1320

12(2): Medicinal and poisonous plants 2

Tabernaemontana L.

Sp. pl. 1: 210 (1753); Gen pl. ed. 5: 100 (1754).

APOCYNACEAE

x = 11; for most species: 2n = 22, Tabernaemontana divaricata: 2n = 22, (23), 33, (34), Tabernaemontana sphaerocarpa: 2n = 66

Major species Tabernaemontana divaricata (L.) R.Br. ex Roem. & Schult., Tabernaemontana pandacaqui Poir.

Malaysia: susun kelapa.

Tabernaemontana comprises 99 species and has a pantropical distribution. 44 species are found in the New World, 18 in Africa, 15 in Madagascar, 1 in the Mascarene Islands and 21 in Asia, Oceania and Australia. All species are restricted to one of the five geographical areas. Tabernaemontana pandacaqui is by far the most widely distributed. It is known from Thailand to the Pacific, and from Taiwan to south-eastern Australia, with the exception of more humid areas. The closely allied Tabernaemontana pauciflora Blume is found where Tabernaemontana pandacaqui is absent, although there are areas of overlap. Tabernaemontana divaricata, mostly the double-flowered form, is commonly grown throughout the tropics. Tabernaemontana corymbosa Roxb. ex Wallich is known from southern China to Indonesia. Three geographically separate species share the Malesian region. Tabernaemontana macrocarpa Jack is confined to western Malesia, the closely allied Tabernaemontana sphaerocarpa Blume occurs exclusively in Java, Sulawesi and nearby islands to the north and south, and Tabernaemontana aurantiaca Gaud. occurs in the eastern Moluccas, New Guinea and further eastward. Local endemics are also common.

The most common use of Tabernaemontana in Malaysia is for the treatment of ulcerations of the nose. In general pulped roots, or less commonly leaves, are simply drawn into the nostrils. Poultices of leaves and roots of various species are applied to boils. Leaves, bark or latex of several species are an ingredient of mixtures used as dart poison. In Malaysia, a decoction of the leaves of Tabernaemontana pauciflora is used to treat hypertension, while the roots are applied during and after confinement. In Thailand, the roots of Tabernaemontana have been employed in folk medicine, mostly for the treatment of inflammations and fever. Tabernaemontana bufalina Lour. (synonyms Tabernaemontana luensis Pierre ex Pitard, Tabernaemontana microphylla Pitard) is used in Indo-China for its emollient and laxative properties. In China the plant is used against rheumatoid arthritis, and is applied to boils, swellings, sprains and bruises. The latex of Tabernaemontana coagulates into a resinous rubber. However, collecting latex of even the most prolific species proved too laborious to be economically feasible. Flowers of Tabernaemontana, in particular Tabernaemontana pandacaqui and Tabernaemontana divaricata, are used for decoration.

Tabernaemontana is used at the local level only. Plants for ornamental purposes are occasionally sold in local nurseries.

