1360

12(2): Medicinal and poisonous plants 2

Uncaria Schreb.

Gen. pl. 1: 125 (1789).

RUBIACEAE

x = 11, 22; Uncaria elliptica: 2n = 44

Major species Uncaria lanosa Wallich, Uncaria rhynchophylla (Miq.) Miq. ex Havil.

Malaysia: akar ait. Vietnam: c[aa]u d[awf]ng.

Uncaria has a pantropical distribution, and comprises 34 species of which 2 species occur in tropical America, 3 species in Africa and Madagascar, and 29 species in Asia.

Most Uncaria species are morphologically very similar and have similar medicinal uses throughout the South-East Asia. They are mainly applied for their astringent properties. Fresh Uncaria leaves, or parts of the stem with hooks, are employed for making astringent decoctions or preparations for application to wounds and burns, as a gargle for sore throats and for the treatment of intestinal problems, such as diarrhoea and dysentery.
The Chinese in Peninsular Malaysia import pieces of the stem and hooks of Uncaria sinensis (Oliv.) Havil. (synonym Nauclea sinensis Oliv.) and of Uncaria rhynchophylla for the treatment of children with fever or as a sedative and analgesic in nervous or cerebrovascular disorders and convulsions.
In China, Uncaria rhynchophylla is used to treat headaches or dizziness caused by hypertension, cerebral arteriosclerosis, epileptic convulsions and for its spasmolytic, analgesic and sedative properties.
The fresh bark of Uncaria lanosa var. glabrata (Blume) Ridsdale is taken in Sumatra for treating blood poisoning. Uncaria callophylla Blume ex Korth. (synonym Uncaria jasminiflora Hook.f.) is used in Peninsular Malaysia for the treatment of hypertension. In China, the stem with hooks of Uncaria sessilifructus Roxb., occurring from India to Indo-China and southern China, is used for fever and irritability in children, and also for abdominal pain and faintness. In Taiwan, it is used in the same way as the Chinese Uncaria hirsuta Havil. Uncaria tomentosa (Willd.) DC., 'cat's claw', from Central America and northern South America, is traditionally used as a medicinal for its anti-inflammatory, contraceptive, hypotensive and immunostimulant properties. Uncaria gambir Roxb. is well known as a dye and tannin-producing species, because of the astringent substance gambier, but is also used medicinally in the same way as other Uncaria.
Some of the larger Uncaria species have stems which may be cut to draw potable water from them. Uncaria cordata Merr. (synonym Uncaria sclerophylla Roxb.) can also be cut into thin, small planks, and used for hoops and sieves, as they are very tough and rather flexible. The young stems give a black dye. A decoction of the root is used in Sarawak as an antidiarrhoeal. Some Uncaria are used as astringent masticatories because of their tannin content e.g. Uncaria homomalla of Indo-China, a stimulant, and also Uncaria gambir and the Malesian Uncaria longiflora. In India, a decoction of the bark of Uncaria sessilifructus is used as a mordant.

Most Uncaria are only locally used, or cultivated for the local market. Different types of preparations of Uncaria tomentosa, mainly collected in Peru, are sold in North America and Australia. Inner bark is used most often in the tablets or capsules, sometimes inner root bark (which is not better than the stem bark) or even whole ground bark, and the quantity of alkaloids present in the products varies widely.

