaloids
together with other minor constituents. Although these plants are reputable and revered in various
traditional medicine systems, many have not yet been screened chemically or pharmacologically and so
there is a vast amount of research still to be conducted to validate their traditional use.
& 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords:
Cissampelos pareira
Cissampelos sympodialis
Antidepressant
Antidiabetic
Curare
Bisbenzylisoquinoline alkaloids
Contents
1.
2.
3.
4.
Introduction . . . . . . . . . . .
Geographical distribution
Botanical aspects . . . . . . .
Ethnobotanical aspects . .
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Abbreviations: Ig, immunoglobulin; OVA, ovalbumin; PG, prostaglandin; PHF, polyherbal formulation; TGI, total growth inhibition; MIC, minimum inhibitory
concentration; IZD, inhibition zone diameter; MLE, methanolic leaf extract; HLE, hydroalcoholic leaf extract; HRE, hydroalcoholic root extract; ELE, ethanolic leaf extract;
ERE, ethanolic root extract; MRE, methanolic root extract; p.o., per oral; i.p., intra-peritoneal; i.v., intravenous
n
Corresponding author. Tel.: þ 27 12 382 6373; fax: þ27 12 382 6243.
E-mail address: viljoenam@tut.ac.za (A. Viljoen).
http://dx.doi.org/10.1016/j.jep.2014.06.054
0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
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D.K. Semwal et al. / Journal of Ethnopharmacology 155 (2014) 1011–1028
5.
Phytochemical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
Alkaloid constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Non-alkaloid constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Pharmacological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.
Analgesic and antipyretic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.
Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.
Anti-allergic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.
Bronchodilator activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5.
Immunomodulatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.6.
Memory-enhancing activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.7.
Antidepressant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.8.
Neuroprotective activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9.
Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.10. Antimalarial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.11. Antiparasitic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.12. Anti-ulcer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.13. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.14. Anti-oxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.15. Cardiovascular activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.16. Muscle-relaxant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.17. Hepatoprotective activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.18. Antidiabetic activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.19. Antidiarrhoeal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.20. Antifertility activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.21. Antivenom activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.22. Miscellaneous activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Toxicity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Future perspectives and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
The genus Cissampelos (Menispermaceae) has diverse traditional
uses, being applied for its therapeutic as well as toxic effects. In the
rainforests of South America, Cissampelos pareira (called Abuta),
commonly known as the midwives' herb, has a rich history of use to
treat all types of women's ailments including menstrual cramps,
menorrhagia, uterine haemorrhage etc. This is due to its profound
relaxant effect on smooth muscle (Singh et al., 2010; Arora et al., 2012).
At the same time however, it was traditionally included in the
preparation of curares, the well-known South American arrow poison
used in hunting to cause death by asphyxiation. Again, this effect
is due to its muscle-relaxant and neuromuscular blocking effect
(Maurya et al., 2013). The alkaloid isolated from Cissampelos pareira,
hayatin methiodide, showed an equal amount of curariform activity as
compared to the well known d-tubocurarine (Bhattacharji et al., 1952;
Taylor, 1996). The members of this genus mostly contain alkaloids
including bisbenzylisoquinolines, berberines, morphines, and aporphines, etc. along with a moderate quantity of other constituents
(Thornber, 1970; Rocha et al., 1984; Blasko and Cordell, 1988).
Many alkaloids such as tropoloisoquinoline alkaloids isolated
from the genus exhibited potent biological activities. Pareirubrines
A and B (Morita et al., 1993a, 1993b) from Cissampelos pareira showed
antileukemic activity, hayatin methiodide (Pradhan and De, 1953)
and hayatinin methochloride (Basu, 1970) from Cissampelos pareira,
and aporphine alkaloids (þ)-cissaglaberrimine and (þ )-trilobinine
from Cissampelos glaberrima showed muscle-relaxant properties.
Most of the plants including Cissampelos capensis, Cissampelos pareira
and Cissampelos sympodialis have been recognised for their remarkable medicinal properties and these are being used in various
indigenous medicine systems for antibacterial, anti-oxidant, antispasmodic, diuretic, hypotensive, muscle-relaxant, antiseptic, aphrodisiac, analgesic, anti-haemorrhagic and cardiotonic properties (Kaur
et al., 2012). Based on traditional knowledge, some species of the
genus were also studied clinically for malaria (Wilcox et al., 2005),
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dengue (Bhatnagar et al., 2011), diabetes (Jannu et al., 2011), the
treatment of ulcers (Nwafor and Akah, 2003) and many other
diseases and conditions (Roy et al., 1952; Hemraj et al., 2012).
The extremely diverse range of recorded traditional uses for
Cissampelos species is in part due to its very wide geographical
distribution. This review comprises of up-to-date information on
the ethnobotany, phytochemistry and pharmacology of the genus
Cissampelos.
2. Geographical distribution
The genus Cissampelos has a wide global distribution spanning
five continents as well as several islands (Fig. 1). Cissampelos
pareira is the only species that has a pantropical distribution – a
geographical distribution which includes the tropical areas of the
three major continents; Africa, Asia and the Americas. It occurs
in Asia (Indo-China, Southern China, Malaysia, Thailand, India and
Pakistan), Africa (Sierra Leone east to Congo, Rwanda, Tanzania,
south to northern Angola, Zambia), America (Brazil, Argentina,
Peru, Mexico, Colombia and Florida), Australia, the West Indies,
Comores, Mauritius, Seychelles and Madagascar. Cissampelos
ovalifolia is found only in North and South America and Cissampelos
sympodialis only in South America (Brazil). Cissampelos mucronata,
Cissampelos owariensis and Cissampelos capensis is restricted to the
African continent: Cissampelos mucronata is distributed throughout tropical Africa from Senegal east to Ethiopia and south to
southern Africa; Cissampelos capensis has a small natural distribution in Namibia and the Cape Provinces (Eastern Cape, Western
Cape and Northern Cape) of South Africa; Cissampelos owariensis is
found from Sierra Leone east to Uganda and south to Angola,
Zambia and Mozambique. Based on various resources including flora of America, Africa, India, Pakistan, China and Australia,
the distribution of selected ethnomedicinally important species,
D.K. Semwal et al. / Journal of Ethnopharmacology 155 (2014) 1011–1028
1013
Fig. 1. Geographical distribution of selected ethnomedicinally important Cissampelos species: (a) Cissampelos pareira; (b) Cissampelos ovalifolia and Cissampelos owariensis;
(c) Cissampelos sympodialis, Cissampelos mucronata and Cissampelos capensis.
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i.e. Cissampelos pareira, Cissampelos mucronata, Cissampelos
owariensis, Cissampelos capensis, Cissampelos sympodialis and
Cissampelos ovalifolia is depicted in Fig. 1a–c (Chopra, 1958;
Barbosa-Filho et al., 1997b; De Wet, 2006; ; Mosango, 2008;
Muzila, 2008; Oyen, 2008a, 2008b).
3. Botanical aspects
The genus name Cissampelos when directly translated means
ivy–vine, derived from the Greek words for Ivy (Kissos) and vine
(ampelos). The name refers to the ivy-like growth of this plant in
green rambling branches and the vine or grape-like racemes of
fruits (Sudhakaran, 2012). Rhodes (1975) has reported a comprehensive morphological description of 20 Cissampelos species with
descriptive figures for all the plant parts. Cissampelos species are
generally sub-herbaceous or suffrutescent twiners distributed
throughout warmer parts of Asia, Africa, and America (Semwal
et al., 2010). Their leaves are mostly cordate or reniform, often
peltate and alternate. The flowers are in axillary racemes or
clusters; staminate flowers with 4 free sepals and 4 fused petals,
2–5 anthers on a staminal column or disk; pistillate flowers with
1 fleshy sepal, 1 fleshy petal and a solitary carpel, with 3–5 lobed
stigmas. The fruits are a subglobose drupe with a flattened and
tuberculate stone. Wide rays, pitted tyloses and enlarged vessel
pits near the perforation plates highlight the wood of these
plants. Some of the plants have successive cambia; a single vascular
cambium remained functional and showed normal secondary growth
(Don, 1831; Rhodes, 1975; Tamaio et al., 2010).
According to The Plant List (2013), Cissampelos is one of the
major genera of Menispermaceae comprising 21 species. These
plants are mostly climbers or lianes, having simple peltate
or subpeltate and entire angular leaves. The flowers have 1–5
obovate sepals; petals and stamens are mostly connate. The fruits
are hairy, or a glabrous drupe, with thin fleshy mesocarp. The
leaves of Cissampelos sympodialis are peltate with deltoid blades
and petioles swollen at extremities. The epidermis is hipostomatic
with anticlinal walls of epidermal cells; mesophyll dorsiventral;
vascular system formed by 6–7 free collateral bundles ring (Porto
et al., 2008). In particular, Cissampelos pareira has a total of n ¼12
and 2n¼ 24 chromosomes, but in the male plant, these are unequal
pairs, heterogametic with XY type of sex chromosomes (Mathew,
1958). Most of the plants have sieve-like rhizomes in their T.S.
which are easily distinguishable in each species except Cissampelos
hirta and Cissampelos mucronata. Last mentioned species are
differenciated only by their leaf texture, colour and the presence
of a geniculate pulvinus in Cissampelos hirta (De Wet et al., 2002).
