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Ethnobotany & Ethnopharmacology of Tabernaemontana Divaricata

August 26, 2008

By Pratchayasakul, Wasana Pongchaidecha, Anchalee; Chattipakorn, Nipon; Chattipakorn, Siriporn

Tabernaemontana divaricata a common garden plant in tropical countries has been used as a traditional medicine. However, no recent review articles of T. divaricata, particularly discussing its pharmacological properties, are available. This review presents the ethnobotany and ethnopharmacology of T. divaricata as well as its potential therapeutic benefits especially of the alkaloidal and non- alkaloidal constituents. Included, are the characteristics of 66 alkaloids isolated and identified from T. divaricata. Non-alkaloids including the enzymes, pyrolytic oil, hydrocarbons, terpenoid and phenolic acids are also documented. Chemotaxonomic aspects of each alkaloid as well as information regarding the pharmacology of crude extracts and individual alkaloids from T. divaricata have been assembled and appraised. The beneficial properties of T. divaricata are antioxidant, anti-infection, anti-tumour action, analgesia and the enhancement of cholinergic activity in both peripheral and central nervous systems. The augmentation of cholinergic function may be of therapeutic benefit for many neurodegenerative diseases, particularly myasthenia gravis and Alzheimer’s disease. Key words Alkaloids – non-alkaloids – pharmacological properties – Tabernaemontana divaricata

Introduction

Plants are well known as a major source of modem medicines. From ancient times, humans have utilized plants for the treatment or prevention of diseases, leading to the dawn of traditional medicine. Tabernaemontana is one of the genera that is used in Chinese, Ayurvedic and Thai traditional medicine for the treatment of fever, pain and dysentery12. Tabernaemontana plants are widely distributed in Thailand. Species found in Thailand are T. bufalina, T. crispa, T. divaricata, T. pandacaqui, T. pauciflora and T. rostrata3’5. One of the most interesting species is Tabernaemontana divaricata (L.) R. Br. Ex Roem. & Schult. (synonym: Ervatamia coronaria, Ervatamia microphylla, Ervatamia divaricata, T. coronaria). Growing evidence suggests that this plant has medicinal benefits and its extracts could possibly be used as pharmacological interventions in various diseases. In this review, information regarding ethnobotany, ethnopharmacology and therapeutic benefits of T. divaricata is discussed.

Description and taxonomy of T. divaricata

T. divaricata belongs to the Apocynaceae family, Plumeroidae subfamily, Tabermontanae tribe and Tabernaemontana genus. The genus was named after the birthplace of its discoverer, J. Th. Mueller, Bergzabern, and Bergzabern was latinized into Tabernaemontana. The basionym of T. divaricata is T. siamensis6 . Its homotypic synonym is Ervatamia siamensis7. The holotypes of T. divaricata are L, M and W7. The generic synonym, Ervatamia, is widely distributed in tropical countries as a garden plant, which usually has sweet- scented double flowers2. Approximately 100 species of this genus are widely distributed in tropical parts of the world, including Brazil, Egypt, India, Sri Lanka, Vietnam, Malaysia and Thailand. T. divaricata was first described by Linnaeus in 1753(2). The complete taxonomy of T. divaricata is shown in Fig.1 according to Leeuwenberg3. T. divaricata has four typical characteristics including: (i) evergreen shrub forms shaped like symmetrical mounds 6-feet high, (ii) horizontal branches having the appearance of an attractive, almost horizontal shrub (the species name, divaricata, means an obtuse angle), (iii) large, shiny, deep green leaves, 6 or more inches in length and 2 inches wide, and (iv) waxy blossoms with white, five-petal pinwheels, gathered in small clusters on the stem tips.

Phytochemistry of T. divaricata

T. divaricata has been used in traditional medicine and for other purposes. The phytochemistry and a number of chemical constituents from the leaves, stems, and roots have been reported previously. Constituents studied include alkaloids8-36, and non-alkaloid constituents such as terpenoids29,37-40, steroids37,41, flavonoids42, phenyl propanoids41,42, phenolic acids16 and enzymes43,44. Since 1974, 66 different alkaloids of T. divaricata have been identified. The phytochemical data for each alkaloid provide information about its biosynthesis. Such information can assist in the search for new, medically interesting compounds that may be useful against diseases.