In general, Uncaria species contain a wide variety of alkaloids, belonging to the indole (hetero-indole) type and oxindole type. Furthermore, series of quinovic acid glycosides (triterpenes) and tannins are also present. The alkaloids and tannins together may form a complex that can reduce or eliminate bioavailability of extracts containing Uncaria. On the other hand, however, stomach acid is known to dissolve this complex again.
Alkaloidal extracts from several Uncaria species, i.e. Uncaria callophylla, Uncaria canescens Korth., Uncaria cordata, Uncaria elliptica R.Br. ex G. Don, Uncaria gambir, Uncaria lanosa and Uncaria longiflora, collected from various locations in Peninsular Malaysia, showed in vivo anti-hypertensive effects in various animal models. Phytochemical investigations reported isolation of indole alkaloids (dihydrocorynantheine, yohimbine, pseudoyohimbine, gambirine, isocorynoxeine, corynoxeine and callophylline) and oxindole alkaloids (isopteropodine, pteropodine, isorynchophylline and rynchophylline).
The leaves of Uncaria callophylla contain the alkaloids dihydrocorynantheine, gambirine, isogambirine, gambireine, pseudoyohimbine and callophylline A and B. These alkaloids were investigated for cardiovascular effects in Sprague-Dawley normotensive rats in order to study their hypertension effects. It was shown that isolated dihydrocorynantheine and gambirine at a dose of 5 mg/kg, and pseudoyohimbine at a dose of 10 mg/kg, caused similar reductions in the mean arterial blood pressure both in anaesthetized and conscious rats. However, callophylline did not appear to possess any cardiovascular activity. In addition, intravenous injections of gambirine, at a dose range of 0.2—10 mg/kg caused a dose-related fall in both systolic and diastolic blood pressures as well as heart rate of normotensive rats. At all doses gambirine showed a prompt onset of action and at the higher doses, marked persistence of hypotension accompanied by severe bradycardia were observed. It is suggested that the hypotensive effect of gambirine may be peripheral in origin and is associated, at least in part, with a cardiac action.
The stem and root of Uncaria rhynchophylla contain the oxindole alkaloids isocorynoxeine, isorhynchophylline, corynoxeine and rhynchophylline. The hooks contain as much alkaloids as the stems. Uncaria rhynchophylla, Uncaria sinensis, Uncaria macrophylla Wallich and their indole and oxindole alkaloid constituents were studied for their effects on locomotor response in mice, assessed using the home cage activity apparatus. Water extracts of Uncaria macrophylla and Uncaria sinensis and 4 isolated alkaloids (corynoxine at 30 mg/kg, corynoxine B at 30 mg/kg, isorhynchophylline at 100 mg/kg and geissoschizine methyl ether at 100 mg/kg), significantly decreased locomotor activity after oral administration to mice. This effect appeared to be due to mediation of the central dopaminergic system. Furthermore, the anticonvulsant effect of the stem extract and the physiological mechanisms of its action were studied in male Sprague-Dawley rats, treated with kainic acid to induce epileptic seizures and different concentrations of the extract. The number of wet dog shakes, paw tremor and facial myoclonia were counted. The results indicated that both 1000 and 500 mg/kg of the extract decreased in a dose-dependent way the kainic acid-induced effects and also decreased the lipid peroxide level in the cerebral cortex, indicating a free radical scavenging action.
The effects of hirsutine and dihydrocorynantheine, an indole alkaloid and its structural epimer, from Uncaria rhynchophylla on membrane potentials of rabbit sino-atrial node and guinea-pig right ventricle and left atrium were studied with microelectrode techniques. The results showed that hirsutine and dihydrocorynantheine have direct effects on the action potential of cardiac muscle through inhibition of multiple ion channels, which may explain their antihypertensive, negative chronotropic and antiarrhythmic activity. In addition, vasodilative effects of hirsutine (HS) and hirsuteine (HST) were tested in the hind-limb artery of anaesthetized dogs. Intra-arterial administration of HS and HST caused a vasodilatation, and the potency was somewhat stronger in HS than that of HST, while both were approximately equal to that of papaverine. Uncarinic acids A and B, isolated from the hooks of Uncaria rhynchophylla, were found to inhibit phospholipase C'GAMMA'1 with IC₅₀ values of 36 and 45 µM, respectively.
Oral administration of the chloroform soluble fraction of a MeOH extract of hooks of Uncaria sinensis prolonged the thiopental-induced hypnotics and hypotension reaction in rats. Of the three major indole alkaloids from this fraction, geissoschizine methyl-ether, hirsuteine and hirsutine, the first 2 significantly prolonged the pentobarbital-induced hypnotics at 100 mg/kg, whereas hirsuteine and hirsutine enhanced the hypotension reaction at 100 mg/kg in spontaneous hypertensive rats. Effects of hirsuteine on nicotine- and high potassium-induced responses were investigated in rat pheochromocytoma PC12 cells. Hirsuteine inhibited dopamine release evoked by 100 µM nicotine in a concentration-dependent manner and was found to antagonize non-competitively nicotine-evoked dopamine release by blocking ion permeation through nicotinic receptor channel complexes. The hooks were also found to contain the indole alkaloid glycosides cadambine, 3'ALFA'-dihydrocadambine and 3'BETA'-dihydrocadambine. Only the last compound exhibited strong and persistent hypotensive activity in rats. An ethanolic extract from the hooks and stems also contained several 16-carboxy derivatives of pentacyclic oxindole alkaloids and their glucopyranosyl esters: mitraphyllic acid, isomitraphyllic acid, pteropodic acid, isopteropodic acid, rhynchophyllic acid and isorhynchophyllic acid, (16-1)-'BETA'-D-glucopyranosyl ester and mitraphyllic acid (16-1)-'BETA'-D-glucopyranosyl ester.
The protective effect of a water extract of the hooks and stems of Uncaria sinensis against glutamate-induced neuronal death was investigated by microscopic observation and the 3-(4,5-dimethylthiazol)-2-yl-2,5-diphenyl-tetrazolium bromide assay, and action on ⁴⁵Ca²⁺ influx using cultured cerebellar granule cells from 7—8-day-old rats. Glutamate-induced cell death was reduced by the extract in a dose-dependent manner, and increase of ⁴⁵Ca²⁺ influx into cells induced by glutamate was blocked by the extract in a dose-dependent manner. Two different studies on the efficacy of the extract of the hooks and stem on patients with vascular dementia, a non-double blind study (60 patients) and a double-blind controlled study (139 patients), were performed. The medicine tested was found to be superior in global improvement rating, utility rating and improvement of subjective symptoms, psychiatric symptoms and disturbance in daily living activities.