4. Ethnobotanical aspects
Ethnobotanical studies revealed that Cissampelos is one of the
most widely and frequently used genera of the Menispermaceae
family in Asian, American and African traditional medicine. These
species are also used as curare for arrow poison in various
parts of the world including South America (Quattrocchi, 1912). In
Nigeria, the rhizomes of Cissampelos owariensis (Mosango, 2008) and
Cissampelos mucronata (Muzila, 2008) are used in the preparation of
arrow poison.
Since ancient times, Cissampelos pareira has been used in Indian
Ayurvedic medicine for preparing Pusyanug churn, Pathadi kwath,
Mahayograj guggulu and Agnimukh churn (Rawat and Vashistha,
2011). Cissampelos pareira has been used for coughs, delirium,
fever-cerrado habitants, madness, epilepsy, convulsions and also
used as a stimulant, sedative, analgesic, febrifuge, anti-oxidant,
tonic and narcotic in various parts of the globe (Mendes and
Carlini, 2007; Giorgetti et al., 2011; Samanta and Bhattacharya,
2011). An infusion of the roots of Cissampelos pareira has been used
to treat gastrointestinal disorders such as diarrhoea and dysentery,
whereas topically, it is used for treating snake bites in Central
America and Mexico (Morten, 1981; Leonti et al., 2001; Heinrich
et al., 2014). In India, the plant is used for abortion, asthma,
dysentery, fever, hydrocele, gonorrhoea, menstrual cycle regulation, bubo, tumour, piles and puerperal fever. The roots are
specifically used as a diuretic, febrifuge, for heart trouble, dysentery, sores, snakebite and jaundice (Chopra, 1958; Kupchan et al.,
1965; Siddiqui and Husain, 1994; Singh and Ali, 1994; Rana and
Datt, 1997; Sharma et al., 2004; Basha and Sudarsanam, 2012;
Sharma et al., 2012) as well as to prevent a threatened miscarriage
and to stop uterine haemorrhage (Lewis, 1977). This plant, in
combination with Piper nigrum L., Mimosa pudica L. and Hibiscus
rosa-sinensis L., is used in different parts of India for birth control
(Tiwari et al., 1982). The root decoction of Cissampelos pareira is
used in malaria, pneumonia, and snake and dog bite (antidote) in
India (Jain et al., 2005; Namsa et al., 2011). The root and leaves are
used for helminthiasis (worm infestation) (Ramasubramaniaraja
and Babu, 2010), against dyspepsia, diarrhoea, stomach ache,
dropsy, cough, urinary difficulties like cystitis, dysentery, asthma,
heart diseases and also as an anti-spasmodic; the leaves are used
as an antiseptic against inflammation (Kakrani and Saluja, 2002;
Rajan et al., 2002, 2003; Kufer et al., 2005; Kumar et al., 2006;
Gupta et al., 2011; Nagarajan et al., 2011; Kaur et al., 2012). In
Pakistan, the leaves of Cissampelos pareira are used to treat
diarrhoea, and topically to treat abscesses and wounds (Abbasi
et al., 2010; Haq et al., 2011). The roots and leaves of this plant are
also used for snakebite, stomachache, diabetes and malaria in
various countries including India, Mexico and Kenya (Shinwari and
Khan, 1998; Galicia et al., 2002; Chhetri et al., 2005; Bora et al.,
2007; Pattanaik et al., 2008; Rukunga et al., 2009). The tubers
of Cissampelos pareira are used in pseudo-pregnancy in Malawi
(Maliwichi-Nyirenda and Maliwichi, 2010).
Cissampelos glaberrima and Cissampelos ovalifolia are used for
coughs, delirium, fever-cerrado habitants, madness, stimulant,
convulsions, epilepsy, sedative, analgesic, febrifuge, anti-oxidant,
analgesic, as a tonic and narcotic (Giorgetti et al., 2011). The leaves
of Cissampelos torulosa were used in diarrhoea, dysentery and sore
throat complaints (Samie et al., 2005, 2009), whereas Cissampelos
hirta Klotzsch. was used as an antidiarrhoeal in South Africa (De
Wet et al., 2010). The leaves of Cissampelos tropaeolifolia DC. were
used by the Q'eqchi to treat women's health complaints and to
release the placenta (Michel et al., 2007).
Cissampelos sympodialis is used in Brazil to treat several
inflammatory disorders, bronchitis, asthma, rheumatism and gastrointestinal, urinary tract and skin infections (Machado et al.,
2003; Moreira et al., 2003b; Correa et al., 2008; Costa et al., 2008;
Porto et al., 2008; Feily and Namazi, 2009; Bezerra-Santos et al.,
2012; Vieira et al., 2013). In South Africa, the root infusion of
Cissampelos capensis is taken to treat heart and blood pressure
problems (Olorunnisola et al., 2011) and the leaves are used to
treat diabetes (Deutschlander et al., 2009; Afolayan and Sunmonu,
2010). The roots extract of Cissampelos capensis is used in obesity
(Afolayan and Mbaebie, 2010), whilst the roots and rhizomes are
used as emetic, purgative, tincture and also for dysentery, syphilis,
snakebite, stomach and skin cancer (Van Wyk and Gericke, 2000;
Van Wyk, 2008). In addition, it is used as a digestive and for
endocrine, genitourinary and infection problems (De Wet and Van
Wyk, 2008).
The roots of Cissampelos mucronata were taken in Ethiopia for
stomach ache, gastrointestinal complaints and to expel retained
placenta (Giday et al., 2009; Tripathi et al., 2013), and the plant is
used in liver diseases such as hepatitis (Mukazayire et al., 2011).
The leaves and roots are used for gastrointestinal complaints,
D.K. Semwal et al. / Journal of Ethnopharmacology 155 (2014) 1011–1028
menstrual problems, venereal diseases, malaria and wounds in
Nigeria, Tanzania and Senegal (Tor-anyiin et al., 2003; Benoit-Vical,
2005; Nondo et al., 2011). The leaves and roots were used in
Uganda for inducing labour and expelling the placenta (Mugisha
and Origa, 2007), and as a tocolytic (uterine relaxant) agent
(Nwafor et al., 2002).
Cissampelos owariensis P. Beauvais ex D.C. is used in Nigeria for
the management of various forms of female infertility problems
(Elujoba, 1995). The decoction of Cissampelos owariensis (together
with Heteranthera callifolia Rchb. Ex Kunth) is used against
dementia-type loss of memory, whilst the plant is used for
circulatory gynaecological problems, asthenia, diarrhoea, wounds
and snakebite in various African countries. In association with
Rauwolfia vomitoria Afzel., the plant is used for psychosis. In Benin,
this species is used for cognitive disorders and in Tanzania, it is
used for amnesia and psychosis (Hage et al., 2010).
Apart from the medicinal uses, these plants are reported for
various other properties such as Cissampelos pareira is used for
augmenting milk production in dairy cows in many parts of India
(Behera et al., 2013) and is also introduced for its ornamental value
in various countries (Oyen, 2008a). The leaves of Cissampelos
pareira are commonly used in food systems for various purposes
including thickeners, gelling agents, texture modifiers and stabilisers in Asia (Vardhanabhuti and Ikeda, 2006).
5. Phytochemical studies
Although, the genus Cissampelos comprises about 21 species,
only a few have been phytochemically explored. A comprehensive
literature survey revealed that alkaloids are the major constituents
reported from the genus together with moderate levels of nonalkaloids. The chemical structures of the reported alkaloid and nonalkaloid constituents of the genus are depicted in Figs. 2 and 3,
respectively.
5.1. Alkaloid constituents
In 1840, Wiggers (1840) reported an amorphous bisbenzylisoquinoline alkaloid, pelosine (1) from the roots of a South American
Cissampelos pareira species which was later found to be identical
to that of l-curine (2) (Scholtz, 1896). During the 1950s, three
bisbenzylisoquinoline alkaloids, hayatine or l-curine (2), hayatinine (3) and hayatidine (4), also known as (-)-4″-O-methylbebeerine or (-)-O-methylcurine, were reported from the Indian species
(Bhattacharji et al., 1952; 1956) and their chemical structure and
stereochemistry were described in the 1960s (Bhattacharji et al.,
1962; Bhatnagar et al., 1967; Bhatnagar and Popli, 1967). Haynes
et al. (1966) also isolated (þ þ)-4″-O-methylcurine (4) which was
found stereochemically different to that previously reported. The
roots and vines yielded d-isochondodendrine (5) and hayatine or
l-curine (2) whereas a cytotoxic bisbenzylisoquinoline alkaloid,
cissampareine (6) was also isolated from the plant. The stereochemistry of cissampareine (6) was confirmed by its methylation
with diazomethane, which yielded O-methylcissampareine and by
reduction with sodium borohydride, which afforded dihydrocissampareine (Kupchan et al., 1960, 1965, 1966). Boissier et al.
