See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/282569178 Medicinal plants of the genus Anthocleista - A review of their ethnobotany, phytochemistry and pharmacology Article in Journal of ethnopharmacology · October 2015 DOI: 10.1016/j.jep.2015.09.032 CITATIONS READS 9 2,954 4 authors: Gabriel OLUWABUNMI Anyanwu Nisar Ur-Rahman Bingham University COMSATS University Islamabad 21 PUBLICATIONS 69 CITATIONS 62 PUBLICATIONS 274 CITATIONS SEE PROFILE SEE PROFILE Eusebius Chukwu Onyeneke Khalid Rauf University of Benin COMSATS University Islamabad, Abbottabad campus 48 PUBLICATIONS 183 CITATIONS 41 PUBLICATIONS 164 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Phytomedicine View project Chromatographic profile of anthocleist vogelii extracts and fractions nd their hypolipidemic effect on triton- induced hyperlipidemia in wistar rats View project All content following this page was uploaded by Gabriel OLUWABUNMI Anyanwu on 08 January 2018. The user has requested enhancement of the downloaded file. Journal of Ethnopharmacology 175 (2015) 648–667 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep Review Medicinal plants of the genus Anthocleista—A review of their ethnobotany, phytochemistry and pharmacology Gabriel O. Anyanwu a,c, Nisar-ur-Rehman a,n, Chukwu E. Onyeneke b, Khalid Rauf a a Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad 22060, K.P.K., Pakistan Department of Biochemistry, University of Benin, Benin City, Edo State, Nigeria c Department of Biochemistry, Bingham University, Karu, Nasarawa State, Nigeria b art ic l e i nf o a b s t r a c t Article history: Received 25 May 2015 Received in revised form 26 September 2015 Accepted 28 September 2015 Ethnopharmacological relevance: The genus Anthocleista of the Gentianaceae family contains 14 species of trees and shrub-like plants distributed in tropical Africa, in Madagascar and on the Comoros. Traditionally, they are commonly used in the treatment of diabetes, hypertension, malaria, typhoid fever, obesity, diarrhea, dysentery, hyperprolactinemia, abdominal pain, ulcer, jaundice, asthma, hemorrhoids, hernia, cancer, wounds, chest pains, inﬂammations, rheumatism, STDs, infertility and skin diseases. They serve as an anthelmintic, laxative, diuretic and contraceptive. This review aims to provide for the ﬁrst time a repository of ethnopharmacological information while critically evaluating the relation between the traditional medicinal uses, chemical constituents and pharmacological activities of the Anthocleista species so as to unveil opportunities for future research. Materials and methods: A search for relevant information on Anthocleista species was performed on scientiﬁc databases (Pubmed, Google Scholar, SciFinder, Web of Science, Scopus, PubChem and other web sources such as The Plant List, Kew Botanical Garden and PROTA) and books, PhD and MSc dissertations for un-published resources. Results: Out of the 14 species of Anthocleista, 6 have been reported in literature to be widely used in traditional medicine for the treatment of various ailments. The six species include: A. djalonensis, A. vogelii, A. nobilis, A. grandiﬂora, A. schweinfurthii, and A. liebrechtsiana. The chemical compounds isolated from Anthocleista species fall into the class of phytochemicals such as secoiridoids, nor-secoiridoids, xanthones, phytosterols, triterpenes, alkaloids, and others of which majority of the compounds were isolated from A. djalonensis and A. vogelii. The in vitro and in vivo pharmacological studies on the crude extracts, fractions and few isolated compounds of Anthocleista species showed antidiabetic, antiplasmodial, antimicrobial, hypotensive, spasmogenic, anti-obesity, antiulcerogenic, analgesic, anti-inﬂammatory, antioxidant, antitrypanosomal, anthelmintic, fertility, diuretic and laxative activities which supports most of their uses in traditional medicine. However, the bulk of the studies where centered on the antidiabetic, antiplasmodial and antimicrobial activities of Anthocleista species, although the evidence of its antiplasmodial effect was not convincing enough due to the discrepancies between the in vitro and in vivo results. Conclusion: A. djalonensis and A. vogelii are potential antidiabetic and antibacterial agents. The antibacterial potency relates to infections or diseases caused by E. coli, S. typhi and S. aureus such as urinary tract infections, typhoid, diarrhea, skin diseases, and food poisoning. Pharmacological research on this genus is quite elementary and limited, thus, more advanced research is necessary to isolate and determine the activities of bioactive compounds in vitro and in vivo, establish their mechanisms of action and commence the process of clinical research. & 2015 Elsevier Ireland Ltd. All rights reserved. Keywords: Anthocleista Gentianaceae Traditional uses Antidiabetic Antiplasmodial Antiobesity Chemical compounds studied in this article: 1-hydroxy-3,7-dimethoxyxanthone (PubChem CID: 5488808) 3-oxo-Δ4′5-sitosterone (PubChem CID: 9801811) 6-ketobauerenone (not found) 7α-hydroxysitosterol (PubChem CID: 161816) anthocleistenolide (not found) anthocleistin (not found) anthocleistol (not found) bauerenol (PubChem CID: 111220) bauerenone (not found) caryophyllene oxide (PubChem CID: 6604672) D-(þ )-bornesitol (PubChem CID: 440078) decussatin (PubChem CID: 5378284) de-O-methyllasiodiplodin (PubChem CID: 14562693) djalonenol (not found) djalonenoside (not found) djalonensin (PubChem CID: 5360741) djalonensone (PubChem CID:5359485) Abbreviations: ACE inhibitors, Angiotensin-converting enzyme inhibitors; ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; ATCC, American Type Culture Collection; ATPase, adenosine triphosphatase; b.w, body weight; CCl4, carbon tetrachloride; COX, cyclooxygenase; DPPH, 2,2-diphenyl-1-picrylhydrazyl; EC50, half maximal effective concentration; ED, effective dose; Hb, hemoglobin; HCD, high carbohydrate diet; HDL-C, high-density lipoprotein cholesterol; IC50, compound inhibition (50% inhibition); LD50, median lethal dose, LDL-C, low-density lipoprotein cholesterol; MCH, mean corpuscular hemoglobin; MDA, Malondialdehyde; MIC, minimum inhibitory concentration; PCV, Packed cell volume; STDs, sexually transmitted diseases; STIs, sexually transmitted infections (STIs); TC, total cholesterol; TG, triglycerides; WBC, white blood cells n Corresponding author. E-mail addresses: email@example.com, firstname.lastname@example.org (G.O. Anyanwu), email@example.com (Nisar-ur-Rehman), firstname.lastname@example.org (C.E. Onyeneke), email@example.com (K. Rauf). http://dx.doi.org/10.1016/j.jep.2015.09.032 0378-8741/& 2015 Elsevier Ireland Ltd. All rights reserved. G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 649 fagaramide (PubChem CID: 5281772) gentianine (PubChem CID: 354616) grandiﬂorol (not found) grandiﬂoroside (not found) hexadecanoic acid (PubChem CID: 985) humulene epoxide II (PubChem CID: 10704181) irlbacholine (PubChem CID: 177983) lichexanthone (PubChem CID: 5358904) lupenone (PubChem CID: 92158) methyl grandiﬂoroside (not found) schweinfurthin (PubChem CID: 643463) scopoletin (PubChem CID: 5280460) secologanin (PubChem CID: 161276) sitosterol (PubChem CID:222284) sitosterol 3-O-β-D-glucopyranoside (PubChem CID: 70699351) stigmasterol (PubChem CID: 5280794) sweroside (PubChem CID:161036) swertiamarin (PubChem CID: 442435) swertiaperennin (PubChem CID: 5281653) ursolic acid (PubChem CID: 64945) vogeloside (not found) α-humulene (PubChem CID: 5281520) β-caryophyllene (PubChem CID: 5281515) Contents 1. 2. 3. 4. 5. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The classiﬁcation, botanical description and distribution of Anthocleista . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnomedicinal uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Antidiabetic activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Antiplasmodial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Antihypertensive and antihypotensive activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Spasmolytic and spasmogenic activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Anti-obesity activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Antiulcerogenic/analgesics, wound healing and anti-inﬂammatory activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.9. Antitrypanosomal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.10. Anthelmintic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.11. Fertility activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.12. Diuretic and laxative activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Toxicity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction The Anthocleista species are trees and shrub-like plants presently in the Gentianaceae family, and formerly of the Loganiaceae family, in the major group Angiosperms. The genus Anthocleista contains about 14 species distributed in tropical Africa, in Madagascar and on the Comoros (Leeuwenberg, 1973, 1992; Leeuwenberg and Leenhouts, 1980; De Wilde, 2011). The tribe Potalieae includes the genera Anthocleista, Fagraea and Potalia. The African genus Anthocleista has 15 species, Fagraea has about 35 species in Southeast Asia, tropical Australia and the Southwest Paciﬁc; and the American genus Potalia is monotypic (Punt, 1978). Although Punt (1978) mentioned that Anthocleista had 15 species, the 14 accepted species in Anthocleista genus include: Anthocleista amplexicaulis Baker, Anthocleista djalonensis A. Chev., Anthocleista grandiﬂora Gilg, 649 650 650 654 654 654 657 657 660 661 661 662 662 663 663 663 663 663 664 665 665 Anthocleista laxiﬂora Baker, Anthocleista liebrechtsiana De Wild. & T. Durand, Anthocleista longifolia (Lam.) Boiteau, Anthocleista madagascariensis Baker, Anthocleista microphylla Wernham, Anthocleista nobilis G. Don, Anthocleista obanensis Wernham, Anthocleista procera Lepr. ex Bureau, Anthocleista scandens Hook.f., Anthocleista schweinfurthii Gilg, and Anthocleista vogelii Planch (http://www.theplantlist.org/). Anthocleista are generally called “cabbage tree” in English language. This is because the stem of some species are unbranched or branched only at the top with huge leaves clustered at the end of the shoot (Keay, 1989). A large proportion of the names used to describe Anthocleista species seemed to be within the areas or regions of the country in which they are found. For example, in the Ijebu land of the western part of Nigeria, Anthocleista spp is called Sapo sapo (Richards, 1939; Ross, 1954). The Hausas (Northern Nigeria) call it ‘Kwari’ (quiver), the Yorubas (Western Nigeria) call it 650 G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 ‘Apa oro’ (Keay Onochie et al., 1964) or sapo and the Ibos (Eastern Nigeria) call it ‘Mpoto’ (Anyanwu et al., 2013). The local name for A. vogelii in Cameroon is Kewanten (Neba, 2006). Also, it is called Ekoka ngowa (Bakweri) in the Southwest and Littoral region of Cameroun (Jiofack et al., 2010). It is commonly known as ‘AwudifoAkete’ (murderer’s mat) by the Ashante people in Ghana (Irvine, 1961). Anthocleista has conservative and other traditional uses besides its medicinal uses. They are a source of food for animals in the forest, such