A Review of the Ethnobotany and Pharmacological Importance of Alstonia boonei De Wild (Apocynaceae)

Alstonia boonei De Wild is a herbal medicinal plant of West African origin, popularly known as God's tree or “Onyame dua”. Within West Africa, it is considered as sacred in some forest communities; consequently the plant parts are not eaten. The plant parts have been traditionally used for its antimalarial, aphrodisiac, antidiabetic, antimicrobial, and antipyretic activities, which have also been proved scientifically. The plant parts are rich in various bioactive compounds such as echitamidine, Nα-formylechitamidine, boonein, loganin, lupeol, ursolic acid, and β-amyrin among which the alkaloids and triterpenoids form a major portion. The present paper aims at investigating the main research undertaken on the plant in order to provide sufficient baseline information for future work and for commercial exploitation.


Introduction
Many cultures throughout the world still rely on indigenous medicinal plants for their primary health care needs [1]. To date, 25% of modern medicines are derived from plants that have been used by traditional medical practitioners [2]. It is a fact that traditional systems of medicine have become a topic of global importance. Although modern medicine may be available in many developed countries, people are still turning to alternative or complementary therapies including medicinal herbs. Yet, few plant species that provide medicinal herbs have been scientifically evaluated for their possible medical applications. The safety and efficacy data are available for even fewer herbs, their extracts and active ingredients and the preparation containing them. Tropical and subtropical Africa contains between 40-45,000 species of plant with a potential for development and out of which 5,000 species are used medicinally [3]. Still there is a paradox, in spite of this huge potential and diversity, the African continent has only contributed 83 of the 1100 classic drugs globally [3]. African countries are at a stage where traditional medicine is considered more for its capacity to generate other medicine than for its own sake. In many cases research undertakings and the commercial use stemming from that research have always relied on information provided by the local communities and, in many instances, have hardly benefited from the research results [4]. In Africa, traditional healers and remedies made from plants play an important role in the health of millions of people. The relative ratios of traditional practitioners and university-trained doctors in relation to the whole population in African countries are revealing. In Ghana, for example, in the Kwahu district, there are 224 people for every traditional practitioner, compared to nearly 21,000 people for one university-trained doctor [4].
Typically, studies on the medicinal plants such as Alstonia boonei have focused on the bioactivity of its chemical constituents, ethnobotany, pharmacology, and taxonomy. However, a comprehensive or systematic review on the plant is lacking. Furthermore, in much of the older literature concerning West Africa, the name Alstonia congensis has been erroneously used for Alstonia boonei. Consequently, this paper synthesizes studies on Alstonia boonei ( Figure 1). This is necessary to recapitulate the findings on the plant and thereby provide a comprehensive and current repository for references on the plant.   parts of the plant are very useful but the thick bark cut from the matured tree is the part that is most commonly used for therapeutic purposes.The bark of the tree is highly effective when it is used in its fresh form; however, the dried one could equally be used. Therapeutically, the bark has been found to possess antirheumatic [7], anti-inflammatory [7], analgesic/pain-killing, antimalaria/antipyretic, antidiabetic (mild hypoglycaemic), antihelminthic, antimicrobial and antibiotic properties [8][9][10]. A decoction could be sweetened with pure honey and be taken up to 4 times daily as an effective painkiller for the following conditions. Painful menstruation (dysmenorrhoea), when associated with uterine fibroid or ovarian cysts in women; lower abdominal and pelvic congestion associated with gynaecological problems such as pelvic inflammatory diseases; to relieve the painful urethritis common with gonococcus or other microbial infections in men. Alstonia decoction also exerts a mild antibacterial effect in this case, relieving the aches and pains associated with malaria fever. Alstonia is taken in the form of preparations that exhibits antipyrexia and anti-malaria effects, to combat rheumatic and arthritic pains. The decoction of Alstonia bark could be taken alone as an effective pain-killing agent. A cold infusion made from the fresh or dried bark of Alstonia taken orally two to three times daily exerts a mild hypoglycaemic effect on diabetic patients. The cold infusion is also administered orally for the purpose of expelling round worms, threadworms [7], and other intestinal parasites in children.