(1965) reported two bisbenzylisoquinaline alkaloids, hayatine (2)
also known as ( 7)-bebeerine or (7)-curine and ( þ)-isochondodendrine (5), whereas Anwer et al. (1968) isolated cyclanoline or
cissamine (7) as chloride from the roots of Cissampelos pareira.
Dwuma-Badu et al. (1975) reported isochondodendrine (5), dicentrine (8), dehydrodicentrine (9), cycleanine (10) and insularine (11)
from the roots. Bhakuni et al. (1987) reported the biosynthetic
pathway for bisbenzylisoquinaline alkaloids, (R,R)-bebeerine (2),
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hayatidine (4), (R,R)-isochondodendrine (5) and (R,R)-cycleanine
(10), along with sepeerine (12) isolated from Cissampelos pareira.
The study revealed that hayatidine (4) is biosynthesised stereospecifically by intermolecular oxidative coupling of (R)- and
(S)-N-methylcoclaurine, whilst (R,R)-bebeerine (2), (R,R)-isochondodendrine (5) and (R,R)-cycleanine (10) are formed by oxidative
dimerisation of (R)-N-methylcoclaurine. The study also confirmed
the absolute configuration as ‘S' and ‘R' at the asymmetric centres
C-1 and C-10 , respectively in hayatidine (4). Ahmad et al. (1992)
reported five alkaloids, laudanosine (13), nuciferine (14), bulbocarpine (15), corytuberine (16) and magniflorine (17) (as hydrochloride) from the leaves and stems. Morita and coworkers (Morita
et al., 1993a, 1993b) reported two tropoloisoquinoline alkaloids,
pareirubrines A (18) and B (19) as antileukemic substances
together with grandirubrine (20) and isoimerubrine (21) having
similar skeletons from Cissampelos pareira. The conformation of
tropolone ring in their structures was elucidated by NMR studies,
whereas their solid-state tautomeric forms were examined by XRD
analysis. In addition an azafluoranthene alkaloid, norimeluteine
(22), as a cytotoxic substance together with norruffscine (23) was
also reported from this source (Morita et al., 1993c) and a cytotoxic
condensed tropone-isoquinoline alkaloid, pareitropone (24), was
isolated from the roots (Morita et al., 1995). The plant roots
contain berberine (25), reserpine (26) and cissampeline (1) which
was found to be structurally similar to that of pelosine (Sharma
et al., 2004; Stepp, 2004; Bafna and Mishra, 2010). Hullatti and
Sharada (2010) isolated a principle marker compound l-bebeerine
(2) in pure form to establish quality control parameters of
Cissampelos pareira roots, since the concentration of bebeerine
(2) has been suggested as a main criterion for the authentication of
Cissampelos pareira (Singh et al., 2012).
From the aerial parts of Cissampelos fasciculata Benth., a tropical
American species and well-known repellant for leaf cutter ants,
Acromyrmex octospinosus (Reich), a bisbenzylisoquinoline cissampentin (27) was isolated as an oil together with an aporphine
alkaloid corydine (28). The authors could not explain the stereochemistry of cissampentin (27) at C-1 and C-10 , however, it was
found to be a racemic mixture (Galinis et al., 1993).
A tertiary aporphine alkaloid cissaglaberrimine (29), established as 1,2-methylenedioxy-3-hydroxyaporphine, was isolated
from the stems and leaves of Cissampelos glaberrima A. St.-Hil.
together with magnoflorine (30) and oxobuxifoline (31). The
structure of magnoflorine (30) may have been confused with that
of N,N-dimethyllindcarpine (30a) due to their closely related
chemical structures (Barbosa-Filho et al., 1997a). A stephaoxocane
(isoquinoline alkaloid bearing an oxocane ring) eletefine (32)
was isolated from Cissampelos glaberrima roots. It appeared as a
mixture of isomers with or without intramolecular H-bonding
from O–H to the oxygen of the oxocane ether bridge. The hydroxy
group at C-12 of eletefine (32) was oxidised with pyridinum
dichromate to produce oxoeletefine (32a) which does not convert
to a mixture. The study revealed that the property of always
reverting to the equilibrium state mixture could be related to the
hydroxy group at C-12 (Da-Cunha et al., 1998). In addition, the roots
of the plant also afforded a quaternary aporphine alkaloid, (þ)-trilobinine (33) along with (þ )-cissaglaberrimine (29) (Cornelio
et al., 1999).
The rhizomes of Cissampelos ovalifolia D.C. yielded three tertiary
bisbenzylisoquinoline bases possessing a p-xylyl moiety, named
warifteine (34), methylwarifteine (35) and dimethylwarifteine (36),
together with the corresponding dihydro compounds. Dimethylwarifteine (36) was found to be identical to a known alkaloid,
O-methylcissampareine whereas methylwarifteine (35) was found
to be isomeric with cissampareine (6) since both gave dimethylwarifteine (36) on permethylation (Gorinsky et al., 1972; Mukherjee
and Keifer, 2003). Aguirre-Galvis (1995) phytochemically studied
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Cissampelos ovalifolia and Cissampelos pareira species from India,
Colombia and Guyana and reported various bisbenzylisoquinoline
alkaloids including warifteine (34) and methylwarifteine (35).
Moreover, a benzylisoquinoline alkaloid, (S)-6-methoxyjuziphine
(37) was also reported from the South American antimalarial
plant Cissampelos ovalifolia (Steele, 2000; Steele et al., 2002).
A bisbenzylisoquinoline alkaloid, l-isochondodendrine (5) was
reported from Cissampelos mucronata A. Rich. (Ferreira et al., 1965).
Fig. 2. Chemical structures of alkaloid constituents isolated from the genus Cissampelos.
D.K. Semwal et al. / Journal of Ethnopharmacology 155 (2014) 1011–1028
Fig. 2. (continued)
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D.K. Semwal et al. / Journal of Ethnopharmacology 155 (2014) 1011–1028
Fig. 3. Chemical structures of non-alkaloid constituents isolated from the genus Cissampelos.
De Wet (2006) attempted a study based on the chemotaxonomical distribution of alkaloids from Cissampelos mucronata and
found that the leaves contained dicentrine (8), salutaridine
(38), reticuline (39) and pronuciferine (40), whereas the rhizomes contained dicentrine (8) and cycleanine (10) as major
alkaloids.
Two bisbenzylisoquinoline alkaloids, warifteine (34), methylwarifteine (35) and an aporphine alkaloid, laurifoline (41) were
reported from the leaves and roots of Cissampelos sympodialis
Eichl. (Cortes et al., 1995; Barbosa-Filho et al., 1997b; Aragao et al.,
2001). The leaves of Cissampelos sympodialis yielded a 8,14dihydromorphinandienone alkaloid, milonine (42); its structure
was established as (þ)-(9β,13β,14α)-5,6-didehydro-4-hydroxy-3,
6-dimethoxy-17-methylmorphinan-7-one which was found to be
an isomer of (-)-8,14-dihydrosalutaridine by its absolute configuration (De Freitas et al., 1995). A bisbenzylisoquinoline alkaloid,
roraimine (43) and an oxoaporphine alkaloid, liriodenine (44)
were isolated from the roots of Cissampelos sympodialis. The
NMR data of roraimine (43) were found to be analogous to that
of warifteine (34) with the exception of chemical shifts of the
carbonyl and adjacent carbons and protons (De Lira et al., 2002).
Marinho et al. (2012) developed an analytical method for the
simultaneous quantitation of the bioactive markers including
warifteine (34), methylwarifteine (35) and milonine (42) from
Cissampelos sympodialis leaves and applied the method to a
phenological study of their relative concentrations.
From the aerial parts of Cissampelos capensis, two anthelmintic
aporphine alkaloids, (S)-dicentrine (8) and (S)-neolitsine (45) were
isolated (Ayers et al., 2007). Furthermore, two aporphine alkaloids,
bulbocapnine (15), dicentrine (8) and a morphinane alkaloid
salutaridine (38) with four minor alkaloids, glaziovine (46), lauroscholtzine (47), crotsparine (48) and cycleanine (10) were isolated from the leaves of Cissampelos capensis, and from the stems,
bulbocapnine (15), three bisbenzyltetrahydroisoquinoline alkaloids
cycleanine (10), insularine (11), cissacapine (49), together with 12-Omethylcurine (4), dicentrine (8), reticuline (39) and insulanoline (50)
were isolated. The rhizome of the plant furnished 12-O-methylcurine
(4), cycleanine (10) and cissacapine (49) as the major alkaloids,
whereas insularine (11), bulbocapnine (15), pronuciferine (40) and
glaziovine (46) were obtained as minor alkaloids. The study suggested
that the plant part, the developmental stage, the time of harvesting
and the geographical distribution must be taken into account for
chemotaxonomic purposes due to the chemical variations in different
parts (De Wet et al., 2011).