as birds (turacos), ruminants and primates (gorillas and chimpanzees) (Gautier-Hion et al., 1980; Dubost, 1984; Calvert, 1985; Basabose, 2002; Babalola et al., 2012). As a tree with rough and coarse bark, Anthocleista is a preferred host for some epiphytes in a tropical semideciduous forest of Ghana (Addo‐Fordjour et al., 2009), thereby providing support for this epiphytes which are food and habitats for many of the animals inhabiting the rainforest canopies. According to Burkill (1985c), the wood-ash of A. vogelii is used in making dyes, stains, inks, tattoos and mordants; the wood is used in carpentry and related applications; the trunk and branches are used in farming, forestry, hunting and ﬁshing apparatus; the leaf is used in the production of tobacco, snuff, abrasives, cleaners, etc. The traditional medicinal uses of Anthocleista is in the treatment of stomach ache, fever, constipation, inﬂammatory diseases, diabetes, wounds, etc. (Dalziel, 1955; Ateufack et al., 2014). The use of medical plants is still popular today because they are considered safe, less expensive, easily available and effective. The social and economic statuses of the people are no barrier to their patronage of herbal medicines in different parts of the world, and most especially in developing nations. This review aims to provide for the ﬁrst time a repository of ethnopharmacological information while critically evaluating the relation between the traditional medicinal uses, chemical constituents and pharmacological activities of the Anthocleista species so as to unveil opportunities for future research. 2. The classiﬁcation, botanical description and distribution of Anthocleista The tribe Potalieae is divided into three subtribes: Faroinae, Lisianthiinae, and Potaliinae. The last subtribe, Potaliinae (composed of Fagraea, Anthocleista, and Potalia), was formerly circumscribed as tribe Potalieae within the family Loganiaceae (Leeuwenberg and Leenhouts, 1980; Struwe et al., 1994). The Potaliinae are aberrant in Gentianaceae in having ﬂeshy berries and a preponderance of large trees (Struwe et al., 2002). This controversy on the family of Anthocleista either in the Loganiaceae or Gentianaceae has been on for decades in the past. Bremer et al. (1994) and Struwe et al. (1994) had provided further evidence that the hypothesis that Loganiaceae sensu Leeuwenberg and Leenhouts (1980) are a paraphyletic assemblage with members showing closest relationships to other families both within and outside of the Gentianales as reported (Meszaros et al., 1996). As far as Gentianaceae is concerned, Struwe et al. (1994) main conclusion is to formally include Potalia Aubl., Fagraea Thunb. and Anthocleista Afzel. ex R. Br. (tribe Potalieae of Loganiaceae sensu Leeuwenberg and Leenhouts, 1980) in the Gentianaceae. This transfer had already been proposed by Bureau (1856), then by Fosberg et al. (1980) on the basis of gross morphology and later by Jensen (1992) on the basis of the presence of advanced iridoid glucosides as reported (Meszaros et al., 1996). Anthocleista is presently under the Gentianaceae family but its afﬁnities were previously considered to be with the Loganiaceae (Leeuwenberg, 1992). The phytochemical, morphological and molecular data of Anthocleista supports its transfer to the Gentianaceae (Jensen, 1992; Meszaros et al., 1996; Backlund et al., 2000). Therefore, the suitable classiﬁcation of the genus Anthocleista is the family Gentianaceae of the order Gentianales. Generally, Anthocleista is a genus of trees, 6–20 m high or more, trunk 15–55 cm diameter, twigs with spines; leaves opposite, extremely large (up to 150 45 cm2), sessile or very shortly petiolate; lamina dark green and often glossy above; inﬂorescence terminal, dichasial or otherwise, large, much-branched; sepals 4, circular or broader than long. Corolla white (or creamy), actinomorphic, thick, ﬂeshy; lobes 8–16, contorted in bud; ovary is superior and fruit a berry (Bruce, 1955; Leeuwenberg, 1983; De Wilde 2011; Hyde et al., 2015). However, there are few disparities among the species as observed in their morphology (Punt and Nienhuis, 1976; Punt, 1978; Molina and Struwe, 2009; EdwinWosu et al., 2015), phylogenetics (Albach et al., 2001) chemotaxonomy (Jensen and Schripsema, 2002; Sonibare et al., 2007); and chemical compounds (Jensen et al., 1975; Jensen, 1992). Anthocleista species are present in tropical Africa, from Sierra Leone in the west to Uganda in the north and to Angola in the south (Leeuwenberg, 1983) including Zambia, and Kenya in the East. Anthocleista species are found in lowland forest and/or aquatic ecosystem. They are perennial trees with marked preference for tropical climates and prevalent in lowland secondary rainforests. Anthocleista species are common seral plants on abandoned farmland in the forest regions of tropical Africa (Keay, 1959). A. djalonensis and A. nobilis show preference for both normal terrestrial (low land dry rainforest) and wetland (seasonally ﬂooded) environments. A. vogelii shows a preference for normal terrestrial habitat while A. liebrechtsiana prefers wetland or semi aquatic habitats (Edwin-Wosu et al., 2015). A. grandiﬂora are riparian in habitat (Dowsett-Lemaire, 2008). There is little information about the cultivation of Anthocleista species, as the plants in this genus are not cultivated plants. However, A. vogelii has been reported to be grown by traditional medicine practitioners in Osun State, Nigeria (Alade et al., 2011). Aside for its medicinal beneﬁts, the reasons for cultivation of the plant might not exactly be known as the authors did not specify; however, it might not be far from one or all of the reasons mentioned in the study, which included: easily cultivated, frequently used, very costly/scarce in the market, easily perishable and plants that must be used fresh (Alade et al., 2011). 