Uncaria tomentosa has undergone intensive phytochemical analysis, which revealed the presence of 2 important groups of compounds, i.e. oxindole alkaloids and quinovic acid glycosides. HPLC analysis confirmed the presence of 6 pentacyclic alkaloids (pteropodine, isopteropodine, speciophylline, uncarine F, mitraphylline, isomitraphylline) and 2 tetracyclic alkaloids (rhynchophylline, isorhynchophylline) in the roots and bark. Extracts and pure alkaloids were tested using a granulocyte-smear test and a chemiluminescence model to evaluate the stimulatory effect on the phagocytic activity of granulocytes. Phagocytosis was enhanced by pteropodine, isomitraphylline and isorhynchopylline. The strongest stimulation was observed with isopteropodine, whereas mitraphylline and rhynchophylline had no effect. Furthermore, the mixture of the 6 pentacyclic oxindole alkaloids induced EA.hy926 human endothelial cells in culture to release some factors into the supernatant. These factors were subsequently shown to significantly enhance proliferation of normal human resting or weakly activated B- and T-lymphocytes. An extract containing approximately 6 mg/g oxindoles (mixture of pteropodine, isopteropodine, speciophylline, uncarine F, mitraphylline, isomitraphylline) also stimulated IL-1 and IL-6 production by rat macrophages in a dose-dependent manner. In the carbon-clearance test in mice, used to evaluate the stimulatory effect on the phagocytic activity of granulocytes, a water extract of the drug showed good activity at concentrations of 10 mg/kg. An isolated mixture of the tetra- and pentacyclic alkaloids was inactive in this test system; however, activity was restored after the admixture of catechin to it. Several extracts of Uncaria tomentosa root bark were furthermore tested for anti-inflammatory activity using the carrageenan-induced rat paw oedema test. The quinovic acid glycoside reduced the inflammatory response by 33% at 20 mg/kg orally. It could not be ruled out, however, that the strong anti-inflammatory effect as seen by extracts could be due to a combination of compounds. Single dose toxicity (LD₅₀) in mice is over 16 g/kg orally. Repeated dose toxicity, daily doses for a month of up to 1 g/kg of a root extract containing 7.5 mg total oxindole alkaloids, to rats revealed no relevant differences between treated and non-treated groups, except for a slight increase of lymphocyte count, a slight decrease of neutrophil granulocyte count, and an increase of the relative weight of the kidneys in the treated group. In addition, Uncaria tomentosa bark showed no mutagenic effects in several strains of Salmonella typhimurium, but rather a protective antimutagenic activity in vitro against photomutagenesis.
An aqueous extract from Uncaria tomentosa, depleted of indole alkaloids, was tested with female W/Fu rats at doses between 5 and 80 mg/kg for a period of 8 weeks in order to evaluate its effects on enhanced DNA repair, immune function and toxicity. Phytohaemagglutinin stimulated lymphocyte proliferation was significantly increased in splenocytes of rats treated at the higher doses, and white blood cell numbers were significantly elevated, thus indicating its anti-inflammatory effect. These results were confirmed in a human volunteer study. No toxicity was observed, and no body weight, food consumption, organ weight, kidney, liver, spleen, or heart pathological changes were found to be associated with this particular extract. The extract was furthermore examined in vitro for antitumour properties using two human leukaemic cell lines (K562 and HL60) and one human EBV-transformed B lymphoma cell line (Raji). The proliferative capacities of HL60 and Raji cells were strongly suppressed in the presence of the extract while K562 was more resistant to the inhibition. The suppressive effect of Uncaria tomentosa extracts on tumour cell growth appears to be mediated through induction of apoptosis which was demonstrated by characteristic morphological changes, internucleosomal DNA fragmentation after agarose gel electrophoresis and DNA fragmentation quantification.
The bark of Uncaria elliptica, from continental Asia and Malesia, contains roxburghines A-BE, formosanine, ajmalicine and mitraphylline. Sometimes the roxburghines are not detected however. Fresh leafy shoots revealed rutin (up to 20%) and (—)-epicatechin as the major flavonoids present. The leaves generally contain much more rutin than the woody tissues, the content in young leaves being particularly high. The leaves of Uncaria homomalla contain 4 pentacyclic oxindole alkaloids, isopteropodine, pteropodine, speciophylline and uncarine F, and the bark contains catechutannic acid and catechin. The indole alkaloids uncarine C, D and E, and the glucindole alkaloids glabratine and deoxycordifoline were extracted from fresh bark of Uncaria glabrata. Uncaria lanosa f. setiloba (Benth.) Ridsdale (synonym Uncaria florida Vidal) contains uncarine C (pteropodine), uncarine D (speciophylline), uncarine E (isopteropodine) and uncarine F, while Uncaria lanosa f. philippinensis (Elmer) Ridsdale (synonym Uncaria kawakamii Hayata) contains isomitraphylline, mitraphylline, uncarine A (isoformosanine) and uncarine B (formosanine). A methanolic extract of the stem bark and hooks of Uncaria attenuata Korth. (synonym Uncaria salaccensis Bakh.f.), from Peninsular Malaysia, Sumatra, Java, Borneo and the Philippines, contains the oxindole alkaloids salacin, 3-oxo-7-hydroxy-3,7-secorhynchophylline as well as rhynchophylline, isorhynchophylline and corynoxine, and 3-isoajmalicine, 19-epi-3-isoajmalicine, mitraphylline and uncarine B. Uncaria perrottetii (A.Rich.) Merr. from the Philippines contains the alkaloids pteropodine and isopteropodine. An extract of Uncaria gambir, containing catechin and tannin, was tested for its fungicidal activity, and was found to control the growth of Fusarium sp. causing leaf spot on Clausena anisata (Willd.) Hook.f. ex Benth. The stem also contains the alkaloids gambirdine, isogambirdine and gambirine.