5.2. Non-alkaloid constituents
Apart from alkaloids as the major constituents of Cissampelos
species, some non-alkaloidal constituents were reported. The
roots of Cissampelos pareira contain d-quercitol (51), sterols, fixed
oil and essential oil, which contains thymol (52) as a major
constituent (Srivastava, 1956; Chowdury, 1972; Dwuma-Badu et
al., 1975). The roots of Cissampelos glaberrima yielded four
alkamides (small bioactive lipid signals), deca-2E,4E-dienoic acid
isobutylamide (53), octa-2E,4E-dienoic acid isobutylamide (54),
decen-2-oic acid isobutylamide (55) and decanoic acid isobutylamide (56), the last two being isolated as traces and identified
using mass spectrometry (Rosario et al., 1996). Ramirez et al.
(2003) reported a chalcone-flavone dimer, cissampeloflavone
(57) elucidated as 2-(4-hydroxy-3-methoxyphenyl)-7-(4-methoxyphenyl)-6-(2-hydroxy-4,6-dimethoxybenzoyl) furano[3,2-g]
benzopyran-4-one from the aerial parts of Cissampelos pareira.
Singthong et al. (2005) extracted a pectin from Cissampelos
pareira leaves which was a low methoxyl pectin consisting
mainly of uronic (galacturonic) acid (58) ( 70–75%) and a small
amount of neutral sugars. This pectin when studied for its
rheological properties showed shear thinning flow behaviour. In
addition, a well known flavonoid, 2-(3,4-dihydroxyphenyl)-3,5,
D.K. Semwal et al. / Journal of Ethnopharmacology 155 (2014) 1011–1028
7-trihydroxy-4H-chromen-4-one (quercetin) (59) (Amresh
et al., 2007a) and a saturated fatty acid, arachidic or eicosanoic
acid (60) were also reported from Cissampelos pareira
(Ramasubramaniaraja and Babu, 2010). The leaves of Cissampelos
pareira have been reported to produce polysaccharides (hydrocolloids) (Vardhanabhuti and Ikeda, 2006), and pectins [(1-4)α-D-galacturonan] mainly composed of galacturonic acid with
trace amounts of neutral sugars (Singthong et al., 2004).
6. Pharmacological activities
6.1. Analgesic and antipyretic activity
The hydroalcoholic leaf extract (HLE) of Cissampelos sympodialis
showed significant (po0.05) activity against acetic acid and formalin
models of analgesia in mice. The extract reduced the number of
abdominal contortions in the acetic acid test, whereas it inhibited the
second phase in the formalin test at a dose of 200 mg/kg i.p. (Mendes
de Oliveira et al., 2011). The hydroalcoholic root extract (HRE) from
Cissampelos pareira showed resistance against mechanical pain in
analgesymeter-induced pain in mice. The HRE lowered the writhing
episodes in acetic acid-induced writhing (0.6%; i.p.) by protection of
22.73% and 51.63% at doses of 200 and 400 mg/kg, body weight,
respectively. The HRE also exhibited protective effects against complete Freund's adjuvant-induced arthritis by 40.54% and 71.52% at
similar doses (Amresh et al., 2007f; Arya et al., 2011). The extract
from Cissampelos pareira and its polyherbal formulation (PHF) in
combination with Pongamia pinnata (L.) Pierre and Vitex negundo var.
negundo, showed remarkable analgesic effects against acetic acidinduced writhing in mice by 21.44 and 24.22 s at doses of 400 and
600 mg/kg, respectively, whereas aspirin, used as a positive control,
exhibited an effect by 27.64 s at 300 mg/kg (Bansod et al., 2010,
2011). The aqueous extract of the PHF of Cissampelos pareira with
Hemidesmus indicus (L.) R. Br. ex Schult., Rubia cordifolia L., Terminalia
chebula (Gaertn.) Retz., Emblica officinalis Gaertn., Terminalia bellirica
(Gaertn.) Roxb., Vitis vinifera L., Grewia asiatica L., Salvadora persica L.,
and Saccharum officinarum L., showed potent antipyretic and analgesic activity at a dose of 60 mg/kg/day and a lesser ulcer effect even at
a very high dosage compared to that of aspirin (60 mg/kg/day) in
human patients. The study was conducted on outpatients of the
Institute of Post Graduate Ayurvedic Education and Research Hospital, Kolkata, India, and the study suggested that the PHF reduces body
temperature and the level of PGE2 (Gupta et al., 2008a, 2008b).
6.2. Anti-inflammatory activity
An aqueous fraction of the ethanolic leaf extract (ELE) of
Cissampelos sympodialis Eichl., showed anti-inflammatory activity
in mice and inhibited both 12-O-tetradecanoylphorbol 13-acetate
and capsaicin-induced ear oedema by 58% and 37% respectively,
at a dose of 100 mg/kg, i.p. The effective dose to inhibit
carrageenan-induced rat paw oedema was 50 mg/kg (24%). The
subcutaneous administration of 100 and 200 mg/kg in rats inhibited the carrageenan-induced neutrophil migration measurement
after the administration of the irritant by 53% and 50% respectively
(Batista-Lima et al., 2001). The extract from Cissampelos pareira
and its PHF with Pongamia pinnata (L.) Pierre and Vitex negundo L.,
showed in vivo anti-inflammatory activity at doses of 400 and
600 mg/kg on carrageenan-induced hind paw oedema by 0.30 and
0.16 ml, respectively, whereas on formaldehyde-induced paw
oedema, the activity was recorded at 0.15 and 0.07 ml, respectively
when compared to aspirin (0.02 and 0.13 ml). The PHF (200, 400
and 600 mg/kg) showed anti-arthritic activity against Freund's
complete adjuvant-induced arthritis in rats and reduced hind paw
swelling and bodyweight along with a significant improvement in
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haematological parameters, whilst histopathology revealed a significant reduction in mononuclear infiltration, pannus formation
and bone erosion (Bansod et al., 2010, 2011). The ethanolic extract of
the aerial parts of Cissampelos pareira exhibited anti-inflammatory
(paw oedema induced by carrageenan and arachidonic acid) and
analgesic activity (abdominal writhes and hot plate) in rats and mice
respectively, at a dose of 100 mg/kg, p.o. (Amresh et al., 2007b). The
ethanolic root extract (ERE) of Cissampelos pareira showed antiinflammatory activity on acute, subacute and chronic rat models at
doses of 200 and 400 mg/kg, p.o. The total protection produced for
acute inflammation was 59.55% and 64.04% for carrageenan; 15.38%
and 30.77% for histamine; 17.78% and 31.11% for 5-hydroxytryptamine, and 19.23% and 30.77% for PGE2-induced hind paw oedema,
respectively. Similarly, in subacute inflammation, the protection was
38.36% and 47.95% for formaldehyde-induced hind paw oedema,
whereas in chronic inflammation it was 15.02% and 19.19% in the
cotton-pellet granuloma test (Amresh et al., 2007g).
6.3. Anti-allergic activity
The extract from Cissampelos sympodialis (40 mg/kg, p.o.) and
its alkaloid, warifteine (34) (50 μg/animal) showed anti-allergic
activity on allergic eosinophilia in which two allergic inflammation models, asthma and allergic pleurisy, in actively sensitised
Balb/c mice were used. The extract reduced pleural eosinophil
influx triggered by allergen challenge and also affected the
eosinophil activation by inhibiting new cytoplasmic lipid bodies
formation and cysteinyl leukotriene secretion (Bezerra-Santos et al.,
2006; Piuvezam et al., 2012). The extract and/or warifteine (34)
from Cissampelos sympodialis inhibited allergen-induced airway
hyperreactivity to inhale methacholine and IL-13 levels in the
bronchoalveolar lavage on allergen-triggered lung remodelling in
the murine model of asthma. Both the extract and warifteine
decreased ovalbumin (OVA)-induced eosinophil tissue infiltration,
mucous production and subepithelial fibrosis (Bezerra-Santos et al.,
2012). The HLE (containing warifteine, methylwarifteine and milonine) from Cissampelos sympodialis showed promising activity in
different animal models of asthma (Marinho et al., 2012), whereas
warifteine and methylwarifteine produce a reversible, nonspecific
and noncompetitive antagonism of histamine anti-allergic therapy
(Gomes et al., 2012). Warifteine (34) isolated from Cissampelos
sympodialis was studied to evaluate IgE production, leucocyte
activation, thermal hyperalgesia, mast cell degranulation and
scratching behaviour in a murine model of immediate allergic
reaction. BALB/c mice treated with warifteine (0.4–10 mg/kg) one
hour before OVA-sensitisation reduced OVA-induced paw oedema
as well as the OVA-specific IgE serum titres. It also reduced death
evoked by the IgE-dependent anaphylactic shock reaction at 30 min
after intravenous OVA challenge. Thermal hyperalgesia evoked by
IgE or an histamine/5-hydroxytryptamine challenge was inhibited
in rats at a dose of 4.0 mg/kg. Warifteine (0.6 or 6.0 μg/mL) also
decreased the IgEαDNP-BSA sensitised mast cell degranulation after
DNP-BSA challenge measured by histamine release (Costa et al.,
2008). Blomia tropicalis extract-induced allergy in mice was treated
orally with an extract (400 mg/kg) containing a total alkaloid
fraction of 8 mg/kg as well as 4 mg/kg of warifteine. All samples
reduced the number of total cells and eosinophils in bronchoalveolar fluid (BAF) and eosinophil peroxidase (EPO) levels in the BAF.