3. Ethnomedicinal uses Out of the 14 species of Anthocleista, 6 have been reported in literature to be widely used in traditional medicine for the treatment of various ailments. The six species include: A. djalonensis, A. vogelii, A. nobilis, A. grandiﬂora, A. schweinfurthii, and A. liebrechtsiana. They are commonly used for treating constipation, malaria fever, typhoid fever, hypertension, stomach aches, hemorrhoids, syphilis, diabetes, and used as a contraceptive, laxative and purgative (Kadiri, 2009; Musa et al., 2010; Olubomehin et al., 2013). The use of the bark and root of A. vogelii, A. nobilis and A. schweinfurthii as purgative and antidote for snake bite; the barksap for ear and eye treatments; and the bark and root in the healing of dropsy, swellings, edema, gout and venereal diseases have been documented (Burkill, 1985a, b and c). A. vogelii is widely used by traditional medicine practitioners either singly or in combination with other plant materials to treat several diseases or ailments in humans, including infertility problems both in male and female (Oladimeji Igbalaye, Coleshowers 2014). Many young women in Nigeria use A. vogelii and in combination with other plants as contraceptives usually preferred after sexual intercourse and before pregnancy (Kadiri, 2009). Root Table 1 Ethnomedicinal uses of Anthocleista species. Scientiﬁc name Country Plant part used Disease condition Preparation form/ Ethnomedicinal receipe Reference Metabolic disorders A. djalonensis Bheino modyo (P) Sapo (Y) Sapo (Y) Assoubobissaou (K) Guinea Nigeria Nigeria Togo Diabetes Diabetes diabetes diabetes Decoction Maceration with ﬁve other plants ni Decoction or powder, administrated by oral or anal rout Diallo et al. (2012) Soladoye et al. (2012) Olowokudejo et al. (2008) Tchacondo et al. (2012) A. vogelii Diabetes Mellitus Decoction A. nobilis A. vogelii Sapo (Y), Kwari (H), Awudifo-Akete (As) Ekoka ngowa (Bk) Mpoto (I) Konibou Kankan (M); Artaninﬁro (M) uko nkirisi (I) Nigeria, Ghana Root Bark Bark, Leaves Roots, the stem bark, and the leaves Root Cameroun Nigeria Guinea Stem bark, Leaves Root bark Stem bark Diabetes Obesity Diabetes Decoction Maceration Decoction Ampofo, (1977), Abuh et al. (1990) and Soladoye et al. (2012) Jiofack et al. (2010) Anyanwu et al. (2013) Diallo et al. (2012) Nigeria Root bark Diabetes Mellitus Decoction Madubunyi et al. (1994) Ezenukpogan (B) Nigeria Leaves and root Hypertension Sapo (Y) Nigeria Roots Hypertension Assoubobissaou (K) Togo Benin rope (B) Kwari (H) Nigeria Roots, the stem bark, Hypertension and the leaves Stem Hypertension Decoction of the grounded leaves and root with little Gbolade (2012) water and heat; one spoon taken trice daily Maceration in combination C. Pilosa, S. Londepedunculata Olorunnisola et al. (2015) and N. Latifolia/ 1tea spoon 3times daily Decoction or powder, administrated by oral or anal rout Tchacondo et al. (2012) Diuretic and purgative A. djalonensis Sapo (Y) A. vogelii ni ni Urugba (Ig) A. liebrechtsiana Sapo (Y) Nigeria Africa region, Cameroun Nigeria Nigeria Nigeria Fertility A. djalonensis Nigeria A. vogelii A. nobilis A. schweinfurthii Ohangbakire (Ig) Ibu (In) Sapo (Y) Sapo (Y) Assoubobissaou (K) Sapo (Y) Sapo (Y) Moukoro (P) Wudifokεtε/ Hohoroho (A) Wudifokεtε/ Hohoroho (A) Abanga'a ni Maceration; soaked in water for 3day; half glass cup daily Gbolade (2012) ni Stem bark antidiuretic, purgative purgative ni ni Bark and stems Root/ stem bark Bark, Leaves Purgative Laxative, purgative Purgative ni Boil and drink ni Lawal et al. (2010) Dalziel, (1955) and Adjanohoun et al. (1986) Ariwaodo et al. (2012) Okorie, (1976) and Igoli et al. (2005) Olowokudejo et al. (2008) Infertility (male) Adjanahoun et al., (1991), Igoli et al. (2005) and Erhabor et al. (2013) Olowokudejo et al. (2008) Soladoye et al. (2014) Tchacondo et al. (2012) Decoction ni Steeping Decoction Sharaibi et al. (2014) Omobuwajo et al. (2008) Akoué et al. (2013) Diame (2010) Ghana Bark Decoction Diame (2010) Cameroon, Gabon, Equatorial Guinea Congo Bark Impotence Female infertility female infertility and male infertility Hyperprolactinemia Menstrual Dysfunction Sexual dysfunction Protrusion retention during pregnancy Abdominal pains during pregnancy; menstrual disorders Ovarian problems A concoction of the three plants is taken once daily. Decoction of roots and leaves ni ni Decoction or powder, administrated by oral or anal rout Nigeria Nigeria Gabon Ghana Leaves, Roots and leaves Bark, Leaves Bark Roots, the stem bark, and the leaves Bark Leaf Root Bark; leaf Decoction Bark female infertility Decoction Kerharo, (1974) and Christophe et al. (2015) Schmelzer (2008), Bouquet (1972) Christophe et al. (2015) Nigeria Nigeria Togo G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 Hypertension A. djalonensis Local name (ethnic) 651 652 Table 1 (continued ) Scientiﬁc name Contraceptive A. vogelii A. nobilis Malaria A. djalonensis A. vogelii A. nobilis A. schweinfurthii Country Plant part used Disease condition Preparation form/ Ethnomedicinal receipe Reference ni Wudifokεtε/Hohoroho (A) Nigeria Ghana Roots Bark/leaf Contraceptive Contraceptive Maceration with three other plants Decoction Kadiri et al. (2009) Diame (2010) ni Samatlo (Br) Mbabaigana (KL) Nigeria Mali Côte-d’Ivoire Nigeria Nigeria Guinea Ghana Côte d'Ivoire Guinea Southern Africa South Africa