Classification, Cultivation, and Ethnobotanical Uses of Alstonia
The fresh bark of Alstonia could be used in preparing herbal tinctures; it is particularly useful as an effective antidote against snake, rat, or scorpion poison. It is also useful in expelling retained products of conception and afterbirth when given to women. Asthma can be treated with a drink prepared from parts of Trema orientalis and decoction of the bark of Alstonia boonei mixed with the roots and bark of cola and fruits of Xylopia parviflora with hard potash [7]. The bark decoction of Alstonia boonei is used with other preparations in the treatment of fractures or dislocation [7], jaundice, and for inducing breast milk. Its latex is taken as a purgative. The hardened latex is used for the treatment of yaws. Alstonia boonei De Wild is regarded as one of few herbs with potential anti-HIV indicators. In some African countries Alstonia boonei is considered a sacred tree and worshiped in the forest and hence human beings in those countries do not eat its parts.
The structure of N-formylechitamidine (3) is as shown in Scheme 3.
Iridoids isolated from Alstonia boonei include boonein and loganin. Loganin  Boonein (5) is a C-9 monoterpenoid α-lactone, isolated from the bark of A. boonei (Apocynaceae). The structure was established by chemical and spectroscopic methods and by X-ray analysis. Its structure is as shown in Scheme 5. It is a possible precursor in the indole alkaloid biogenesis [49].
Lupeol is also known as (3β)-Lup-20(29)-en-3-ol, monogynol B, β-viscol, or fagarasterol. Its structure is as shown in Scheme 6. It has a melting point of 215 • C and a molecular weight of 426.73 with a molecular formular of C 30  For example, five compounds, which are triterpenes and sterols, were isolated from the hexane fraction of the alcohol extract of the leaves of Alstonia scholaris R. Br. The compounds are identified as 4α,14α,24-trimethyl-9β,19-cyclo-5α-cholest-24(29)-en-3β-ol, stigmasterol, betulin, betulinic acid, and α-amyrin acetate [50]. The structures of the isolated compounds were principally deduced by physiological and chromatographic characters as well as by spectroscopic analyses. The isolated compounds were reported for the first time.

Pharmacological Properties
Triterpene compounds (R1 = H, C ≥ 10 fatty acid acyl) are useful as anti-inflammatory and antiarthritic agents [73]. α-Amyrin acetate isolated from petroleum ether extract of Alstonia boonei root bark was hydrolyzed with NaOH to αamyrin followed by esterification with palmitoyl chloride to obtain α-amyrin palmitate (9). Rats were injected with 150 μL of complete Freund's adjuvant containing 10mg/mL Mycobacterium tuberculosis in the right hind footpad. Its structure is as shown in Scheme 9. From days 11-19 rats were fed orally with 56 mg I/kg in 1 mL of water. Regression analysis of the rate of the ankle diameter change from days 11-19, postadjuvant injection showed that the diameter of the ankle decreased by 31% in treated animals.
In a similar research work, the triterpenes-α-amyrin acetate, β-amyrin acetate, β-amyrin, and lupeol acetate isolated from the petroleum ether extract of Alstonia boonei De Wild, root barks were tested for their anti-inflammatory effects in CFA-induced arthritic rats [74]. When administered orally daily from days 11 to 19 after adjuvant, lupeol acetate and β-amyrin acetate were most effective in preventing further increases in ankle adjuvant swelling. All triterpenes abrogated the increases in WBC count, increased liver and/or kidney weights but only α-amyrin acetate significantly increased serum GOT levels. In the presence of β-amyrin, there was significant neutrophil degeneration. Triterpenes of Astonia boonei root barks were shown to be antiarthritic but the effects on liver and kidney weights raised the possibility of toxicity in antiarthritic therapy.
In another development, lupeol acetate isolated from the petroleum ether fraction of Alstonia boonei root barks was tested for its anti-arthritic effect in CFA-induced arthritic rats [75]. It was administered orally every 48 hrs (66 mg/kg body wt.) from days 32 to 40 after adjuvant and assessed on day 60. Lupeol acetate was able to return the increase in spleen weight and the reduction in serum alkyl phosphatase to nonarthritic control values.
The anti-inflammatory triterpenoids are also inhibitors of serine proteases [56]. The lupane triterpenoid lupeol, the ursane triterpenoid alpha-amyrin, and esters of these compounds present in the bark of roots of Alstonia boonei (Apocynaceae) have anti-inflammatory properties. Alpha-Amyrin is a competitive inhibitor of bovine trypsin and chymotrypsin (Ki values 29 microM and 18 microM, resp.). Lupeol linoleate, lupeol palmitate, and alpha-amyrin linoleate are noncompetitive inhibitors of trypsin (Ki values 7 microM, 10 microM, and 16 microM, resp.). Alphaamyrin linoleate is also a non-competitive inhibitor of chymotrypsin (Ki value 28 microM). Lupeol is a competitive inhibitor of both trypsin and chymotrypsin (Ki values 22 and 8 microM, resp.). Alpha-amyrin palmitate is a potent non-competitive inhibitor of chymotrypsin (Ki 6 microM). Lupeol, alpha-amyrin, and the palmitic and linoleic acid esters of these compounds are ineffective or very weak as inhibitors of porcine pancreatic elastase and of Lucilia cuprina and Helicoverpa punctigera leucine aminopeptidases. These hydrophobic triterpenoids represent further examples of anti-inflammatory triterpenoids that are PKA inhibitors as well as being selective protease inhibitors. When the methanol extract of the stem bark of Alstonia boonei was investigated for anti-inflammatory, analgesic, and antipyretic properties [76], it was found out that the extract caused a significant (P < 0.05) inhibition of the carrageenan-induced paw oedema, cotton pellet granuloma, and exhibited an anti-arthritic activity in rats. Vascular permeability induced by acetic acid in the peritoneum of mice was also inhibited. The extract also produced marked analgesic activity by reduction of writhing induced by acetic acid, as well as the early and late phases of paw licking in mice. A significant (P < 0.05) reduction in hyperpyrexia in mice was also produced by the extract. This study has established anti-inflammatory, analgesic, and antipyretic activities of the stem bark of Alstonia boonei.
The anti-inflammatory activity of a Ghanaian antiarthritic herbal preparation was also investigated [76]. The herbal preparation is made of a boiling water extract from a powdered sample containing Alstonia boonei root bark (90%), Rauvolfia vomitoria root bark (5%), and Elaeis guineensis nut without pericarp (5%). The herbal preparation was tested intraperitoneally for its anti-inflammatory activity by measuring rat hind paw oedema induced by the subplantar injection of carrageenin in the presence or absence of arachidonic acid. Arachidonic acid increased swelling during the early phase of carrageenin oedema. The extract suppressed the late phase of carrageenin oedema and both phases in the presence of arachidonic acid. These preliminary results are consistent with a herbal preparation known to be used in the management of rheumatoid arthritis [77].
The extract was again tested for its anti-inflammatory activity by measuring over a period of 17 days the changes in rat ankle diameter caused by subplantar injection of complete Freund's adjuvant [76]. The extract fed in drinking water ad libitum reduced ipsilateral ankle adjuvant swelling by an average of 16% for the period of +4 to +17 days and improved weight gain.
α-Amyrin palmitate, present in the Ghanaian antiarthritic herbal preparation of Alstonia boonei, Elates guineensis, and Rauvolfia vomitoria, was synthesized and tested on complete Freund's adjuvant-induced arthritic rats [57]. Administered orally at 56 mg/kg body wt (BW) daily for 8 days from days 11 to 18 after adjuvant (acute) or at 66 mg/kg BW every 48 hours for 5 days from days 32 to 40 (chronic), the drug returned the increases in serum hyaluronate and blood granulocytes towards nonarthritic levels and correct the moderate anemia of adjuvant arthritis. Histological examinations of the proximal interphalangeal foot joints showed reduced synovial proliferation and invasion of joints and reduced leukocyte infiltration of bone marrow and periarticular tissue in treated rats. The results suggest that α-amyrin palmitate contributes to the previously shown antiarthritic effect of the herbal preparation.
Odeku [78] reported the anti-malarial property of the stem bark of Alstonia boonei, which could be formulated in tablet form. Odugbemi et al. [79] studied the anti-malarial activities of Alstonia boonei. Other important pharmacological properties of the plant are shown in Table 1.