The samples also decreased the density of inflammatory cells in the
lung (Cerqueira-Lima et al., 2010). ELE from Cissampelos sympodialis
reduced food intake and bodyweight and also produced numerous
alterations in the open-field test in female rats at doses of 45 and
225 mg/kg, p.o. ELE modified smooth muscle tone, leucocyte effects
and cytokine secretion, which are the main parameters in asthma
pathology (Almeida et al., 2005). The alcoholic leaf extract of
Cissampelos sympodialis reduced eosinophil infiltration into the lung
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of OVA-sensitised mice. The inhaled extract inhibited eosinophil
recruitment to the pleural cavity, bronchoalveolar lavage and
peripheral blood. This treatment reduced the OVA-specific IgE
serum titre and leucocyte infiltration in the peribronchiolar and
pulmonary perivascular areas as well as mucous production. Flow
cytometric analysis showed that the isolated alkaloid, methylwarifteine as well as the extract reduced the number of CD3 þT cells
and eosinophil-like cells (Vieira et al., 2013). The aqueous fraction
(10–300 μg/mL) of the ELE of Cissampelos sympodialis inhibited
N-formyl-Met-Leu-Phe-induced release of lysozyme and myeloperoxidase from human neutrophils. Inhibition by the fraction, as well
as by dibutyryl-cAMP and PGE2, was substantially greater when the
cells were pre-treated with the phosphodiesterase inhibitor isobutyl methyl xanthine, indicating that the effect may be mediated
by cAMP. Cyclic AMP dependent protein kinase-A activity was also
increased by the fraction (1.5–100 μg/mL) (Thomas et al., 1999). The
ERE from Cissampelos sympodialis reduced spontaneous tone and
inhibited the contractions induced by submaximal concentrations
of carbachol, histamine, PGF2α and substance P, in guinea-pig
tracheal preparations with the IC50 value range being 13.9–
95.5 μg/mL. The extract improved the intracellular levels of cyclic
AMP in guinea-pig bronchoalveolar leucocytes with IC50 range
1–100 μg/mL (Thomas et al., 1995).
6.4. Bronchodilator activity
The HLE of Cissampelos sympodialis showed bronchodilator
activity in a guinea pig model by inhibiting the spontaneous tone
of the trachea with an IC50 value of 13.9 μg/mL. It was potentiated
by 3-isobutyl-l-methylxanthine and blocked by timolol (β2-adrenoceptor blocking agent) with an IC50 4.6 μg/mL. However, no
effect was noted on removal of the epithelium or addition of
methylene blue. The extract also antagonised contractions induced
by carbachol, capsaicin and arachidonic acid in normal trachea and
by OVA in trachea obtained from sensitised guinea pigs with IC50
ranges of 34.1–70.5 μg/mL. In addition, the extract increased the
preconvulsive time of animals exposed to an aerosol of histamine
to 63.5 s at a dose of 100 mg/kg, i.p. (Thomas et al., 1997b).
6.5. Immunomodulatory activity
The leaf extract of Cissampelos sympodialis exhibited an immunomodulatory effect on the murine model of OVA-induced allergy
in BALB/c mice with doses ranging from 200 to 600 mg/kg, p.o.
The extract at 400 or 600 mg/kg also reduced paw oedema
induced by local OVA challenge. It increased the in vitro production
of IFN-γ and IL-10 by Con-A stimulated cells (Bezerra-Santos et al.,
2004). The hydroalcoholic extract of Cissampelos sympodialis leaves
exhibited an immunomodulatory effect on B-lymphocyte function
(Moreira et al., 2003b). The methanolic root extract (MRE) of
Cissampelos pareira was studied for its immunomodulatory activity
in mice and stimulatory activity on DTH response was found at
200–800 mg/kg dose. Higher doses of extract also offered protection
against cyclophosphamide-induced myelosuppression by increasing total WBC count significantly (Bafna and Mishra, 2005). The
berberine-containing alkaloidal fraction from Cissampelos pareira
roots exhibited an immunosuppressive effect at doses of 25 and
50 mg/kg, p.o. and significantly lowered the humoral antibody titre.
The fraction did not show any activity at higher doses, i.e. 75 and
100 mg/kg, p.o. (Bafna and Mishra, 2010). The extract of Cissampelos
sympodialis used as an immunomodulator altered the activity of
immune function through the dynamic regulation of informational
molecules such as cytokines. The extract demonstrated modulation
of IL-1, IL-6, TNF and IFN cytokines when tested in vitro as well as
in vivo (Spelman et al., 2006).
6.6. Memory-enhancing activity
The hydroalcoholic extract (400 mg/kg) of Cissampelos pareira
considerably improved learning and memory of mice and significantly reversed amnesia induced by scopolamine (0.4 mg/kg, p.o.).
The extract also decreased whole brain acetylcholinesterase activity when compared to piracetam (200 mg/kg) (Kulkarni et al.,
2011).
6.7. Antidepressant activity
The total tertiary alkaloid fraction (containing warifteine) from
Cissampelos sympodialis reduced the total immobility time on two
mouse models of depression (forced swim test and reserpine test),
and reversed the reserpine-induced hypothermia, demonstrating
an antidepressant effect in both models at a dose of 12.5 mg/kg
(Mendonca-Netto et al., 2008). The hydroalcoholic leaf extract of
Cissampelos sympodialis (containing warifteine) exhibited antidepressant effects together with anti-oxidant activity at dose ranges
of 62.5–500 and 10–160 mg/kg, i.p. in the forced swimming test in
mice (Zhang, 2004). The ELE of Cissampelos sympodialis was found
to potentiate the toxicity of pentylenetetrazol in mice. Similar to
imipramine, the extract also reduced the immobility period in the
forced swimming test in mice and reversed the degree of ptosis
and catalepsy induced by reserpine in rats (Almeida et al., 1998).
The ERE of Cissampelos mucronata showed sedative activity,
in mice, at up to 282.84 mg/kg (LD50). The extract progressively
reduced ephedrine-induced spontaneous motor activity in rats
and prolonged pentobarbitone-sleeping time in mice (Akah et al.,
2002).
6.8. Neuroprotective activity
Hexane, dichloromethane, ethylacetate and water extracts from
aerial parts of Cissampelos owarensis exhibited activity on
β-amyloid peptide production which is important in Alzheimer's
disease treatment. The extracts were tested at non-toxic concentrations on Chinese hamster ovary (CHO) cells overexpressing the
human neuronal β-amyloid peptide precursor to measure variations of APP processing. Cytotoxicity on CHO cells was recorded at
IC50 values of 122.4, 20.5, 4200 and 4 200 mg/mL with chosen
concentrations of 25, 6.25, 100 and 200 mg/mL for hexane, dichloromethane, ethylacetate and water extracts respectively (Hage
et al., 2010). A combined extract of Cissampelos pareira and
Anethum graveolens (1:5) exhibited protective action against
age-related cognitive impairment in rats at doses of 2, 10, and
50 mg/kg. The research showed that this extract can be served as a
food supplement for protection against mild cognitive impairment
and the early phase of Alzheimer's disease (Thukham-mee and
Wattanathorn, 2012). The methanolic extract from aerial parts
of Cissampelos owarensis showed activity of 19.59% against
acetylcholinesterase and 78.96% against butyrylcholinesterase
with a test concentration of 42.5 μg/mL and physostigmine as
the positive control (Elufioye et al., 2010).