Tanzania Malaria Malaria Malaria Malaria fever malaria malaria Malaria Malaria Malaria Malaria Malaria Malaria ni Decoction (leaves) or Maceration (roots) Decoction Decoctions with ﬁve other plants Decoction Decoction Decoction Body smeared with mashed bark Decoction Decoctions Decoction Decoction Ajibesin et al. (2008) Diarra et al. (2015) Zirihi et al. (2010) Okorie, (1976) and Igoli et al. (2005) Madubunyi et al. (1994) Baldé et al. (2015) Asase and Oppong-Mensah(2009) Malan et al. (2015) Traore et al. (2013) Palmer and Pitman (1972) Bapela et al. (2014) Nondo et al. (2015) ni Tanzania Leaves, stem bark Leaves, roots Stem bark Leaves/ stem bark Root bark Root Stem bark and root Bark Stem bark Bark Stem bark and leaves Leaves, stem bark and roots Root Bark and leaves Malaria Decoction N.Transvaal Bark Malaria Decoction Kerharo (1974), Burkill (1995), Fowler (2006), and Christophe et al. (2015) Fowler (2006) Nigeria Roots diarrheoa, dysentery Decoction Stem bark ni Bark Stem bark Gastro-intestinal disorders, stomach ache, abdominal pains Ulcer Stomach aches Decoction Decoction Urugba (Ig) uko nkirisi (I) ni Odeefuor kete (S) ni Bomon (G) ni Stomach disorders A. djalonensis ni Akubue et al. (1983), and Nweze and Ngongeh (2007) Dalziel (1955) and Adjanohoun et al. (1986) Odukoya et al. (2012) Etonde and Ekwalla (1997), Kerharo (1974) and Christophe et al. (2015) Adongo et al. (2012) A. vogelii ni A. nobilis A. schweinfurthii A. grandiﬂora Epo sapo (Y) Bopolopolo (D) Africa region, Cameroun Nigeria Cameroon Murigurigu (C) Kenya Stem bark ameba ni Anthelmintic conditions A. djalonensis Nigeria Roots Worms Decoction A. A. A. A. Cameroun Nigeria Kenya Tanzania ni Root bark Stem bark Root Bark and leaves Intestinal worms gastrointestinal worms worms worms ni Decoction ni Decoction Nigeria Togo STDs syphilis ni Kayode et al. (2004) Decoction or powder, administrated by oral or anal rout Tchacondo et al. (2012) STDs Gonorrhea Syphilis Syphilis/gonorrhea Jiofack et al. (2010) Omobuwajo et al. (2008) Okorie (1976) and Igoli et al. (2005) Kerharo, (1974) and Christophe et al. vogelii nobilis grandiﬂora schweinfurthii ni uko nkirisi (I) Murigurigu (C) ni Sexually transmitted diseases A. djalonensis Sapo (Y) Assoubobissaou (K) A. vogelii A. nobilis A. Ekoka ngowa (Bk) Sapo (Y) Urugba (Ig) Cameroun Nigeria Nigeria Root Roots, the stem bark, and the leaves Stem bark, Leaves Leaf Root Root Sapo (Y) Sapo (Y) Wudifokεtε/ Hohoroho (A) Abanga'a Nigeria Nigeria Stem Root Gonorrhea STIs STDs (Gonorrhea) Decoction ni Scrape and squeeze or macerate inner root bark, add salt and take. ni ni Decoction Cameroon, Gabon, Bark venereal disease Decoction Akubue et al. (1983), and Nweze and Ngongeh (2007) Dibong et al. (2011) Madubunyi et al. (1994) Adongo et al. (2012) Kerharo (1974), Burkill, (1995), Fowler (2006) and Christophe et al. (2015) Olukoya et al. (1993) Gbadamosi (2014) Diame (2010) G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 A. grandiﬂora Local name (ethnic) schweinfurthii Equatorial Guinea Pain, wounds and inﬂammations A. djalonensis Sapo (Y) Sapo (Y) A. vogelii A. nobilis A. grandiﬂora A. schweinfurthii Bark, Leaves Stem bark antipyretic Asthma ni Cold infusion with 8 other plants/ two tablespoon daily Cameroun Nigeria Guinea Nigeria Côte d'Ivoire Kenya Tanzania Stem bark, Leaves Leaves Root Bark Root Stem bark Bark and leaves Wounds, Inﬂammations Wounds Inﬂammatory diseases Wounds Rheumatism Chest pains wound healing Decoction Applied as poultice on swellings and to cleanse wound Decoction Hot infusion Topical application with crushed roots ni Decoction Nigeria Nigeria Ghana Leaves Root Bark/leaf Typhoid fever Throat problems Candidiasis/white Decoction ni Decoction Musa et al. (2010) Omobuwajo et al. (2008) Diame (2010) Nigeria Kenya Cameroon, Gabon, Equatorial Guinea Congo Tanzania Bark, Leaves Stem bark Bark antimicrobial cold bronchitis Ni ni Decoction Stem bark Bark and leaves Mycosis Fever Crushing Decoction Olowokudejo et al. (2008) Adongo et al. (2012) Kerharo (1974) and Christophe et al. (2015) Ngbolua et al. (2014a) Kerharo (1974), Burkill (1995), Fowler (2006) and Christophe et al. (2015) Sapo (Y) Sapo (Y) Nigeria Nigeria Bark, Leaves Bark, Leaves Skin diseases – rashes and eczema ni Skin infection Ni Olowokudejo et al. (2008) Olowokudejo et al. (2008) Sapo (Y) uko nkirisi (I) Nigeria Nigeria ni Root bark Jaundice Jaundice, liver protecting effects Lawal et al. (2010) Madubunyi et al. (1994) Assoubobissaou (K) Togo Decoction or powder, administrated by oral or anal rout Tchacondo et al. (2012) Sapo (Y) Wudifokεtε/Hohoroho (A) Nigeria Ghana Roots, the stem bark, hemorrhoids and the leaves Bark Hemorrhoid Leaves Hemorrhoids, piles Assoubobissaou (K) Togo Decoction or powder, administrated by oral or anal rout Tchacondo et al. (2012) Wudifokεtε/ Hohoroho (A) ni Ghana Roots, the stem bark, Hernia and the leaves Leaves hernia Infusion/decoction Diame (2010) Congo Bark Hernia Decoction Schmelzer (2008), Bouquet (1972) and Christophe et al. (2015) Sapo (Y) Nigeria Leaves Cancer Decoction Soladoye et al. (2010b) Ekoka ngowa (Bk) Odogwu (Ia) ni Epo sapo (Y) ni Murigurigu (C) ni Hemorrhoids A. djalonensis A. nobilis Hernia A. djalonensis A. nobilis A. schweinfurthii Cancer A. nobilis ni Decoction Decoction and maceration Infusion/Decoction Olowokudejo et al. (2008) Borokini et al., (2013), and Sonibare and Gbile (2008) Jiofack et al. (2010) Musa et al. (2010) Baldé et al. (2015) Odukoya et al. (2012) Malan et al. (2015) Adongo et al. (2012) Kerharo, (1974), Burkill (1995), Fowler (2006) and Christophe et al. (2015) Soladoye et al. (2010a) Diame (2010) G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 Nigeria Nigeria Microbial infections A. vogelii Odogwu (Ia) Sapo (Y) A. nobilis Wudifokεtε/ Hohoroho (A) A. liebrechtsiana Sapo (Y) A. grandiﬂora Murigurigu (C) A. schweinAbanga'a furthii Mpuku mpuku (Kg) ni Skin diseases A. djalonensis A. liebrechtsiana Jaundice A. djalonensis A. nobilis (2015) A: Akan; As: Ashante; B: Benin; Bk: Bakweri; Br: Bambara; C: Chuka; D: Douala; G: Guerzé; H: Hausa; I: Igbo; Ia: Igala; Ig: Igede; In: Ifa Nkari; K: Kotokoli; Kg: Kikongo; KL: Kagera and Lindi regions; M: Maninka; P: Pular; P: Pygmy; S: Southern Ghana; T: Tumu Fang; Y: Yoruba; ni: not indicated. 