Alkaloids of T. divaricata: According to van Beek et al2 alkaloids of T. divaricata are arranged in 11 main classes: Vincosan, Corynanthean, Vallesiachotaman, Strychnan, Aspidospermatan, Plumeran, Eburan, Ibogan, Tacaman, Bis-indole and Miscellaneous. The details of structure in each class and subdivision are shown in Tables I and II.

At least 66 alkaloids were extracted from T. divaricata by several methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and gas chromatography- mass spectrophotometry (GC-MS). Table III summarizes the currently known alkaloids isolated from T. divaricata in alphabetical order, together with their alkaloid subdivision, molecular weight, formula, plant part in which they occur and country of origin. Fig. 2 illustrates all chemical structures of alkaloids from T. divaricata.

Non-alkaloids of T. divaricata: Although most of the phytochemical work on T. divaricata has been concerned with the alkaloidal constituents, and most of the ethnomedical uses are probably related to the pharmacological activity of these substances, some nonalkaloidal constituents such as terpenoids, steroids, enzymes, and hydrocarbons have also been isolated from T. divaricata. Terpenoid-indole alkaloids are formally derived from a unit of tryptamine, obtained by decarboxylation of tryptophan catalyzed by the enzyme tryptophan decarboxylase (TDC), and a C^sub 10^ unit of ferpenoid origin (secologanin). The stereospecific condensation of these two units is catalyzed by the enzyme strictosidine synthase (SSS) as shown in Fig. 32. The biosynthesis and metabolism of terpenoid is involved with many enzymes. Several studies demonstrated about the role of those enzymes that regulate biosynthesis and metabolism of terpenoids in T. divaricata2. For example, Pennings & Verpoorte50 detected the enzyme anthranilate synthase from T. divaricata cell cultures by HPLC assay. Fulton and colleagues51 also demonstrated five known enzymes that were detected for the first time in T. divaricata cellsuspension culture: isopentenyl diphosphate isomerase, prenyl transferase, squalene synthetase, qualene 2,3-oxide cycloartenol cyclase and squalene 2,3- oxide cyclase. These enzymes act as key regulatory agents in controlling the flux of carbon into the cytosolic-microsomal pathway of terpenoid synthesis. Dagnino and colleagues52 found five enzymes from T. divaricata cell lines including tryptophan decarboxylase, strictosidine synthase, strictosidine glucosidase, isopentenyl pyrophosphate isomerase and geraniol 10-hydroxylase. It has also been suggested that these five enzymes relate to the biosynthesis of terpenoid indole alkaloids of T. divaricata. In addition, the enzyme strictosidine alpha-D-glucosidase was partially purified from cell suspension cultures of T. divaricata53. Another non-alkaloidal enzyme, squalene synthase, was also partially purified from a membrane-rich fraction obtained from cell suspension cultures of T. divaricata54. Ramas-Valdivia and colleagues55 discovered the enzyme farnesyl diphosphate synthase from T. divaricata cultured cells by chromatography and Western blotting assay.

Many plant species produce a wide range of chemical products that are not involved in primary metabolism and called secondary metabolites56. secondary metabolites are metabolic intermediates or products found as differential products in restricted taxonomic groups and are not essential to the growth and life of the producing organism. They are biosynthesized from one or more primary metabolites by a wider variety of pathways than those available in primary metabolism57. Alkaloid and terpenoids are main secondary metabolites that have many physiological and pharmacological properties to living cells56. However, their biosynthesis are normally restricted to certain developmental stages of the organism58. Some of those biosynthesis are the phase-dependent formation for some enzymes58. Therefore, the expression of secondary metabolites is based on the process of plants’ differentiation. Thus, it is not surprising that the synthesis of secondary metabolites does not occur in the meristematic cells of intact plants59. Moreover, some studies suggested that cell cultures of plants could produce secondary metabolites when they stopped being meristematic and rather acquired a certain degree of biochemical modification and maturation56. Therefore, several studies used cell cultures techniques to investigate the biosynthesis and metabolism of these secondary metabolites13,14,60,61.