Toxicology, Contaminants, and Side Effects
Modern synthetic medicines have undergone various levels of experiments for safety and efficacy unlike some herbal preparations. Large proportion of public assumes that herbal remedies or complementary and alternative medicine (CAM) are inherently safe because it is natural. It is important to remember that the majority of powerful chemicals found in plant, which can be used to treat human diseases, have evolved to serve different purposes in the plant itself. For instance, the chemical is being used to protect the plant from insects. These natural insecticides will soon poison the bugs. In sufficient high doses, it can harm human too. The World Health Assembly has highlighted the need to develop herbal pharmacopoeias and to develop and apply scientific criteria and methods for proof of safety and efficacy of medicinal plant products. However, only few countries have developed national herbal pharmacopoeias; limited plant species that provide medicinal herbs have been scientifically evaluated for their possible medical applications; the safety and efficacy data are available for even fewer herbs. Without well-documented information on the safety, efficacy, and phytochemical characteristics of different compounds, it is difficult for external buyers to assess the likely utility or value of some new raw materials and extracts of African origin. In order to address these lacunae, the Association of African Medicinal Plants Standards is developing an African Herbal Pharmacopeia with trading standards which provide information and technical data on some 50 important medicinal plants.

Conclusion
Notwithstanding the potential pharmacological benefits of Alstonia boonei in particular and medicinal plants in general, herbal pharmacopeia are largely lacking. The main problem facing the use of traditional medicines is the proof requirement that the active components contained in medicinal plants are useful, safe, and effective. This is required to assure the medical field and the public regarding the use of medicinal plants as drug alternatives. The proofs of pharmacology activity that are available at present are mostly based on empirical experience. The scientific proof then becomes the most important thing, in order to eliminate the concern of using medicinal plants as drugs for alternative treatment. This study attempted to synthesize work on Alstonia boonei De Wild, a medicinal plant used in African alternative medicine for its anti-malarial, aphrodisiac, anti-diabetic, antimicrobial, and antipyretic activities. This study shows the potential of the plant that research on dose-dependent safety, side effects. and toxicological issues regarding the use of the plant in alternative medicine are essentially lacking; the situation might limit widespread commercial adoption.