653 654 G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 decoctions of A. djalonensis, A. vogelii and A. kerstingii are used in Nigeria and Ghana by herbalists for the treatment of diabetes mellitus (Ampofo, 1977). A summary of the ethnomedicinal uses of Anthocleista species with their local names and methods of preparation are presented in Table 1. 4. Chemical constituents Previous studies on Anthocleista showed the presence of alkaloids, xanthones, secoiridoids, terpenes, and phthalides (Irvine, 1961; Chapelle, 1976). Important phytochemicals such as saponins, ﬂavonoids, terpenoids, alkaloids, and steroids are present in the leaf, stem–bark and root bark of A. vogelii (Jegede et al., 2011; Anyanwu et al., 2013; Gboeloh et al., 2014; Ngbolua et al., 2014c). Reducing sugar, tannin, phlobatanins, glycosides were found to be absent in both the leaf and the stem bark of the Anthocleista species (Njayou et al., 2008; Jegede et al., 2011; Oladimeji Igbalaye, Coleshowers, 2014), however, tannins are present in the root bark (Anyanwu et al., 2013) and anthraquinones in the leaves (Oladimeji Igbalaye, Coleshowers, 2014). It has been reported that complex indole alkaloids appear to be absent in Anthocleista, while secoiridoids and alkaloids derived from these during the isolation procedure are present (Jensen, 1992). The secoiridoids found in Anthocleista are typical of those found in Gentianaceae species, namely sweroside (1) and swertiamarin (2). Secoiridoid glycosides are responsible for the bitter taste of the species. A compilation of the chemical compounds isolated from Anthocleista species, their structures and class of phytochemicals which include; secoiridoids, nor-secoiridoids, xanthones, phytosterols, triterpenes, alkaloids, and others is found in Fig. 1. The presence of tetraoxygenated xanthones and the secoiridiod glycosides, sweroside (1) and vogeloside, have been reported in the leaves and roots of A. vogelii (Chapelle, 1976). Sweroside has revealed signiﬁcant anti-inﬂammatory activity (Baba and Usifoh, 2011). Tene et al. (2008) was the ﬁrst to report the isolation and structural elucidation of a rearranged nor-secoiridoid, anthocleistenolide from the stem bark of A. vogelii. Other chemical compounds isolated from A. vogelii include: secologanin (3), decussatin (4), swertiaperennin (6), 1-hydroxy-3,7-dimethoxyxanthone (7), 7α-hydroxysitosterol (8), stigmasterol (9), hexadecanoic acid (10), sitosterol 3-O-β-D-glucopyranoside (11), fagaramide (18) and triterpenes (Chapelle, 1974; Okorie, 1976; Kojima et al., 1990; Guerriero et al., 1993; Monte et al., 2001; Valentão et al., 2002; Tene et al., 2008; Alaribe, et al., 2012). Decussatin has demonstrated very weak antiplasmodial activity (Alaribe et al., 2012). Anthocleistenolide has revealed low antibacterial activities against S. aureus and E. faecalis while 1-hydroxy-3,7-dimethoxyxanthone and 1-hydroxy-3,7,8-trimethoxyxanthone showed antifungal activity against Candida parapsilosis (Tene et al., 2008). Bierer et al. (1995) reported the isolation and structure elucidation of the then novel plant metabolite, 1,22-bis[[[2-(trimethylammonium) ethoxy]phosphinyl]oxy]docosane, which they named Irlbacholine (23), from the plant species Irlbachia alata and A. djalonensis. Irlbacholine revealed potent in vitro activity against three pathogenic fungi: C. albicans, C. neoformans, and A. fumigatus (Biere et al. 1995). Ogunwande et al. (2013) pioneering work on the volatile oil contents of A. djalonensis revealed sesquiterpene compounds (82.5%) are the dominant class of the 49 compounds in A. djalonensis, and the main compounds are α-humulene (20), βcaryophyllene (21), humulene epoxide II (22) and caryophyllene oxide (24). A monoterpene diol, djalonenol have been isolated from A. djalonensis and the isolation of dibenzo-α-pyrone, djalonensone (27) from a plant source and it’s structurally elucidation as tetrahydro-3-hydroxy hydroxymethylene-4-(3-hydroxymethylene prop-1-ene)-2H-pyran-2-one was reported for the ﬁrst time (Onocha et al., 1995). The isolation of sweroside (1), djalonenoside, lichexanthone (5), stigmasterol (9), 3-oxo-Δ4′5-sitosterone (12), sitosterol (13), ursolic acid (14), djalonensin (25) and D-(þ)-bornesitol (26) from A. djalonensis have also been reported (Okorie, 1976; Onocha et al., 1995). Two iridoid glucosides, grandiﬂoroside and methyl grandiﬂoroside, one coumarin, scopoletin (27) and the secoiridoid sweroside (1) were found in A. grandiﬂora (Chapelle, 1973, 1976). Some compounds which have been isolated from the stem bark of A. grandiﬂora are grandiﬂorol, bauerenol (15), bauerenone, 6-ketobauerenone; scopoletin (28) and (þ)-de-O-methyllasiodiplodin (29); while lupenone (16) and the iridoid sweroside (1) were additional compounds isolated from the root bark (Mulholland et al., 2005). Within the other species of Anthocleista much work with regards to isolation has not been done. The investigation of the occurrence of secoiridoids in methanol extract of the root bark of A. nobilis by Madubunyi et al. (1994), led to the isolation and identiﬁcation of anthocleistol. The secoiridoid swertiamarin (2) have been isolated from A. liebrechtsiana (Cornelis and Chapelle, 1976) and bauerenone and bauerenol (15) schweinfurthin (19) from the roots of A. schweinfurthii (Mbouangouere et al., 2007). Although no literature was found on the traditional use of A. procera, phytochemical research on the plant revealed the isolation of the secoiridoid swertiamarin (2), the alkaloid gentianine (17) and anthocleistin, a triterpene (Koch et al., 1964; Lavie and Taylor-Smith, 1963; Taylor-Smith, 1965). 