Monoterpenoid terpene alkaloids occur particularly in Loganiaceae (e.g. Strychnos), Apocynaceae (e.g. Catharanthus, Rauvolfia, Voacanga) and Rubiaceae (e.g. Cinchona). Several species of these genera have similar uses comparable to Uncaria. In Thailand, the leaves of Uncaria are used as a substitute for the leaves of Mitragyna speciosa (Korth.) Havil., known for its stimulant properties. Many species of Uncaria contain alkaloids similar to those in the closely related genus Mitragyna.

Woody lianas; young branchlets angular to rounded, glabrous or pubescent, branches differentiated into monopodial orthotropic and plagiotropic systems; vegetative lateral branches of the plagiotropic system modified into hooks. Leaves opposite, simple, domatia usually present in the axils of the lateral veins, tertiary veins usually impressed; petiole present; stipules interpetiolar, entire or bifid, inside with colleters at the base or over the whole surface. Inflorescence a terminal or axillary head on the plagiotropic shoot. Flowers bisexual, 5-merous, (sub)sessile or pedicellate on the receptacle, pedicels free or fused into groups, sometime accrescent, with or without interfloral bracteoles; receptacle sparsely to densely hairy; calyx tube short, often bottle-shaped, lobes variable in shape, glabrous to hairy, epicalyx present or absent; corolla tube hypocrateriform to infundibular, outside glabrous to hairy, lobes ovate-oblong to elliptical, valvate in bud, inside and outside glabrous or pubescent; stamens 5, inserted high in the corolla tube, exserted and spreading, filaments short, glabrous; ovary inferior, 2-locular, ovules numerous, style exserted, stigma globose to elongate-clavate, papillate. Fruit a dry capsule, 2-celled, exocarp thick, splitting loculicidally but long remaining intact below the calyx remnants, endocarp thick, horny, splitting septicidally and then slightly loculicidally from apex to base; seeds numerous. Seed small, centre reticulate, long winged at both ends, lower wing deeply bifid. Seedling with epigeal germination.

