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12(1): Medicinal and poisonous plants 1

Cyclea Arn. ex Wight

Ill. Ind. Bot. 1: 22 (1840).

MENISPERMACEAE

x = unknown

Major species Cyclea barbata Miers and Cyclea laxiflora Miers.

Cyclea includes about 30 species and occurs in India, Burma (Myanmar), Indo-China, southern China, Thailand and western and central Malesia (Peninsular Malaysia, Sumatra, Java, Borneo and the Philippines). In Malesia, 10 species have been found. Cyclea is occasionally planted, e.g. in Java.

A decoction of the roots is used in local medicine in Indonesia and Malaysia against fever and haemorrhoids, after childbirth and as a vermifuge for children. In Thailand, Cyclea barbata ('krung khamao') is a rather well-known medicinal plant; the bitter decoction of its roots is used against (malarial) fever, in the treatment of lower abdominal pains, eye diseases, jaundice and as a tonic. Cissampelos pareira L., which has similar attributed and qualities, is also called 'krung khamao'. In Java, fresh crushed leaves of Cyclea barbata are mixed with water, filtered and kept overnight to prepare a jelly called 'cincau' or 'cincau hijau' (green cincau), which is used as a refreshment and as a remedy against stomach complaints and fever as it has a cooling effect. In Thailand, a comparable preparation is used as appetizer and in the treatment of lower abdominal pains associated with malaria. The stem and roots of Cyclea are used in local medicine in southern China and Indo-China as diuretic, depurative, febrifuge and antidysenteric, and to treat jaundice, eye diseases and framboesia. In Chinese medicine extracts from the roots are used as anaesthesia during surgery.

The roots are traded and used on a local scale, and have no importance on the international market. The jelly is traded in a small-scale syrup industry.