5. Pharmacological activities 5.1. Antidiabetic activity In African traditional medicine, the leaves, stems and roots of A. djalonensis, A. vogelii and A. nobilis are prepared as a decoction or macerated in water or alcohol, and the solution is given orally as a treatment for diabetes in Guinea, Nigeria, Togo, Ghana and Cameroun (Ampofo, 1977; Abuh et al.,1990; Madubunyi et al., 1994; Olowokudejo et al., 2008; Jiofack et al., 2010; Diallo et al., 2012; Soladoye et al., 2012; Tchacondo et al., 2012). The hypoglycemic effect of the leaves, stem bark and roots of A. djalonensis and A. vogelii, and roots of A. schweinfurthii has been scientiﬁcally proven by in vitro and in vivo studies (Abuh et al., 1990; Olagunju et al., 1998; Mbouangouere et al., 2007; Okokon et al., 2012; Olubomehin et al., 2013; Osadebe et al., 2014a, 2014b; Sunday et al., 2014). The leaves, stem barks and roots of A. djalonensis and A. vogelii revealed α-amylase inhibitory activity at 1mL of 250 mg/mL concentration of their aqueous methanol extracts (Olubomehin et al., 2013), although, A. djalonensis had the better activity which indicated that it might contain more of the active principles necessary for the management of diabetes. Alpha-glucosidase has been effectively inhibited by schweinfurthin, bauerenone and bauerenol isolated from the dichloromethane/methanol extracts of the roots of A. schweinfurthii (Mbouangouere et al., 2007). The inhibition of α-glucosidase and α-amylase by A. djalonensis, A. vogelii and A. schweinfurthii prevents the digestion of carbohydrates (starch and table sugar), thus serving as potent antidiabetic agents. In the in vivo studies, while Olubomehin et al. (2013) reported hypoglycemic activity of a high dose (1000 mg/kg) of A. djalonensis extracts, Okokon et al. (2012) showed the dose- dependent activity of same plant at lower doses (37 mg/kg, 74 mg/kg and 111 mg/kg). All the doses for other in vivo hypoglycemic studies fell within 37– 1000 mg/kg (Abuh et al., 1990; Olagunju et al., 1998; Osadebe et al., 2014b; Sunday et al., 2014), however, results of the various studies showed that the extracts/fractions of A. djalonensis and A. G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 655 Iridoids and secoiridoids Sweroside (1) Swertiamarin (2) Secologanin (3) Lichexanthone (5) Swertiaperennin (6) Xanthones Decussatin (4) 1-hydroxy-3,7-dimethoxyxanthone (7) Phytosterol 7α-hydroxysitosterol (8) Stigmasterol (9) Hexadecanoic acid (10) Sitosterol 3-O-β-D-glucopyranoside (11) 3-oxo-Δ4'5-sitosterone (12) Sitosterol (13) Fig. 1. Chemical structures and names of compounds reported from Anthocleista species. vogelii produced a dose dependent antidiabetic effect (at 100 mg/ kg p.o minimum dose) which could justify the use of these plants traditionally to manage diabetes. The antidiabetic activity of A. nobilis is yet to be reported despite its traditional use in Guinea (Diallo et al., 2012) and Nigeria (Madubunyi et al., 1994). From the existing antidiabetic studies of A. djalonensis and A. vogelii, the use of solvent fractions of the plants make it is difﬁcult to know which class of phytochemical compounds may be responsible for their antidiabetic effect, except based on polarity. Also, more active compounds should be isolated from the Anthocleista species for the purpose of testing their antidiabetic activity. The mechanisms of action of the extracts/fractions of these plants are not yet known and no study has been done on it. Further research is needed to understand how the 656 G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 Triterpenes Ursolic acid (14) Bauerenol (15) Lupenone (16) Alkaloids Gentianine (17) Steriod Fagaramide (18) Schweinfurthin (19) Volatile oil contents α-humulene (20) Plant metabolite Irlbacholine (24) β-caryophyllene (21) Humulene epoxide II (22) Caryophyllene oxide (23) Phthalide Oligosaccharide Djalonensin (25) D-( + )-bornesitol (26) dibenzo-α-pyrone Coumarin Polyketides Djalonensone (27) Scopoletin (28) de-O-methyllasiodiplodin (29) Fig. 1. (continued) plants exert their blood glucose lowering activities; either by increasing the amount of insulin secreted by the pancreas, increasing the sensitivity of target organs to insulin, and/or decreasing the rate at which glucose is absorbed from the gastrointestinal tract. So basically research on diabetes for this species is still at its crude form. G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 5.2. Antiplasmodial activity Malaria is a major health problem in Africa caused by Plasmodium species transmitted by mosquitos. The Anthocleista species are used to treat malaria in countries like Nigeria, Mali, Côte-d’Ivoire, Guinea, South Africa and Tanzania, of which the mode of preparation is decoction/maceration and administered orally (Table 1), except in Côte-d’Ivoire where the bark of A. nobilis is mashed and smeared on the body (Malan et al., 2015). Both in vitro and in vivo