Many Rubiaceae, including Uncaria, have differentiated growth axes. Each node of the orthotropic axis bears 2 serial buds in every leaf axil, and a lateral, plagiotropic axis develops from the upper bud. These branches monopodially increase in length, either throughout their life span or for a limited period only. During the vegetative phase the lateral buds of the plagiotropic shoot develop into hooks, by which the liana supports itself passively. The lower serial bud, if developing, grows out to produce a new orthotropic shoot.
In Indo-China, Uncaria acida starts flowering in March, and is found fruiting till December. In Java, Uncaria acida flowers from October—December and Uncaria lanosa flowers throughout the year.

Uncaria belongs to the tribe Cinchoneae, subtribe Mitragynae, to which also Mitragyna belongs. This subtribe is characterized mainly by the thick black placentas bearing upwardly-imbricate ovules, and also by the mode of dehiscence of the fruits. Fruiting material of Uncaria, especially in the absence of stipules, is difficult to identify. Uncaria lanosa is a complex species, and many forms have been described as separate species, but these differ only in the degree of pubescence of the leaf and in the shape of the calyx lobes, and intermediates occur in some regions.

Uncaria is a genus of climbers in primary and secondary forest, or forest borders, at low to medium altitudes.

Uncaria can be propagated by seed or cuttings. The highest seedling rate was obtained when the seed was sown on peat. In Japan, transplanting wild plants of Uncaria rhynchophylla to fields was successful. Cuttings of two-year-old branches led to more vigorous root formation than using main stems.

In Japan, the effects of plant growth regulators and nutrients on growth and alkaloid production by callus cultures of Uncaria rhynchophylla, initiated from leaves, were investigated. Gamborg B5 medium supplemented with indole acetic acid at 10^-4 M and 6-benzylaminopurine at 3 x 10^-5 M was best for both growth and alkaloid production. The best alkaloid production was observed on B5 medium supplemented with 2% sucrose, but the best growth was observed in the presence of 3% sucrose. Hirsuteine, hirsutine, 3'ALFA'-dihydrocadambine and ursolic acid were isolated from the callus, and the 3'ALFA'-dihydrocadambine concentration of callus was 50-fold higher than that of the hooks and stems.

Uncaria rhynchophylla plants grown with the application of fertilizers containing both P and K showed an increased crude drug yield but its oxindole alkaloid content was the lowest.
In Japan, Uncaria rhynchophylla was cultivated experimentally under high (30/35°C, night/day), medium (20/25°C, night/day) and low (10/15°C, night/day) temperature conditions in a biotron growth cabinet. When the night temperature was lower, the oxindole alkaloid content tended to be higher. It was concluded that the 20/25—28°C (night/day) condition with a daily temperature difference of 5—8°C was the most suitable for the cultivation of Uncaria rhynchophylla.

There are no major diseases or pests known for Uncaria.

In China, pieces of the stem of Uncaria rhynchophylla are collected in August and September, when the hooks become red. In general, Uncaria stems are harvested after 1—2 years.