By far the most important group of phytochemical constituents of Tabernaemontana are the alkaloids, sometimes also referred to generally as Iboga alkaloids. All of them belong to a group of monoterpenoid indole alkaloids, of which the biosynthetic precursors are the amino acid tryptophan (alkaloid part) and the iridoid secologanin (monoterpenoid part). Extensive reviews of the numerous different compounds isolated can be found in literature; for the important South-East Asian species this is condensed into the following summary.
From Tabernaemontana aurantiaca ibogaine, voacangine, and vobtusine, from Tabernaemontana corymbosa conodiparine ABD (vobasine type) and ervatamine, and from Tabernaemontana dichotoma apparicine, coronaridine, (—)-heyneanine, perivine, tabersonine and vobasine have been isolated. Tabernaemontana divaricata contains apparicine, coronaridine, (+)-heyneanine, (—)-heyneanine, ibogamine, vobasine, voacamine and voacangine, and Tabernaemontana macrocarpa coronaridine, voaphylline, voacangine. Tabernaemontana pandacaqui contains apparicine, coronaridine, ervatamine, iboganine, isovoacangine, pericyclivine, tabernaemontanine, tabernanthine, voacristine and voacangine, Tabernaemontana pauciflora contains coronaridine, and Tabernaemontana sphaerocarpa dregamine and tabernaemontanine.
At present, of the numerous different compounds isolated, some 83 of them have also been studied pharmacologically in more detail and information is summarized here. Many pure alkaloids show chemotherapeutic activity, such as cytotoxic, antimicrobial, antiprotozoal and antiviral effects. For instance apparicine showed activity against Polio III virus in vitro at a concentration of 250 µg/ml, and at a concentration of 1.2% the alkaloid exhibited antimicrobial activity against Corynebacterium, Escherichia, Proteus, Pseudomonas, Salmonella and Staphylococcus. Examples of alkaloids which have antitumour effects include apparicine (P-388 leukaemia, in vitro), camptothecine (from the Indian species Tabernaemontana heyneana Wallich; P-388 and KB cells, in vitro) and olivacine (from the Brazilian Tabernaemontana hystrix Steud.; KB cells, in vitro, L1210 leukaemia in vivo). The latter compound also inhibited the growth of the protozoa Trypanosoma cruzi in culture.
Apart from the chemotherapeutic activity, many alkaloids possess other activities, mostly related to the central nervous system (CNS), such as hypotensive- and cardiac depressant, analgesic and local anaesthetic activities. Coronaridine showed autonomic and CNS activity. In mice it produced analgesia and was effective in suppressing rage caused by foot-shock. The substance showed oestrogenic activity, and there was a partial inhibition of the oxytocin-induced uterine response. Ervatamine and perivine are both examples of alkaloids with local anaesthetic effects, acting by their influence on Na⁺-channels. In cats and dogs, ibogaine has distinct central-stimulating properties, different from those of strychnine, which can be abolished by atropine. In mice, it has weak but definite anticonvulsant properties. Ibogaine furthermore has a transient hypotensive effect. It also acts as a true hallucinogenic agent, and it can be used as a substitute for cocaine. When administered intravenously to anaesthetized guinea-pigs, ibogaine produced a bradycardia that was resistant to vagotomy and administration of atropine. The blood pressure was lowered, but there was no alteration in the electrocardiogram (ECG). In addition, the pharmacology of ibogamine is quite similar to that of ibogaine. Finally, voacamine (as its sulphate) has pharmacological properties comparable with those exhibited by cardiac glycosides. It may therefore be useful in treating cardiac insuffiency. Voacangine exhibited a slight central stimulating effect in a general screening procedure. When injected into guinea-pigs, it produced the same effects as ibogaine.
The effects of a crude alkaloidal (CA) fraction from the stem of Tabernaemontana pandacaqui on the blood pressure and heart rate were investigated in conscious as well as anaesthetized rats. The CA fraction exerted a hypotensive activity in both experimental models. In pentobarbital anaesthetized rats, an intravenous administration of the CA fraction caused two consecutive hypotensive and bradycardiac responses. In order to investigate the mechanism of the responses, the effect of the CA fraction on the blood pressure and the heart rate was tested in various experimental animals such as pithed rats, reserpinized rats under pentobarbital anaesthesia and atropine- or chlorpheniramine-treated rats under pentobarbital anaesthesia. The results obtained suggest that the hypotensive and bradycardiac responses of the first phase might involve cholinergic and central mechanisms, whereas those of the second phase involve mechanisms which are mediated by central, biogenic amines, acetylcholine and histamine. In addition, an alkaloidal fraction of Tabernaemontana dichotoma showed hypotensive activity, and the crude alkaloids from the leaves of Tabernaemontana pauciflora also showed slight but lasting hypotensive effects.
The crude alkaloidal (CA) fraction from the stem of Tabernaemontana pandacaqui was further studied for its pharmacological activity on the central nervous system (CNS) of animals. The CA fraction was found to produce symptoms of CNS depression in conscious rats and mice, in the form of decrease in spontaneous motility, potentiation of pentobarbital sleeping time, prolongation of latency of convulsions induced by pentylenetetrazole, and antinociception; the fraction could not antagonize oxotremorine-induced tremor. The observations suggest that the CA fraction possesses CNS-depressant activity. Sedative effects were also found in experiments with an alkaloid fraction of Tabernaemontana dichotoma.
A screening of ethanolic extracts from 19 Tabernaemontana species indicated that most of them showed a broad spectrum of antibacterial activities; some species also showed antiviral and antiamoebic activities. In particular Tabernaemontana divaricata and Tabernaemontana pandacaqui were strongly active against gram-negative bacteria at low concentration and strongly active against gram-positive bacteria. Tabernaemontana aurantiaca was strongly active against gram-positive bacteria and moderately active against gram-negative bacteria. In addition, the dimeric indole alkaloids seemed to play an important role in the antibacterial activity.
Crude extracts of Tabernaemontana divaricata and Tabernaemontana dichotoma had anticancer activity. Alkaloidal fractions from the seed, roots and pods depressed bone-marrow activity in rats, resulting in temporary leukopenia.
The alkaloid fraction of the methanol extracts of dried twigs of Tabernaemontana divaricata showed hypotensive activity in rats owing to interference in sympathetic transmission, almost abolished the reflex response to bilateral occlusion of the common carotid, and depressed the effect of norepinephrine; it also showed uterine relaxant activity in vitro and in vivo.
Pharmacological effects of Tabernaemontana, without direct mention of the presence of alkaloids include: ethanolic extracts of roots, stems, leaves and flowers of Tabernaemontana divaricata and Tabernaemontana pandacaqui caused sedation, decreased respiration and decreased skeletal muscle tone in rats. All extracts of Tabernaemontana pandacaqui, except for the leaf extract caused vasodilatation of ear vasculature. Analgesic activity was found for all extracts except for the flower extract of Tabernaemontana divaricata. Lethal doses of the extracts caused the animals to die from respiratory paralysis. Root and stem extracts showed the greatest activity. Tabernaemontana pandacaqui extracts were more potent than those of Tabernaemontana divaricata.
Intravenous injection of ethanolic extracts of the stem, leaves and flowers of Tabernaemontana pandacaqui caused hypotension in pentobarbital anaesthetized rats. At high doses (100—300 mg/kg), the flower extract showed a transient hypertensive effect preceding hypotensive activity. The effects of the extract on the heart rate of anaesthetized rats correlated well with the negative chronotropic and inotropic activity observed with isolated atrium. The hypotensive activity was not inhibited by antihistaminic and antimuscarinic agents. The extracts had no effect on the pressor effects induced by norepinephrine or dual carotid occlusion. These results suggest that the hypotensive action of the extracts is not mediated through histaminic and muscarinic receptors stimulation, 'ALFA'-adrenoceptor blockade or interference of sympathetic transmission.
Ether and ethanol extracts of Tabernaemontana divaricata at 1.5% concentration have insecticidal and ovicidal activity against Dysdercus koenigii (red cotton bug) comparable to or even stronger than those of neem extract (Azadirachta indica A.H.L. Juss.).
In a screening experiment to identify possible agents of therapeutic value in immunoglobulin A nephropathy (IgA-N), a crude methanol extract of Tabernaemontana divaricata was tested for its effect on human mesangial cell proliferation. The crude extract inhibited human cells proliferation activated by interleukin-1'BETA' (IL-1'BETA') and IL-6 at a median inhibitory concentration of 50.0 ± 2.1 µg/ml. The herb also decreased IL-1'BETA' and tumour necrosis factor (TNF-'ALFA') production. It is unlikely that cytotoxicity was involved, because no cell deaths were observable. It is hypothesized that the inhibitory mechanisms of the herb may be related to the impairments of gene expression and production of cytokines in human mesangial cells.