Other non alkaloidal constituents, investigated by Mandai and Mukherji62, saw discovery of free radicalscavenging enzymes such as superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase and phenolic peroxidase in T. divaricata from roadside plants in India. Their discoveries indicated that T. divaricata was a very good scavenging system to combat the effects of air pollution. Other non alkaloidal compounds in T. divaricata such as pyrolytic oil, solid char, amino acid and hydrocarbon were also found to have some beneficial effects. Sharma and Prasad63 showed that the stems and leaves of Indian T. divaricata have pyrolytic oil and solid char that can be converted into petroleum and ethanol, which can be exploited to produce gasohol fuel. Behera and colleagues64 also demonstrated that the hexane extract from old leaves, roots, flowers and stems of T. divaricata was rich in hydrocarbons. Rastogi and colleagues29 isolated eight non alkaloid compounds from the root bark of T. divaricata such as alpha-amyrin acetate, lupeol acetate, ce-amyrin lupeol, cycloartenol, beta- sitosterol, campesterol, benzoic acid and aurantiamide acetate. Their compounds are terpenoids and phenolic acid, and plant metabolites, which exhibit pharmacological properties such as anti- inflammatory and anti-oxidant activity in vitro65. A summary of the non alkaloids extracted from T. divaricata is shown in Table IV. Pharmacological properties of T. divaricata

Both in vivo and in vitro pharmacological properties of T. divaricata have previously been investigated. The first direction was to investigate the pharmacological properties of T. divaricata by using crude ethanol extracts or crude alkaloid fractions. The second direction was to identify pharmacological effects of pure alkaloid compounds isolated from T. divaricata or biologically active alkaloids of T. divaricata. The details of pharmacological properties of T. divaricata are summarized in the following paragraphs.

Pharmacological properties of T. divaricata crude extracts or crude alkaloid fractions

Role of T. divaricata in anti-infection and antiinflammation – The most common medicinal use of crude T. divaricata extract involves its antimicrobial action against infectious diseases such as syphilis, leprosy, and gonorrhoea, as well as its antiparasitic action against worms, dysentery, diarrhoea, and malaria2.

The anti-inflammatory effect of T. divaricata was studied in carageenin-induced paw oedema in rats66’69. In this model, male rats were injected with 0.1 ml of carageenin into one of the hind paws. The T. divaricata extracts (150-200 mg/kg) were administrated either orally or intra-peritoneally 1 h prior to the sub-plantar injection of carageenin. Oedema measurements were made using a modified plethymograph 1, 2 and 4 h after carageenin injection. This study demonstrated that T. divaricata extracts had significant anti- inflammatory effect on carageenin-induced paw oedema compared to animals without T. divaricata administration and that this anti- inflammatory effect of T. divaricata was dose dependent16. The anti- inflammatory mechanism of T. divaricata is thought to be due to the presence of phenolic acid, a chemical agent that has a potential antiinflammatory benefit42.

Role of T. divaricata in anti-tumour effects: Immunoglobulin A nephropathy (IgA-N) is the most common pattern of glomerulonephritis (GN). Fifteen to twenty five per cent of GN patients develop endstage renal disease, typically through a slow progression of renal insufficiency over 10 yr or more70. The characteristic of histological renal lesion of IgAN is a tumour of mesangial cell proliferative GN. Causes of IgA-N may involve the activation of mesangial cells in the kidney by the deposition of IgA immune complexes. The activation of those cells stimulates the secretion of immunomodulatory factors from inflammatory cells in the circulation, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha)71,72. These factors have been shown to increase the volume of extracellular matrix and activate mesangial cell proliferation in the kidney. Both changes are characteristics of nephritis. Therefore, the suppression of mesangial cell proliferation may have a therapeutic benefit in the treatment of nephropathy. Kuo and colleagues73 investigated the effect of crude methanol extract from 15 Chinese herbs on human mesangial cell proliferation in an in vitro study. Their results indicated that T. divaricata, one of the 15 herbs, could suppress mesangial cell proliferation via the reduction of IL-1, IL-6 and TNF- alpha expression. These findings suggest that T. divaricata could have benefits as an anti-tumour drug in IgA-N.