6.9. Antimicrobial activity
The methanolic extract from aerial parts of Cissampelos
owarensis showed antimicrobial activity against Staphylococcus
aureus, Staphylococcus pyogenes, Salmonella typhi, Escherichia coli,
Shigella dysenteriae, Proteus vulgaris and Candida albicans with
inhibition zone diameter (IZD), minimum inhibitory concentration
(MIC) and minimum bactericidal concentrations (MBC) ranging
from 18 to 27 mm, 6.25 to 50 mg/ml and 25 to 100 mg/ml,
respectively (Hage et al., 2010). The extract from the whole
D.K. Semwal et al. / Journal of Ethnopharmacology 155 (2014) 1011–1028
plant of Cissampelos pareira exhibited antifungal activity against
Aspergillus niger and Saccharomyces cerevisiae by complete inhibition at concentrations of 500 and 1000 mg/ml in comparison to the
positive controls ciprofloxacin and amphotericin B at a concentration of 3 mg/ml (Kumar et al., 2006). Dichloromethane and
ethanolic extracts from Cissampelos mucronata aerial parts exhibited activity against bacteria including Staphylococcus aureus,
Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Vibrio
cholera, Bacillus anthracis, Streptococcus faecalis as well as against
fungi such as Candida albicans and Cryptococcus neoformans.
Moreover, its root extract showed remarkable larvicidal activity
against Culex quinquefasciatus say (southern house mosquito)
larvae. The dichloromethane root extract was found to be toxic
with an LC50 of 59.6 μg/mL, whereas the ethanolic extract was
found to be non-toxic at an LC50 of 100 μg/mL (Nondo et al., 2011).
The total tertiary alkaloid fraction of Cissampelos capensis was
found active against Bacillus subtilis with IC50 of 0.3 μg/mL. The
alkaloids also inhibited bacteria (Pseudomonas aeruginosa, Proteus
vulgaris and Escherichia coli, Bacillus subtilis, Staphylococcus aureus
and Bacillus licheniformis) and fungi (Candida albicans, Candida
eropiralis and Aspergillus niger) with IZD values ranging from 33
to 45 mm (Babajide et al., 2010). The leaf extract from
Cissampelos torulosa was found to have weak antibacterial activity
against Bacillus cereus and Staphylococcus aureus with MIC values
of 412 mg/ml (Samie et al., 2005). The MLE of Cissampelos
torulosa showed antibacterial activity against clinical strains of
Campylobacter with MIC values ranging from 0.75 to 46 mg/mL
(Samie et al., 2009).
6.10. Antimalarial activity
The ethanolic extracts of Cissampelos andromorpha DC. and
Cissampelos ovalifolia showed in vitro antimalarial activity with IC50
values of 104.1 and 37.4 mg/mL against a chloroquine-resistant strain
and IC50 values of 166.6 and 34.8 mg/mL against a chloroquinesensitive strain of Plasmodium falciparum. Similarly, the total alkaloidal
extracts showed activity with IC50 values of 1.5 and 3.3 mg/mL against
the chloroquine-resistant strain, and an IC50 of 13.6 and 1.0 mg/mL
against the chloroquine-sensitive strain (Fischer et al., 2004). The MRE
from Cissampelos mucronata exhibited in vitro antiplasmodial activity
against chloroquine-sensitive (D6) and chloroquine-resistant (W2)
Plasmodium falciparum strains with IC50 values of 1.5 and 1.1 μg/mL,
respectively. It was found the MRE also inhibited the enzyme tyrosine
kinase p56lck (Tshibangu et al., 2002, 2003). The root extract of
Cissampelos mucronata produced a significant reduction of parasitaemia (59% suppression) for the 4-day suppressive test in Plasmodium
berghei-infected mice at a dose of 500 mg/kg, p.o. (Gessler et al., 1995),
whereas the ethanolic extract showed activity against Plasmodium
falciparum in vitro with IC50 values o10 μg/mL (Gessler et al., 1994;
Benoit-Vical et al., 2008). The ERE of Cissampelos pareira inhibited
the propagation of the rodent parasite Plasmodium berghei in vivo
on BALB/c mice (Jannu et al., 2011). The hydromethanolic extract of
Cissampelos pareira showed significant anti-plasmodial activity against
chloroquine-sensitive (NF54) and chloroquine-resistant (ENT30) Plasmodium falciparum strains in vitro using the 3-hypoxanthine assay
with an IC50 value of 5.85 μg/mL (Rukunga et al., 2009). An ethanolic
root extract of Cissampelos pareira showed a significant inhibition of
Plasmodium berghei with an oral dose of 500 mg/kg in mice. The mean
parasitaemia in treated mice was found to 11.64% in comparison to the
control, cloroquine (no parasitaemia) (Singh and Banyal, 2011).
6.11. Antiparasitic activity
The alkaloidal extract from the leaves of Cissampelos ovalifolia
produced an in vitro antiparasitic effect against Leishmania chagasi
and Trypanosoma cruzi parasites with an EC50 value of 63.88 μg/mL.
1021
The extract reduced the number of infected macrophages at 25 μg/mL
by 86.1% and 89.8%, respectively (Tempone et al., 2005). The aqueous
fraction of the ELE of Cissampelos sympodialis exhibited both immunosuppressive and anti-inflammatory effects by inhibiting cyclic
nucleotide phosphodiesterase activity and increased cAMP levels in
intact smooth cell cultures, pig bronchoalveolar leucocytes and murine
B cells. Normal and thioglycolate-elicited mice peritoneal macrophages
were infected in vitro with the protozoan Trypanosoma cruzi DM28c
clone. The ELE improved Trypanosoma cruzi growth and induced a 75%
decrease in nitric oxide production with doses ranging between 13
and 100 μg/mL (Moreira et al., 2003a; Feily and Namazi, 2009).
Cissampeloflavone (57) isolated from Cissampelos pareira showed
excellent activity against Trypanosoma cruzi and Trypanosoma brucei
rhodesiense (Ramirez et al., 2003). Warifteine (34) isolated from the
leaves and roots of Cissampelos sympodialis showed growth inhibitory
activity (anti-leishmanicidal effect) against Leishmania chagasi
promastigotes in axenic cultures and the occurrence of drug-induced
ultrastructural changes in the parasite with an MIC value of
0.08 mg/mL (Da Silva et al., 2012). The methanolic extract from the
whole plant of Cissampelos torulosa showed in vitro antiamoebic
activity against Entamoeba histolytica with IC50 and IC90 values of
410 mg/mL (Samie et al., 2009).
6.12. Anti-ulcer activity
The ERE from Cissampelos mucronata, exhibited an anti-ulcer
effect on indomethacin-, histamine- and stress-induced ulcer models
in rats. The acute toxicity evaluation showed the LD50 value to be
288.53 mg/kg, p.o. The activity was found to be significant (po0.05)
against indomethacin- and histamine-induced ulcers. This research
revealed cytoprotective and antispasmodic mechanisms of action
responsible for the activity (Nwafor and Okoye, 2005). The MLE
of Cissampelos mucronata showed anti-ulcer activity at a dose of
450 mg/kg on isolated guinea pig ileum and inhibited contractions
evoked by acetylcholine, histamine and serotonin. It showed varying
degrees of protection against ulcers induced by indomethacin when
compared to that of the positive control cimetidine (100 mg/kg, i.p.)
and the LD50 value was calculated as 8.5 g/kg, p.o. (Akah and Nwafor,
1999; Nwafor and Akah, 2003). The ERE of Cissampelos pareira and its
constituent quercetin, showed protective effects against ulceration at
doses of 25–100 mg/kg p.o. in various acute and chronic ulcers
in rats. The extract demonstrated significant (Po0.05 to Po0.001)
protection against ethanol-, aspirin-, cold-restraint stress and pylorus
ligation-induced acute gastric ulcers. The extract also reduced the
ulcer index with decreased perforations in acetic acid-induced
chronic ulcers (Amresh et al., 2007e).
6.13. Anticancer activity
The HRE of Cissampelos pareira showed activity against forestomach cancer and carcinogen metabolising phase I and phase II
enzymes along with anti-oxidant enzymes. The extract reduced
the tumour incidence, the mean number of tumours and the
tumour multiplicity on benzo(a)pyrene-induced gastric cancer in
mice. The enhanced glutathione S-transferase level and enzyme
activities involved in xenobiotic metabolism and maintaining antioxidant status of cells was due to a chemopreventive efficacy of
the extract against chemotoxicity (Amresh et al., 2007c). The
ethanolic extract (containing quercetin) of Cissampelos pareira
showed protective effects on benzo(a)pyrene induced gastric
cancer, tumour multiplicity and micronucleus polychromatic erythrocytes in mice (Amresh et al., 2007a). The crude alkaloid
extracts from the leaves and rhizomes of Cissampelos capensis,
Cissampelos hirta, Cissampelos mucronata and Cissampelos torulosa,
showed cytotoxicity against MCF7 (breast), UACC62 (melanoma)
and TK10 (renal) cancer cell lines. Leaves and rhizomes of
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Cissampelos capensis showed activity with GI50 values of 16, 19 and
16 μg/mL with a TGI value of 37.5 μg/mL each; the rhizomes of
Cissampelos hirta showed activity with GI50 values of 6.25, 12.5 and
12.5 μg/mL and TGI of 25, 18 and 25 μg/mL; Cissampelos mucronata
showed activity with GI50 values of o6.25, 6.25 and 9 μg/mL with
TGI of 18, 15 and 24 μg/mL, whilst Cissampelos torulosa showed
activity with GI50 values of 12.5, 12.5 and 9 μg/mL and TGI of 37.5,
28 and 50 μg/mL against breast, melanoma and renal cancer cell
lines, respectively (De Wet et al., 2009).