Plants producing alkaloids of the ibogan and bis-indole type are mostly confined to closely related genera of the tribe Tabernaemontaneae (e.g. Voacanga), with the exception of e.g Catharanthus roseus (L.) G. Don. Alkaloids such as vincamine are found in large amounts in Vinca minor L. (Apocynaceae), and yohimbane found in South-American Tabernaemontana species is also found in the African Corynanthe johimbe K. Schum. (Rubiaceae).

Shrubs or trees, repeatedly dichotomously branched from low down; trunk terete, bark with much white latex, wood rather soft, branches with conspicuous leaf scars, with usually 2 inflorescences just above each ramification. Leaves simple, opposite, those of a pair equal or subequal, broadly to narrowly elliptical or obovate, base equal or unequal-sided, entire or sometimes sinuate or undulate; petiolate or sessile, petioles of a pair usually connate into a conspicuous ocrea, ocrea frequently widened into intrapetiolar stipules. Inflorescence corymbose, rather lax to congested. Flowers 5-merous, actinomorphic except for the subequal sepals, fragrant; sepals very variable in size, colour and shape; corolla white, pale yellow or mauve, the tube often greenish, the throat often pale yellow, the tube mostly at least twice as long as the calyx, twisted or not, lobes overlapping to the left and folded inwards; stamens included or less often exserted; ovary superior, composed of 2 carpels variably connate at the base; pistil head not coherent with the anthers. Fruit composed of two mericarps variably united at the base, subglobose to pod-like, many-seeded. Seed obliquely ellipsoid, covered by an aril. Seedling with epigeal germination.

Tabernaemontana flowers and fruits throughout the year, with some species flowering and fruiting simultaneously, particularly in areas without a pronounced dry season. However, some periodicity can be observed. Flowering and fruiting of relatively widespread species vary between regions. Flowering and fruiting of various species within a region is not always synchronized.

Tabernaemontana belongs to the tribe Tabernaemontaneae of the subfamily Plumerioideae. It is closely related to the Old World genus Voacanga and the New World genus Stemmadenia. Tabernaemontana has been further divided into 7 sections, of which the following are represented in Malesia: section Ervatamia (e.g. Tabernaemontana corymbosa, Tabernaemontana divaricata, Tabernaemontana pandacaqui, Tabernaemontana pauciflora), section Pagiantha (e.g. Tabernaemontana macrocarpa, Tabernaemontana sphaerocarpa) and section Rejoua (Tabernaemontana aurantiaca). Sinking Tabernaemontana orientalis R.Br. in the synonymy of Tabernaemontana pandacaqui is disputed by some authors on the basis of morphological characters of leaves and stamens and habitat preferences, the species being allopatric on the local scale. Tabernaemontana orientalis in Australia is found in habitats near the sea, whereas Tabernaemontana pandacaqui is found on volcanic soils away from the sea.