Anti-oxidative effects of T. divaricata: The anti-oxidative effects of T. divaricata have been studied by various investigators using the carbon tetrachloride (CCl^sub 4^)-induced hepatotoxicity model62,74. The hepatotoxicity is due to the metabolite of CCl^sub 4^, a free radical that causes the peroxidation of lipids in the endoplasmic reticulum that leads to cell death75. Gupta et al74 found, in an in vivo study, that methanol extract from leaves of T. divaricata produced a significant hepatoprotective effect by decreasing lipid peroxidation and significantly increasing the level of anti-oxidant agents such as glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in a dose dependent manner.

Furthermore, Mandal and Mukherji62 demonstrated that T. divaricata is a very good scavenging system to combat the effects of air pollution. Their results demonstrated that T. divaricata plants in nature have high levels of activity of anti-oxidant agents such as SOD, CAT, GSH, ascorbate peroxidase and phenolic peroxidase.

Analgesic effects of T. divaricata: Roots of T. divaricata have reportedly been used in folk medicine for their analgesic properties. The study of Henriques and colleagues16 confirmed the anti-nociceptive effect of T. divaricata. They demonstrated that mice treated with 150 mg/kg of T. divaricata extract either orally or intraperitoneally 30 min before being placed on a heated plate (50-55[degrees]C), had significantly greater response times to the heat stimulus than the control group without T. divaricata treatment. However, the mechanisms underlying this analgesic effect have not been verified.

Neuropharmacological activities of T. divaricata’. Hippocratic or behaviour screening in an in vivo study of ethanol extract from T. divaricata was studied by Taesotikul and colleague76. The hippocratic screening test is commonly used in the preliminary screening test of medicinal plants to detect interesting pharmacological activities. According to their screening studies, the ethanol extract of T. divaricata was found to cause dose- related decreased motor activity, ataxia, loss of righting reflex, decreased respiratory rate and loss of screen grip. These effects indicated that T. divaricata has depressive effects on the central nervous system (CNS). In addition, the loss of screen grip and decreased muscle tone in the rat model following T. divaricata administration suggest that T. divaricata may act as a skeletal muscle relaxant. Their findings in the animals suggest that T. divaricata has depressive effects on both peripheral and central nervous systems.

In contrast, Ingkaninan et al77 reported that the roots and stems of T. divaricata have been used in Thai traditional medicine as components of rejuvenating and neurotonic remedies. It is believed that these remedies can prevent forgetfulness and improve memory as well as being a CNS stimulant. However, there was no scientific evidence to support this belief, until a in vitro study demonstrated that ethanol extracts from T. divaricata root at a concentration of 0.1 mg/ml inhibit more than 90 per cent of acetylcholinesterase (AChE) activity72. Our recent study also demonstrated that T. divaricata administration in various doses can significantly decrease neuronal AChE activity in the cerebral cortex78. Our data showed that the percentages of AChE inhibition in the cortex at 2 h after T. divaricata administration at 250, 500 and 1,000 mg/kg was 11, 18 and 12 per cent, respectively. These results suggest that T. divaricata has inhibitory effects on neuronal AChE activity in animal models. Therefore, T. divaricata may be a new therapeutic target for Alzheimer’s disease. Moreover, T. australis has also shown AChE inhibiting activity in vitro71,79.