The MLE of Cissampelos torulosa showed in vitro cytotoxic activity
against Vero cells with a median inhibitory concentration of
206.4 mg/mL (Samie et al., 2009). The ethanolic extract of Cissampelos
mucronata showed cytotoxic activity in human carcinoma cell lines
in vitro (Gessler et al., 1995). An azafluoranthene alkaloid, norimeluteine (Morita et al., 1993c), tropone-isoquinoline alkaloid, pareitropone (Morita et al., 1995), bisbenzylisoquinoline alkaloid and
cissampareine (Kupchan et al., 1965) isolated from Cissampelos
pareira, exhibited cytotoxic activity against P-388 cells, whereas
cissampeloflavone (57) had a low toxicity to the human KB cell line
(Ramirez et al., 2003). Warifteine (34) and milonine (42) isolated
from the leaves of Cissampelos sympodialis exhibited cytotoxic effects
in cultured hepatocytes and V79 fibroblasts in vitro. The IC50 values
determined in the three assays (nucleic acid content, tetrazolium
reduction and neutral red uptake) were about 100 and 400 μM after
milonine treatment whereas a dose ranging from 10 to 35 μM were
obtained for warifteine in the viability tests evaluated in V79 cells
and hepatocytes. Cimetidine (1.0 mM), a traditional cytochrome P450
inhibitor, did not protect the cells from the toxic action of warifteine
or milonine (Melo et al., 2003). The aqueous fraction of the ELE of
Cissampelos sympodialis decreased the lymphocyte proliferative
response of concanavalin-A-activated BALB/c spleen cells (proliferation and cytokine secretion) in the presence of the mitogen (5 μg/mL)
at concentration ranges of 6.25–50 μg/mL, in vitro. It reduced the
levels of secreted IFN-γ and increased the production of both IL-10
and IL-4. The increased IL-10 production down-regulates IFN-γ
secretion and T cell proliferative responses (Piuvezam et al., 1999).
Warifteine from Cissampelos sympodialis inhibited the proliferative
response and Ig secretion on B-lymphocytes by blocking B cell
function in vitro and in vivo. Warifteine also induced an increase in
cAMP and its effect on LPS-induced proliferation was mimicked by
the control adenyl cyclase activator, forskolin. In vivo Ig production
induced by the TI-2 antigen TNP-ficoll was also inhibited by
warifteine (Rocha et al., 2010). The hydroalcoholic extract of Cissampelos sympodialis leaves inhibited the in vitro proliferative response of
resting B cells induced by LPS, anti-delta-dextran and anti-IgM with
IC50 values of 17.2, 13.9 and 24.3 μg/mL, respectively. The extract
inhibited B cell function through an increase in intracellular cAMP
levels and inhibited Ig secretion (Moreira et al., 2003b).
6.14. Anti-oxidant activity
The ERE of Cissampelos pareira (containing polyphenols) showed
anti-oxidant activity in the 2, 2-diphenyl-1-picrylhydrazyl (DPPH)
assay at doses ranging between 50 and 400 μg/kg in vitro. The
extract showed potent protective effects in an acute oxidative tissue
injury on benzo(a)pyrene-induced gastric toxicity in mice at doses
of 50 and 100 mg/kg (Amresh et al., 2007d; Hussain et al., 2010).
The methanolic extract from aerial parts of Cissampelos owarensis
had 91% anti-oxidant activity at 125 μg/mL (Habila et al., 2011). The
alkaloidal fraction from Cissampelos pareira roots exhibited potent
anti-oxidant activity by scavenging the stable free radical DPPH,
superoxide ion and by inhibiting lipid peroxidation in rat liver
homogenate induced by iron/ADP/ascorbate complex. The fraction
scavenged the superoxide radical generated from the riboflavinNBT-light system in vitro with IC50 31.99 μg/mL when compared to
the positive control ascorbic acid which showed activity with IC50
value of 23.52 μg/mL (Bafna and Mishra, 2010).
6.15. Cardiovascular activity
The aqueous fraction of ELE from Cissampelos sympodialis exhibited
cardiovascular effects on conscious, free-moving rats. The extract
increased mean arterial pressure by 7, 16, 33, 43 and 38 mmHg at
doses of 0.5, 1, 2, 4 and 8 mg/kg, i.v. respectively and decreased heart
rate significantly. The hypertensive effect was exhibited at doses of
2 and 4 mg/kg after cardiac autonomic blockade by atenolol and
atropine at a dose of 2 mg/kg. The extract significantly increased blood
pressure in experimental rats and improved heart rate and contractility in isolated perfused atrial preparations (Medeiros et al., 1998).
The ERE from Cissampelos pareira exhibited cardioprotective activity
(po0.05) on isoproterenol-induced cardiac dysfunction in rats. The
ERE improved the heart weight/body weight ratio, serum calcineurin,
nitric oxide, lactate dehydrogenase and thiobarbituric acid reactive
substance levels (Singh et al., 2013). The hydroalcoholic extract of
Cissampelos sympodialis produced contractions (EC50 value of 76.6
μg/mL) in the presence of functional endothelium whereas in the
absence of functional endothelium, the concentration–response curves
were shifted to the left (EC50 values of 1.3 μg/mL) without modification
of its maximal contractile effect. In the presence of L-NAME (300 μM)
and indomethacin (10 mM), the concentration–response curves produced were shifted to the left (EC50 values of 21.8 and 24.3 μg/mL,
respectively). The contractions induced by the extract in the rat aorta
were due to activation of α-adrenoceptors (Freitas et al., 2000).
Warifteine from Cissampelos sympodialis caused vasorelaxation of the
rat thoracic aorta. Warifteine (1 pmol/L-10 μmol/L) induced relaxation
(pD2 ¼9.40) of both endothelium-intact aortic rings precontracted
with noradrenaline (10-100 μmol/L) and PGF2α (1-10 mmol/L)-precontracted rings (pD2 ¼9.2). In vascular myocytes, warifteine (100 nmol/L)
significantly increased whole-cell K þ currents (at 70 mV) (Assis et al.,
2013). The regulation of intracellular Ca2þ as a mechanism of
spasmolytic activity of warifteine (from leaves of Cissampelos
sympodialis) was studied in the rabbit aorta. Warifteine (pD'24.12)
antagonised the KCl-induced contractions in a noncompetitive and
reversible manner mediated by Ca2þ entry which was found similar
to verapamil (pD'26.89). Noradrenaline-induced sustained contractions were also inhibited by warifteine (IC50 6.03 10 5 M) as
compared to the standard, sodium nitroprusside (IC50 1.9 10 8 M)
(De Freitas et al., 1996). Warifteine (from Cissampelos sympodialis)
produced reversible, nonspecific, noncompetitive antagonism of histamine-, carbachol- and bradykinin-induced contractions of guineapig ileum with pD'2 values of 4.90, 4.95 and 5.03 respectively.
Oxytocin- and bradykinin-induced contractions of the rat uterus was
antagonised by pD'2 4.30 and 3.76, respectively and inhibited spontaneous tone and carbachol-induced sustained contractions in guinea
pig trachea with IC50 values of 1.1 10 5 M and 2.9 10 5 M,
respectively (Cortes et al., 1995).