Many Menispermaceae species are known to contain mixtures of alkaloids; in the case of Cyclea barbata contents of 4-7% in the roots are reported. This mixture is of complex nature. The principal components are a series of related bisbenzylisoquinoline alkaloids, including (+)-S,S-tetrandrine (main alkaloid, up to 3% in the roots), (±)-tetrandrine, (+)-R,S-isotetrandrine, (-)-R,R-limacine, (±)-fangchinoline, (+)-R,S-isofangchinoline (= thalrugosine), (+)-R,S-berbamine, (+)-R,S-homoaromoline, (+)-S,S-N-methyltetrandrine, (+)-S,S-tetrandrine-2'-'BETA'-N-oxide, (-)-cycleapeltine, (-)-2'-norlimacine, (+)-cycleabarbatine, (-)-repandine, (+)-cycleanorine, (+)-daphnandrine, (+)-coclaurine, (-)-N-methylcoclaurine, (-)-curine (= (-)-berbeerine = R,R-chondodendrine), R,R-isochondodendrine and R,S-chondocurine. Besides the bisbenzylisoquinoline alkaloids, 'ALFA'-cyclanolin and its epimer 'BETA'-cyclanolin (two tetrahydroprotoberberine type alkaloids) and magnoflorine (an aporphine type alkaloid) have also been isolated from Cyclea barbata roots. Dicentrine, an alkaloid structurally related to magnoflorine has been isolated from the roots of Cyclea laxiflora. The only non-alkaloid isolated from Cyclea barbata roots is the sugar protoquercitol, which is often found in Menispermaceae.
An extract derived from the roots of Cyclea barbata has demonstrated in vitro cytotoxic and anti-malarial activity. Using bioactivity guided isolation procedures, 5 bisbenzylisoquinoline alkaloids (i.e. (+)-tetrandrine, (-)-limacine, (+)-thalrugosine, (+)-homoaromoline and (-)-cycleapeltine) have been isolated as active principles. These compounds are capable of inhibiting the growth of both cultured Plasmodium falciparum strains and tumour cell lines. However, their 'selectivity index' (activity against mammalian cells/activity against cultured Plasmodium falciparum strains) typically ranges from 2 to 100, which is low compared to a selectivity index over 1000 for quinine or artemisinin.
Methylation of (-)-curine has yielded dimethyl-(-)-curine dimethochloride, whose chemical structure is closely related to (+)-tubocurarine from South American Chondrodendron tomentosum Ruiz & Pavón (Menispermaceae). The muscle-relaxant activity of dimethyl-(-)-curine dimethochloride was found to be within the range of that of (+)-tubocurarine. Both have a non-depolarizing mode of action, and the blocking site is at the cholinergic (nicotinic) receptor in the postsynaptic membrane. The muscle-relaxant action and the inhibition of breathing could be antagonized by neostigmine. Side-effects are limited to mild hypotension and temporary facial cooling, whereas cardiovascular disturbances are insignificant. Dimethyl-(-)-curine dimethochloride is therefore considered a safe muscle relaxant for surgery.
S,S-tetrandrine, one of the pure isolated bisbenzylisoquinolines, has undergone extensive pharmacological investigations. It has been shown that this compound is a new kind of blocker of the voltage-activated L-type Ca²⁺ channel in a variety of excitable cells, such as cardiac, GH₃anterior pituitary, neuroblastoma cells and rat neurohypophysial nerve terminals. As well as blocking L-type Ca²⁺, it also blocks the voltage-dependent T-type Ca²⁺ channel. S,S-Tetrandrine's action in the treatment of cardiovascular diseases, including hypertension and supraventricular arrhythmia, is primarily due to its blocking of these voltage-activated Ca²⁺ channels. Furthermore, the alkaloid is a potent blocker of the Ca²⁺ activated K⁺ channels of neurohypophysial nerve terminals. There is no obvious clinical application of this action, but S,S-tetrandrine makes a promising ligand for the study of the K⁺ channel function.
Other pharmacological effects include anti-inflammation and immunosuppression. These actions often require higher doses than those needed to produce the cardiovascular effects. The mechanism(s) by which S,S-tetrandrine exerts these actions are unknown, although in vitro experiments have demonstrated inhibition of the production and release of inflammatory mediators and cytokines such as histamine, prostaglandins, leukotrienes, platelet activating factor, interleukin-1, tumour necrosis factor and nitric oxide. The inhibition of tumour necrosis factor has also been shown in vivo, using a mouse model for fulminant hepatitis. A selective inhibition of T-cell dependent immune responses by S,S-tetrandrine has been observed in mice, and suppression of the chronic inflammation in an arthritis model in the rat.
In media containing calcium, the stereoisomer of S,S-tetrandrine, R,S-isotetrandrine, exerts similar, although less specific, calcium channel activities. In contrast to S,S-tetrandrine, the mechanism of action of R,S-isotetrandrine also involves intracellular mechanisms, since it has been shown that this component is also active in calcium-free media, whereas S,S-tetrandrine is not. Other activities of R,S-isotetrandrine are inhibition of histamine release (in vitro), inhibition of nitric oxide production (in vitro) and selective inhibition of T-cell dependent immune responses (in vivo, mouse). Isotetrandrine also markedly suppressed the tumour-promoting effect of 12-O-tetradecanonylphorbol-13-acetate in a mouse-skin carcinogenesis test.
Biological activities of R,S-chondocurine include suppression of nitric oxide production (in vitro), selective inhibition of T-cell dependent immune responses (in vivo, mouse), suppression of delayed type hypersensitivity (in vivo, mouse) and reduction of the level of tumour necrosis factor in a fulminant hepatitis model (in vivo, mouse).
Finally, (+)-homoaromoline and fangchinoline show inhibition of the histamine production by RBL-2H3 cells in vitro.

Other Menispermaceae have similar or related alkaloids such as bisbenzylisoquinolines and protoberberines, and have similar applications. There is a report of Cyclea barbata being substituted by Cissampelos pareira. In Java, Cyclea barbata leaves are sometimes substituted by the leaves of Stephania capitata (Blume) Sprengel or Canthium horridum Blume, for the production of 'cincau' jelly.

Slender dioecious lianas up to 15 m long; stem herbaceous or woody, hispid to glabrous; roots sometimes tuberous. Leaves arranged spirally, simple and entire, often peltate, palmately veined; stipules absent. Inflorescence axillary, terminal or cauliflorous, pseudoracemose or thyrsoid. Flowers unisexual, calyx with free or connate sepals, corolla with free or connate petals (rarely absent); male flower 4(-5)-merous, with stamens fused into a peltate synandrium with 4-5 anthers; female flower 2-3-merous, with 1 carpel having a 3-5-fid stigma, without staminodes. Fruit a curved, obovate to rotund drupe with style-scar near base; endocarp bony, dorsally ornamented with 3-6 rows of tubercles. Seed horseshoe-shaped; embryo narrow, embedded in endosperm.

The flowers are pollinated by insects such as small flies and bees and possibly also small beetles and moths, which are attracted by the scent of the flowers and possibly also by the smell of the leaves.

Cyclea is closely related to Stephania, which differs in its 2 whorls of sepals in the male flowers and its umbelliform or disciform inflorescences.

Cyclea occurs in forest, often in secondary forest, coastal forest, teak forest and bamboo forest, and in scrub vegetation, hedges, cultivated land and alang-alang (Imperata cylindrica (L.) Raeuschel) fields, up to 1200 m altitude. Some Cyclea species have been found at altitudes as high as 2800 m.