Pharmacological properties of T. divaricata alkaloids

12-hydroxy akuammicine (2): In an in vivo study, a concentration of 1 mg/kg of 12-hydroxy akuammicine(2), administered intravenously, caused an increase in frequency or tone of the rabbit uterus75. In mice and rats, the intraperitoneal administration of 12-hydroxy akuammicine(2), at a concentration of 5-15 mg/ kg/day for 9-20 days, inhibited the growth of ascites and alveolar lymphoma2. In addition, 12-hydroxy akuammicine(2) had gonadotropic activity via follicular stimulation2. These findings suggest that this alkaloid of T. divaricata may play roles in both gonadotropic and anti-tumour effects.

19, 20 dihydrotabernamine (3) and 19,20 dihydroervahanine A (4): The 19, 20 dihydrotabernamine(3) and 19,20-dihydroervahanine A (4) are alkaloids found in the roots of T. divaricata. They can inhibit acetylcholinesterase (AChE) activity in vitro47. The inhibitory effect of both alkaloids was proved to be specific, reversible and competitive. In addition, the compounds showed greater inhibitory activity on AChE than galanthamine, a well known acetylcholinesterase inhibitor47.

Apparicine (18): An in vitro study demonstrated that apparicine(18) at the concentration of 250 [mu]g/ml can inhibit the activity of Polio III virus79,80. This alkaloid at a concentration of 1.2 per cent also exhibited antimicrobial activity against Shigella, Salmonella, Pseudomonas, Escherichia, Proteus, Staphylococcus and Corynebacterium in an in vitro study81. Moreover, apparicine(18), as shown in an in vitro study, acts as an opioid agonist to opioid receptors82.

Catharanthine (19): In an in vitro study by Ehrlich of ascite tumour cells, a convenient biological model for the investigation of tumour cells83, catharanthine( 19) inhibited the effect of alpha – aminoisobutyric acid, an amino acid transporter in tumour cells. This finding suggested that catharanthine( 19) could have anti- tumour properties via inhibition of tumour cell proliferation84. In addition, catharanthine( 19) has been shown to inhibit the calcium- calmodulin-stimulated activity of brain cyclic adenosine monophosphate (cAMP) phosphodiesterase in an in vitro study, which resulted in an increased intracellular level of cAMP85 . The increased intracellular level of cAMP in neurons may lead to improved neuronal activity86. Conophylline (27): Conophylline (27) is a vinca alkaloid from T. divaricata. It has been shown to induce differentiation of pancreatic precursor cells86. In the rat pancreatic rudiment of organ culture, Conophylline (27) inhibited the formation of cystic structure and increased the number of insulin-positive cells86. In addition, conophylline (27) has also been shown to induce insulin production in rat pancreatic acinar carcinoma cells87. Conophylline (27) is effective in reversing the condition of hyperglycaemia in neonatal streptozotocin-treated rats87. Both the insulin content and the beta cell mass are increased by the administration of conophylline (27) in these animal models. The histological study demonstrated that conophylline (27) increased the numbers of ductal cells positive for pancreaticduodenal-homeobox protein-1 and islet-like cell clusters88. Therefore, conophylline (27) induced pancreatic beta cells differentiated both in vivo and in vitro. Conophylline (27) has recently been employed as a health food for preventing and ameliorating diabetes and obesity. It is used for lowering blood glucose level88 and, also, it is a new anti-tumour alkaloid89-92. A study showed that conophylline (27) inhibited both TNFalpha-induced activations and phosphorylation as well as degrading of I-kB-alpha in human T-cell leukaemia cells88. In addition, conophylline (27) inhibited TGF-beta-induced apoptosis in rat hepatoma cells. The conophylline (27) inhibition of TGF-beta-induced promoter activity could be attributed to its potency in modulating the interaction of downstream transcriptional factors via up-regulation of c-Jun expression89. Conophylline(27) also inhibited expression on tumour cell adhesion and infiltration in the human endometrial cancer cell line91. The effect of conophylline (27) on the growth properties of K-rasNRK cells was investigated both in vitro and in vivo. Conophylline (27) induced reversible flattening and almost complete growth inhibition of K-ras-NRK and K-ras-NIH3T3 cell lines, and lowered the increased uptake of 2-deoxyglucose. It inhibited the growth of K-ras-NRK and K-ras-NIH3T3 tumours transplanted in nude mice at a concentration of 0.01-0.5 and 0.0010.1 mg/mouse, respectively92.