6.16. Muscle-relaxant activity
The ELE from Cissampelos sympodialis relaxed the spontaneous
tone of guinea pig tracheal smooth muscle rings with an IC50 value
of 20.5 μg/mL, inhibited cyclic nucleotide phosphodiesterase activity in isolated smooth muscle homogenates and stimulated an
increase in intra-cellular cAMP synthesis in intact cultured smooth
muscle cells (Thomas et al., 1997a). The quaternary alkaloid fraction
(Kupchan et al., 1960) as well as hayatin methiodide (Pradhan and
De, 1953) and hayatinin methochloride (Sur and Pradhan, 1964;
Basu, 1970) from Cissampelos pareira, exhibited muscle-relaxant
properties and were recognised as curariform drugs. Two aporphinic alkaloids (þ )-cissaglaberrimine and (þ)-trilobinine isolated
from the root bark of Cissampelos glaberrima showed relaxant
D.K. Semwal et al. / Journal of Ethnopharmacology 155 (2014) 1011–1028
effects in guinea pig tracheal preparations. The alkaloids reduced
the spontaneous tone and inhibited the contractions induced by
carbachol and histamine. Trilobinine was 6 times more potent than
cissaglaberrimine in reducing the spontaneous tone and it was
1.5 times more potent in antagonising the effects of carbachol and
histamine. The inhibitory effect of cissaglaberrimine in contractions
induced by histamine was not attenuated in the presence of timolol
(10 μM) (Cornelio et al., 1999). The aqueous leaf extract from
Cissampelos mucronata showed uterine relaxant and antiabortifacient properties. The extract was found to have deleterious
effects on the blood vessels of the kidneys of wistar rats. The
photomicrographs of the kidneys of the rats which had received
1 ml extract for 2 weeks, showed ruptured blood vessels with
distorted cytoplasm and the basement membrane of the sections
treated with 0.6 ml extract had collapsed (Falana et al., 2011). The
ERE of Cissampelos mucronata displayed significant in vitro relaxant
activity on isolated gravid and non-gravid rat uterine smooth
muscles (Nwafor et al., 2002).
6.17. Hepatoprotective activity
The HRE of Cissampelos pareira showed significant hepatoprotective action against CCl4-induced hepatotoxicity in rats at doses
of 100, 200 and 400 mg/kg. The catalase levels for anti-oxidant
superoxide dismutase (SOD) enzymes were increased at doses of
200 and 400 mg/kg. At similar doses, it decreased cholesterol
levels and increased triglyceride levels when compared to silymarin (Surendran et al., 2011).
6.18. Antidiabetic activity
The HLE (200 and 400 mg/kg, p.o.) of Cissampelos pareira showed
antidiabetic activity on streptozotocin-induced diabetic rats and
significantly decreased fasting blood glucose and increased the body
weight of rats compared to glibenclamide (5 mg/kg) (Jannu et al.,
2011).
1023
exhibited activity on snake proteins from B. diporus (a venomous
pit viper) (Badilla et al., 2008; Camargo et al., 2011; Dey and De,
2012).
6.22. Miscellaneous activities
The hydroalcoholic extract of Cissampelos sympodialis leaves
was evaluated to determine the possible toxic effects on the
development of the offspring of pregnant female rats. The duration
of pregnancy, weight gain, litter size, body weight of the pups,
righting reflex, eye opening, hind paws supporting, body lifting
and external malformation occurrence were found normal, with
no signs of side effects after treatment (Maior et al., 2003).
Warifteine (34) hydrochloride isolated from Cissampelos
ovalifolia exhibited potent neuromuscular blocking and local
anaesthetic activities (Gorinsky et al., 1972). The methiodide of
hayatine isolated from Cissampelos pareira, was shown to possess
powerful neuromuscular blocking activity comparable to that of
d-tubocurarine chloride (Kupchan et al., 1965). The alcoholic and
aqueous extract of Cissampelos pareira showed anthelmintic activity against earthworms at doses of 5, 10, 25, 50 and 100 mg/mL;
both extracts were found to paralyse (vermifuge) as well as kill
the earthworms (vermicide) (Shukla et al., 2012). The aqueous
extract of Cissampelos mucronata was found to have significant
molluscicidal activity on 2-week old Lymnaea natalensis Krauss (snail)
with upper and lower fiducial limits of LC50 (Kela et al., 1989).
Two aporphines, (S)-dicentrine and (S)-neolitsine, from the
aerial parts of Cissampelos capensis showed activity on larval
motility, with EC90 values of 6.3 and 6.4 μg/mL, respectively. The
dicentrine reduced the worm counts in mice by 67% at 25 mg/kg,
p.o. (Ayers et al., 2007). The aqueous extract of Cissampelos
glaberrima affected the development of Plutella xylostella (diamondback moth) and caused 93.3% mortality of larvae and 66.7%
of pupae (Torres et al., 2001). The extract from Cissampelos pareira
was reported for its anticonvulsant activity in vivo/in vitro (Adesina,
1982; Quintans et al., 2008).
6.19. Antidiarrhoeal activity
7. Toxicity studies
The ERE of Cissampelos pareira exhibited antidiarrhoeal activity
with doses ranging between 25 and 100 mg/kg, p.o. and a decrease
in the total number of faecal droppings by 29–60% in castor oilinduced diarrhoea. The extract produced a significant (p o0.01)
reduction in intestinal fluid accumulation by 26–59% (Amresh
et al., 2004).
6.20. Antifertility activity
The leaf extract of Cissampelos pareira was studied to evaluate
its antifertility effect and the findings showed that it altered the
oestrous cycle pattern in female mice, prolonged the length of the
oestrous cycle with significant increase in the duration of dioestrus
stage, and reduced the number of litters of albino mice. The
analysis of the principal hormones involved in oestrous cycle
regulation showed that the extract altered gonadotropin release
(Luteinising hormone, Follicle stimulating hormone and prolactin)
and estradiol secretion with an LD50 of 7.3 g/kg, p.o. (Ganguly et al.,
2007).
The hydroalcoholic extract of Cissampelos pareira was evaluated
for acute and subacute toxicity and produced neither mortality,
nor changes in behaviour, or any other physiological effects in
animals at a dose of 2 g/kg, p.o. for a period of 28 days (Amresh
et al., 2008). The ethanolic extract of the aerial parts of Cissampelos
pareira was determined to be safe up to a dose of 2000 mg/kg
(LD50) (Amresh et al., 2007b). The ERE of Cissampelos mucronata
was found to be a sedative in mice at a dose of 288.53 mg/kg (Akah
et al., 2002), an acute lethality test showed an LD50 value of
282.84 mg/kg, p.o. (Nwafor and Okoye, 2005), and an LD50 value of
8.5 g/kg p.o was recorded for the MLE (Nwafor and Akah, 2003). In
female mice, the acute toxicity of the leaf extract of Cissampelos
pareira was found at an LD50 of 7.3 g/kg, p.o. (Ganguly et al., 2007).
The tuber juice of Cissampelos ovalifolia has been used as a
refreshment but due to its toxic effects, the use of this plant is
restricted in various cultures in Brazil (Rodrigues, 2007).
8. Future perspectives and conclusions
6.21. Antivenom activity
The aqueous leaf extract of Cissampelos pareira was studied
to neutralise the haemorrhagic and proteolytic activities of the
venom of Bothrops asper (a venomous pit viper) and produced
total inhibition by injecting a mixture of extract and venom into
the skin of mice. The aqueous, alcoholic and hexane extracts also
The genus Cissampelos has been and is still used to treat a
diverse range of ailments in folk medicine across many centuries,
countries and continents. This genus is a rich source of many
bioactive alkaloids including bisbenzylisoquinolines and aporphines (Bhakuni et al., 1987) and the aporphine alkaloids specifically are gaining popularity due to their promising anticancer,
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antiplatelet, vasodilator and antiprotozoal activities (Semwal and
Semwal, 2013). The chemistry and biological activity of some
species of the genus, including Cissampelos pareira, Cissampelos
sympodialis, Cissampelos capensis and Cissampelos glaberrima, are
well known. However, many other species including Cissampelos
andromorpha DC., Cissampelos friesiorum Diels and Cissampelos
nigrescens Diels have not been phytochemically or pharmacologically explored. Consequently, a broad field of future research is
awaiting the researcher to discover lead molecules or purified
fractions, which may have promising biological activity. In addition, many species are very well known in folk medicine, but no
scientific validation for its use has been reported. There is a need
for proper documentation of traditional knowledge to lead to the
selection of potent as well as authentic medicines to provide a
solid basis for further research (Heinrich, 2000).
The polyherbal formulation, rather than an individual species
extract or isolated compound, is one of the most interesting
concepts in the field of herbal medicines due to its potent and
remarkable synergistic biological activity. Some research groups
attempted the polyherbal formulation concept with Cissampelos
species and found promising antipyretic and analgesic activities
(Gupta et al., 2008a; Bansod et al., 2010). Based on their research,
it can be stated that the synergy of plant extracts showed more
potent action compared to that of individual compounds or
extracts as is frequently the case and there is a need for further
work in this field. Isolated compounds, including warifteine as
well as plant extracts from the genus, showed very good bioactivity (Gorinsky et al., 1972) but many of the mechanisms of action is
still not well defined. Therefore, a detailed study is needed to
clarify the structure–activity relationships or mechanism of action
to determine the standard dose and to minimise the side-effects.
Ideally, traditional knowledge should be translated into basic
scientific studies including biological activity to determine efficacy, toxicity studies to dermine safety, isolation of active compounds and biomarkers to enable quality control and elucidation
of the mechanism of action for combinations of plants, single
extracts and isolated compounds before eventually moving into
the clinical trial phase to validate traditional uses.
Acknowledgements
The work was financially supported by the National Research
Foundation and the Tshwane University of Technology, South
Africa.
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