Tabernaemontana species can be found in a wide range of habitats from relatively open scrub vegetation to forest understorey, from dry limestone outcrops to periodically inundated riverine and swamp forest, ranging from sea-level to 1800 m altitude.

Tabernaemontana is usually propagated by seed. Double-flowered forms and desired cultivars are propagated by semi-ripe cuttings during the growth season or by layering before the new growth starts.

Tabernaemontana divaricata and Tabernaemontana pandacaqui are widely cultivated as ornamentals. They are grown outdoors in frost-free climates, in borders or informal hedges. They may also be grown in large pots or tubs as conservatory plants, moved outdoors for the summer. They prefer full sun or light shade and a well-drained but moisture retentive, high-fertility, loam-based mix. Grown as pot plants, they should be repotted and pruned when necessary to restrict size, before the new growth starts, cutting back flowered stems by about one half.

Aphids, scale insects and mealybug may be pests in pot plants of Tabernaemontana.

Roots of Tabernaemontana are dug up, bark is stripped from the trunk, fruits are collected when ripe and leaves are harvested whenever the need arises. Latex can be obtained by tapping the trunk or by crushing the leaves.

Although the alkaloid composition of Tabernaemontana dichotoma from different localities is fairly constant,the percentage of the alkaloids may vary.

Double-flowered Tabernaemontana divaricata is sometimes traded as cv. 'Flore Pleno', double-flowered and large-leaved plants as cv. 'Grandifolia'.

Many of the alkaloids of Tabernaemontana display various interesting pharmacological effects, which may explain the actions of crude extracts, or even of the simplicia themselves. Some alkaloids or even the plants themselves have been tested in a clinical setting (e.g. voacamine), but in general more informaton is needed, especially on toxicology and/or long term effects of these compounds to evaluate their potential in medicine. Some compounds e.g. the ones with chemotherapeutic activity might be of interest as lead compounds in drug research.

Goh, S.H., Chuah, C.H., Mok, J.S.L. & Soepadmo, E., 1994. Malaysian medicinal plants for treatment of cardiovascular diseases. Institute of Advance Studies, University of Malaya, Kuala Lumpur, Malaysia. pp. 103—104.
Kuo, Y.C., Sun, C.M., Tsai, W.J., Ou, J.C., Chen, W.P. & Lin, C.Y., 1999. Blocking of cell proliferation, cytokines production and genes expression following administration of Chinese herbs in the human mesangial cells. Life Sciences 64(23): 2089—2099.
Leeuwenberg, A.J.M., 1991. A revision of Tabernaemontana I. The Old World species. Royal Botanic Gardens, Kew, United Kingdom. 223 pp.
Taesotikul, T., 1997. Tabernaemontana pandacaqui Poir., a traditional Thai medicinal plant: pharmacological activities and alkaloid contents. PhD thesis, State University Leiden, the Netherlands. 139 pp.
Van Beek, T.A., Deelder, A.M., Verpoorte, R. & Baerheim Svendsen, A., 1984. Antimicrobial, antiamoebic and antiviral screening of some Tabernaemontana species. Planta Medica 50(2): 180—185.
Van Beek, T.A., Verpoorte, R., Baerheim Svendsen, A., Leeuwenberg, A.J.M. & Bisset, N.G., 1984. Tabernaemontana L. (Apocynaceae): a review of its taxonomy, phytochemistry, ethnobotany and pharmacology. Journal of Ethnopharmacology 10: 1—156.

L.S.L. Chua & S.F.A.J. Horsten

Tabernaemontana aurantiaca
Tabernaemontana corymbosa
Tabernaemontana dichotoma
Tabernaemontana divaricata
Tabernaemontana macrocarpa
Tabernaemontana pandacaqui
Tabernaemontana pauciflora
Tabernaemontana peduncularis
Tabernaemontana rostrata
Tabernaemontana sphaerocarpa

Chua, L.S.L & Horsten, S.F.A.J., 2001. Tabernaemontana L.. 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:
Tabernaemontana aurantiaca
Tabernaemontana corymbosa
Tabernaemontana dichotoma
Tabernaemontana divaricata
Tabernaemontana macrocarpa
Tabernaemontana pandacaqui
Tabernaemontana pauciflora
Tabernaemontana peduncularis
Tabernaemontana rostrata
Tabernaemontana sphaerocarpa