Coronaridine (29): Coronaridine (29) is an alkaloid found in the leaves, stems, barks and roots of T. divaricata. It has been demonstrated as having an effect on autonomie and central nervous system activity2. The administration of Coronaridine (29) produced an analgesic effect on noxious stimulation and was effective in suppressing rage caused by foot shock in an animal model93. Taesotikul and colleagues94 also demonstrated that Coronaridine (29) has both analgesic and anti-inflammatory activities in rats in the writhing and pain response to tail immersion in hot water as well as in the carageenin-induced paw edema test in mice. An intravenous injection of Coronaridine (29) has been shown to cause dose-related hypotensive and bradycardial responses in a normal rat model95,96. Moreover, it has been shown, in an in vitro study, to decrease estrogenic activity and could lead to the antifertility action of T. divaricata95. An in vivo study reported by Mehrotra and Kamboj97 demonstrated that this alkaloid did not have any effect on reproductive activity, except for partial inhibition of oxytocin- induced uterine response. Recently, coronaridine (29) has also been shown to have a significant AChE inhibitory activity, at the same concentration, of the physostigmine and galantamine (AChE inhibitors) in an in vitro study79.

Dregamine (31): Dregamine (31) can be found in the leaves, stems, bark and roots of T. divaricate. Dregamine (31 ) has been shown to have convulsive and respiratory stimulating effects97. It inhibited muscular fatigue in both in vitro and in vivo studies, similar to the activity of ibogaine97. Dregamine (31) has been used for the treatment of muscular and nervous asthenia and respiratory depression97.

Ibogamine (36): Ibogamine (36) is an indole alkaloid found in the roots of T. divaricata. It has been shown to reduce the monosynaptic knee-jerk reflex in the cat when a 2 mg/kg concentration of ibogamine (36) was administered intraperitonealy. The mechanism of this action affected neither postsynaptic reflex arcs nor neuromuscular transmission30, but possibly had effect via blockade of nicotinic receptors at the neuromuscular junction98. In addition, ibogamine (36) could act as a weak anticonvulsant agent, as demonstrated in a mouse model99. More recently, the indole alkaloid ibogamine (36) was explored as an agent that combats the symptoms of drug withdrawal100-102. Additionally, preclinical studies of ibogamine (36) in rodent models of cocaine and opiate self- administration support the notion that it is an anti-addictive agent103-109. Ibogamine (36) has been reported to effectively reduce drug cravings, withdrawal symptoms110, and their tremorigenic, hallucinogenic, neurotoxic and cardiovascular side effects in addicts111. The predominant action mechanism of ibogamine (36) as an anti-addictive agent possibly occurs via blocking of the kappa opioid receptors, N-methyl-D-asparate (NMDA) receptors, the serotonin uptake sites and nicotinic receptors107.

Isovoacangine (37): Isovoacangine (37) has been shown to have a high affinity for pacemaker tissue in the regulation of the heart112. Isovoacangine (37) has been demonstrated to cause a negative chronotropic activity on the spontaneously beating isolated guinea pig atrium and a negative inotropic activity on the electrically driven isolated guinea pig left atrium.

Isovoacristine (38): When this alkaloid was tested on the isolated guinea pig ileum, both anti-cholinergic and antihistaminic activities were observed113. In addition, it has been shown that rabbit skeletal muscle was relaxed when this alkaloid was applied. This was due to the anti-cholinergic mechanism. Isovoacristine (38) hydrochloride also caused a negative chronotropic effect in both frog and rabbit models113. This effect on the heart has been thought to occur via the anti-cholinergic activity of this alkaloid.

Tabernaemontanine (52): Tabernaemontanine (52) is an alkaloid found in the leaves, stems, bark and roots of T. divaricata. Tabernaemontanine (52) has been shown to have a vasodilatory effect in dogs2. It is used to dilate the blood vessels in humans following cases of arteriosclerosis, cerebral trauma and circulatory irregularities2.