Cultivated Cyclea barbata fruits erratically, so is by stem or root cuttings. Cuttings from young woody stems, 25-30 cm long, are planted near hedges, trees or trellises, for support at a later stage. Cuttings may also be planted in the field at a spacing of 2 m x 1.5 m, supported by stakes, under shade trees. Before planting 5 kg manure and 10 g triple superphosphate is added per planting hole. Two weeks later an additional 10 g ammonium sulphate and 10 g potassium chlorite is given.

A first harvest of Cyclea barbata leaves from stem cuttings can be expected after 6-8 months. Consecutive harvests are at intervals of 2-3 months.

To make good quality jelly, 'cincau hijau', young well-developed leaves should be used. The shelf-life of the jelly at ambient temperature is 1-2 days.

Cyclea barbata and Cyclea laxiflora are locally rather common, the former in Java and the latter in Peninsular Malaysia, and occur particularly in disturbed forest. They do not seem at risk of genetic erosion. However, some other Cyclea species are endemic to comparatively small areas (e.g. Cyclea kinabaluensis Forman on Mount Kinabalu) and are more likely to become endangered.

Cyclea root extracts show some interesting properties that deserve more research. In particular the powerful neuromuscular blocking property comparable to d-tubocurarine chloride, and the antimalarial activity warrant more attention.

Forman, L.L., 1986. Menispermaceae. In: van Steenis, C.G.G.J. & de Wilde, W.J.J.O. (Editors): Flora Malesiana. Series 1, Vol. 10. Kluwer Academic Publishers, Dordrecht, Boston, London. pp. 237-243.
Forman, L.L., 1991. Menispermaceae. In: Smitinand, T. & Larsen, K. (Editors): Flora of Thailand. Vol. 5(3). The Forest Herbarium, Royal Forest Department, Bangkok, Thailand. pp. 325-331.
Guinaudeau, H., Lin, L.Z., Ruangrungsi, N. & Cordell, G.A., 1993. Bisbenzylisoquinoline alkaloids from Cyclea barbata. Journal of Natural Products 56(11): 1989-1992.
Klughardt, G. & Zymalkowski, F., 1982. Magnoflorin und Protoquercit als Inhaltsstoffen von Cyclea barbata Miers [Magnoflorine and protoquercitol as constituents of Cyclea barbata Miers]. Archiv der Pharmazie (Weinheim) 315(1): 7-11.
Lin, L.Z., et al., 1993. Cytotoxic and antimalarial bisbenzylisoquinoline alkaloids from Cyclea barbata. Journal of Natural Products 56(1): 22-29.
Martin, H.-J., Pachaly, P. & Zymalkowski, F., 1977. Alkaloide aus der thailändischen Menispermaceen-Droge Krung Kha Mao (Cyclea barbata), 6. Mitt. Isolierung und Strukturaufklärung quartärer Tetrahydroprotoberberin-Alkaloide [Alkaloids from the Thai Menispermaceae drug krung kha mao (Cyclea barbata), part 6. Isolation and structural elucidation of quaternary tetrahydroprotoberberine alkaloids]. Archiv der Pharmazie (Weinheim) 310(4): 314-319.
Nguyen Van Duong, 1993. Medicinal plants of Vietnam, Cambodia and Laos. Mekong Printing, Santa Ana, California, United States. p. 259.
Siwon, J., 1982. A pharmacognostical study of some Indonesian plants of the family Menispermaceae. PhD thesis, Leiden University, the Netherlands. pp. 10, 100-103.
Wu, J. & Xie, F.S., 1987. Dimethyl-1-curine dimethochloride an alternative for D-tubocurarine chloride. Chinese Medical Journal 100(3): 173-176.
Yang, Q.Z. & Lin, L.R., 1981. Mode of action of dimethyl-levo curine dimethochloride on neuro-muscular transmission. Acta Pharmacologica Sinica 2(1): 19-23.

R.H.M.J. Lemmens & S.F.A.J. Horsten

Cyclea barbata
Cyclea laxiflora

Lemmens, R.H.M.J. & Horsten, S.F.A.J., 1999. Cyclea Arn. ex Wight. In: de Padua, L.S., Bunyapraphatsara, N. and Lemmens, R.H.M.J. (Editors): Plant Resources of South-East Asia No 12(1): Medicinal and poisonous plants 1. PROSEA Foundation, Bogor, Indonesia. Database record: prota4u.org/prosea

The following species in this genus are important in this commodity group and are treated separatedly in this database:
Cyclea barbata
Cyclea laxiflora