In Japan, Uncaria rhynchophylla was cultivated under various shade conditions (20, 40, 60 or 80% shade) for 3 years, during which time hooks were collected every year from newly regenerated shoots. The yield of hooks increased with plant age. Plant growth rate and hook yield were highest when the plants were cultivated under 40% shade, and alkaloid content in the hooks increased with the degree of shade up to 40%. Analysis of dried stem segments with hooks showed that the total oxindole alkaloid content of the stem was similar to that of the hook portion. The area closest to the hook showed a slightly higher alkaloid content than the hook, and the oxindole alkaloid content decreased as the distance from the hook increased. Therefore, the presence of the hook does not affect the quality of the crude drug as far as the oxindole alkaloid content is concerned. Oxindole alkaloids comprised about 97% of the total alkaloids in the hook, twig and leaf, whereas about 96% of the root bark alkaloids were indole alkaloids. The wood had a very low alkaloid content, mostly of rare types. The yield of the crude drug and the oxindole alkaloid content of the plants vegetatively propagated by stem or root cuttings and those grown from seeds were compared. Only the productivity of individual alkaloids (isocorynoxeine, isorhynchophylline, corynoxeine and rhynchophylline) seemed to have been passed on from a mother plant to the vegetatively propagated plants, the yield of oxindole alkaloids was lower in the cuttings and variable in the seedlings.

In China, pieces of the stem of Uncaria rhynchophylla are dried in the sun, or may be roasted before drying.

Most Uncaria species are widespread throughout South-East Asia, and do not seem to be at risk of genetic erosion.

Extracts of Uncaria, and the isolated constituents such as (ox-)indole alkaloids and triterpenes, display a range of interesting biological activities in several fields, including the vascular system, hypotension, cardiac activity and the immune system. It is possible that several of these compounds have potential as lead substances in future development, and therefore the genus merits further research. As a consequence, the potential for cultivation of Uncaria species from China or South America in South-East Asian countries needs further investigation.

Hsieh, C.L., Chen, M.F., Li, T.C., Li, S.C., Tang, N.Y., Hsieh, C.T., Pon, C.Z. & Lin, J.G., 1999. Anticonvulsant effect of Uncaria rhynchophylla (Miq.) Jack. in rats with kainic acid-induced epileptic seizure. The American Journal of Chinese Medicine 27(2): 257—264.
Kawazoe, S., Mizukami, H. & Ohashi, H., 1991. Cultivation and breeding of Uncaria rhynchophylla (Miq.) Miquel. VII. Effect of temperature on growth, crude drug 'Cho-to-ko' yield and oxindole alkaloid content. Japanese Journal of Pharmacognosy 45(4): 281—288. (in Japanese)
Kohda, H., Namera, A., Koyama, A., Yamasaki, K. & Tani, T., 1996. Indole alkaloid production in callus cultures of Uncaria rhynchophylla (Miq.) Miquel. Chemical and Pharmaceutical Bulletin 44(2): 352—357.
Phillipson, J.D., Hemingway, S.R. & Ridsdale, C.E., 1978. Alkaloids of Uncaria. Part V. Their occurrence and chemotaxonomy. Lloydia 41(6): 503—570.
Ridsdale, C.E., 1978. A revision of Mitragyna and Uncaria - Rubiaceae. Blumea 24(1): 43—100.
Shimada, Y., Goto, H., Kogure, T., Shibahara, N., Kita, T., Itoh, T. & Terasawa, K., 1998. Extract prepared from the hooks and stems of Uncaria sinensis prevents glutamate-induced neuronal death in cultured cerebellar granule cells. Journal of Traditional Medicines 15(3): 141—146.

Anas Subarnas

Uncaria acida
Uncaria homomalla
Uncaria lanosa
Uncaria longiflora
Uncaria rhynchophylla

Subarnas, A., 2001. Uncaria Schreb.. In: van Valkenburg, J.L.C.H. and Bunyapraphatsara, N. (Editors): Plant Resources of South-East Asia No 12(2): Medicinal and poisonous plants 2. 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:
Uncaria acida
Uncaria homomalla
Uncaria lanosa
Uncaria longiflora
Uncaria rhynchophylla