Voacamine (55): Voacamine (55) is an alkaloid found in the leaves, stems, bark and roots of T. divaricata. Voacamine (55) has been shown to have cardiotonic effects and use as a treatment of heart conditions2,114. This alkaloid has a positive inotropic effect without chronotropic effect on the heart. In addition, voacamine (55) demonstrated a strong antimicrobial activity against Gram- positive bacteria such as Bacillus subtilis and Staphylococus aureus, and moderate activity against Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa2.

Voacangine (56): Voacangine (56) is an alkaloid found in the leaves, stems, bark and roots of T. divaricata. Voacangine (56) potentiated the hypnotic effects of barbiturates and had an analgesic as well as a local anesthetic activity in a mouse model115. Voacangine (56) had negative chronotropic and inotropic activities on the spontaneously beating isolated guinea pig atrium and the electrically driven isolated guinea pig left atrium112. In another study with isolated guinea pig atria, it antagonized the positive chronotropic and inotropic effects of noradrenaline on the heart116. In contrast, one study showed that voacangine (56) had no effect on the heart rate114. The discrepancy of results obtained from these studies suggests that further investigation is required to determine the effect of voacangine (56) on the heart, as well as determine its definite pharmacological properties. Voacangine (56) was also shown to have an AChE inhibitory effect in vitro79, which may explain the variation in heart beat in previous studies.

Voacristine (58): In general pharmacological screening tests, voacristine (58) exhibited a weak stimulating effect on the central nervous system. For example, head-shaking behaviour in mice occurred when this compound was administrated2. Moreover, this alkaloid has been shown to cause a negative chronotropic effect in rats112.

Vobasine (66): Vobasine (66) is an alkaloid found in the leaves, stems, bark and roots of T. divaricata. In the hippocratic screening test, the administration of vobasine (66) at 300 mg/kg into mice caused lacrimation, mydriasis, respiratory depression and a depression of central nervous system activity117.

Since at least 66 alkaloids have been isolated from this species and the yield of alkaloid fraction obtained from dry stems of T. divaricata was at least 0.98 per cent16, it is these alkaloidal activities that possibly justify its use in traditional medicines. The alkaloidal components of T. divaricata could play important roles in these pharmacological activities of T. divaricata extracts as summarized in Table V and VI. The most interesting is its effect on cholinergic activity. This effect may be the basis for the traditional use of T. divaricata in cardiovascular and nervous systems. According to previous studies, several alkaloids in T. divaricata enhance cholinergic activity94,118. However, the alkaloid, isovoacristine, acts as an anti-cholinergic agent. Therefore, further investigations into each alkaloid from T. divaricata should be greatly beneficial for human medicine. Other Tabernaemontana species in Thailand: Tabernaemontana pandacaqui (T. pandacaqui) and its pharmacological activities

In addition to T. divaricata, T. pandacaqui is another species commonly grown in the northern part of Thailand and used as traditional medicine for treatment of fever and pain4. Its synonyms are Ervatamia pandacaqui and Ervatamia angustisepala. T. pandacaqui is known in Thailand as ‘Phut’. The characteristics of T. pandacaqui are similar to those of T. divaricata in that their flowers are numerous, white, with a slender tube and five spreading lobes. However, the flowers of T. pandacaqui are smaller than those of T. divaricata4. From the crude alkaloid fraction of the T. pandacaqui stem, at least 24 indole alkaloids can be isolated. Among these alkaloids, coronaridine is the main alkaloid found in T. pandacaqui. Since these alkaloids are similar to those isolated from T. divaricata, their pharmacological activity might be the same. It has been demonstrated that the extract of T. pandacaqui could cause dose- related decreased motor activity, ataxia, and loss of righting reflex, decreased respiratory rate, analgesia and hyperemia of the ear76. These effects were generally similar to those obtained from the extract of T. divaricata. However, at the same dose, the intensity of the pharmacological activity caused by T. pandacaqui was stronger than that observed with T. divaricata. Other interesting properties of T. pandacaqui extracts include hypotensive and negative chronotropic and inotropic effects observed in a rat model95. They further indicated that hypotensive and bradycardia responses to T. pandacaqui administration might involve cholinergic and central mechanisms118. In Thai folk medicine, the root of T. pandacaqui is boiled in water and used for the treatment of pain and inflammation. Taesotikul and colleagues94,118 studied the effect of T. pandacaqui administration on carrageenin-induced rat paw odema, yeast-induced hyperthermia in rats and writhing response induced by acetic acid in mice. Their results demonstrated that the alcoholic extract of T. pandacaqui stems has significant anti-inflammatory, anti-pyretic and anti-nociceptive activities. The opioid active compounds isolated from the leaves of T. pandacaqui support their analgesic effect17. Furthermore, it is possible that the analgesic activities of T. pandacaqui in traditional use are due to the activity of its other alkaloids such as voacangine and coronaridine115, both of which are also found in T. divaricata.

Toxicity of T. divaricata

Since T. divaricata has a number of pharmacological activities, further toxicological studies were necessary. Henriques and colleagues16 investigated the toxicity of T. divaricata using the behaviour screening test in mice treated with alcoholic or aqueous extracts of T. divaricata at doses of 150-200 mg/kg. They reported that the results were indistinguishable from control animals, indicating that no toxicity was found at these concentrations. On the other hand, Melo and colleagues119 demonstrated that voacristine, one of the major alkaloids of T. divaricata, presented dose-dependent cytostatic and cytotoxic effects on cultures of yeast. Since only a few studies have reported the toxicity of T. divaricata, further investigations on its toxicity will be needed to understand its adverse effects.

Conclusions

Tabernaemontana plants have been used in folk medicine for the treatment of high blood pressure, pain and inflammation, as well topical application for healing wounds. T. divaricata exhibit different roles in CNS, cardiovascular, gonadotropic, anti-tumour, anti-infectious and anti-oxidative activity and most recently enhancement of cholinergic activity in the nervous system. Evidence suggests that T. divaricata could possibly be a useful therapeutic agent for several neurodegenerative diseases such as Alzheimer’s disease, vascular dementia and delirium, since the possible cause of these disorders is cholinergic deficiency. The possible cholinergic candidate alkaloids in T. divaricata, are coronaridine, voacangine, isovoacristine, 19, 20 dihydrotabernamine, and 19, 20 dihydroervahanine A . However, further detailed studies of T. divaricata and its alkaloids in vivo are needed to investigate this possibility. There are still many T. divaricata alkaloids and their derivatives, whose pharmacological activities have not yet been investigated. It is possible that they may contain beneficial pharmacological properties. Therefore, in vivo investigations regarding their effects could provide insights into the benefits of T. divaricata for future clinical management of many human diseases.

Acknowledgment

The authors thank Professor M. Kevin O Carroll, Professor Emeritus, University of Mississippi School of Dentistry and Faculty Consultant, Faculty of Dentistry, Chiang Mai University, for editorial assistance during manuscript preparation. This work is supported by the Thailand Research Fund grants TRF-RMU 4880013 to SC, TRF-RMU 4980001 to NC and Faculty of Medicine Endowment Fund, CMU to AP, SC and NC.

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Wasana Pratchayasakul*, Anchalee Pongchaidecha*, Nipon Chattipakorn*& Siriporn Chattipakorn*#

* Cardiac Electrophysiology Research & Training Center, Faculty of Medicine, # Department of Odontology & Oral Pathology, Faculty of Dentistry, Chiang Mai university, Chiang Mai, Thailand

Received May 22, 2006

Reprint requests: Dr Siriporn Chattipakorn. Department of Odontology & Oral Pathology, Faculty of Dentistry.

Chiang Mai University, Chiang Mai, 50200 Thailand

e-mail: s.chat@chiangmai.ac.th

Copyright Indian Council of Medical Research Apr 2008

(c) 2008 Indian Journal of Medical Research. Provided by ProQuest LLC. All rights Reserved.




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