antiplasmodial studies have been carried out on Anthocleista. While the in vivo results were positive, the in vitro results were negative or not impressive among the species. In two different in vitro studies by Zirihi et al. (2005) and Zirihi et al. (2010), A. djalonensis was inactive against Plasmodium falciparum in culture with IC50 value 450 μg/mL at a concentration of 10 mg/mL. Similarly, Bapela et al. (2014) reported that 10 mg/mL of dichloromethane and methanol extracts of A. grandiﬂora showed no in vitro antiplasmodial activity (IC50 450 μg/mL). Again, among the 31 plants tested for in vitro antiplasmodial activity by Nondo et al. (2015), ethanol extracts of A. grandiﬂora at 100 μg/mL was among the least active with growth inhibition rate of less than 30% against chloroquine-resistant Plasmodium falciparum Dd2 strains. The in vitro antiplasmodial studies on the species seems inadequate as most where not dose dependent, variation of extraction solvents from nonpolar to polar, and the laboratory techniques were not exhaustive. No in vitro antiplasmodial studies were found to be reported on A. vogelii and A. nobilis. As in Table 2, the different plant parts of A. djalonensis, A. vogelii and A. grandiﬂora at doses ranging from 50–3000 mg/kg have all revealed in vivo antiplasmodial activities against Plasmodium falciparum or Plasmodium berghei in a dose dependent manner (Bassey et al., 2009; Alaribe et al., 2012; Odeghe et al., 2012a; Okon et al., 2014; Gboeloh et al., 2014; Ogbuehi et al., 2014). The work by Alaribe et al. (2012) revealed a variation in the route of administration, where the petroleum ether leaf extracts (50, 100, 250 mg/ kg) of A. vogelii produced a dose dependent reduction in parasite density compared to the control group when given intraperitoneally. But, there was no reduction when the extract was administered orally at 100–1250 mg/mL in chloroquine sensitive Plasmodium berghei infected mice. It is possible that petroleum ether was not efﬁcient in extracting most of the active principles from the plant compared to more polar solvents like ethanol, for which antiplasmodial activity was reported when the extracts were given orally. Odeghe et al. (2012b) reported the effectiveness of the methanol extract of A. grandiﬂora in increasing the hematological values (PCV, Hb, WBC, platelets, lymphocyte, neutrophils and monocyte) and decreasing the levels of AST and ALT activities of malaria parasite infected rodents. This indicated that the extract possess the ability to enhance blood component to phagocytose, delay or prevent the incidence of anemia, protect the liver by its free radical scavenging activities and improve the disease progression. Typical of herbal medicines all over the world, is the combination of several plants to treat a particular disease condition, which is a function of the understanding that the active principles in the different plants work synergistically to elicit the expected healing. The combination of A. nobilis, Nauclea latifolia and Napoleona imperialis and the individual plants exerted antiplasmodial effect in varying degrees at 125, 250 and 500 mg/kg concentrations; however their combination gave improved symptomatic relief from malaria and extended the mean survival time of the treated mice (Ogbuehi et al., 2014). Similarly, A. vogelii in combination with Ficus exasperata has been shown to be effective against P. berghei berghei (Okon et al., 2014). An isolated compound decussatin (4), from pet ether leaf extract of A. vogelii, demonstrated very weak reduction in parasite 657 density at 10 mg/kg in P. berghei infected mice. Also, the extract and decussatin demonstrated good iron chelating ability at 1 mg/mL concentration which might contribute in its antiplasmodial activities (Alaribe et al., 2012). So far, decussatin is the only isolated compound from the Anthocleista species that has been tested for antiplasmodial activity. However, the results of the in vivo studies support the traditional use of the Anthocleista species in the treatment of malaria. The variation of in vitro and in vivo antiplasmodial results calls for further research while modifying the extraction solvents or standard techniques used for the in vitro antiplasmodial studies in order to determine the most adequate or appropriate. However, the positive in vivo results, and weak/negative in vitro antiplasmodial results is not a new phenomenon, as such weak/negative results are referred to as false negatives. According to Walker (1987), several examples already exist of nucleoside antiviral agents which in vitro show weak or negative activity but work very well in vivo. Furthermore, the identiﬁcation of the bioactive components in the species responsible for the antiplasmodial activity should be investigated with the aim of elucidating their mechanism of action and exploring the species for new malaria drugs. 5.3. Antimicrobial activity The Anthocleista species have been useful in the healing of certain diseases caused by microbial infections such as typhoid, candidiasis, mycosis, bronchitis and fever (Table 1). Also, the treatment of sexually transmitted diseases by Anthocleista species is a common herbal practice in countries like Nigeria, Togo, Cameroun, Gabon and Equatorial Guinea (Kerharo, 1974; Okorie, 1976; Olukoya et al., 1993; Igoli et al., 2005; Omobuwajo et al., 2008; Kayode et al., 2004; Diame, 2010; Jiofack et al., 2010; Tchacondo et al., 2012; Gbadamosi 2014; Christophe et al., 2015). More so, skin diseases such as rashes and eczema are being treated with Anthocleista species (Olowokudejo et al., 2008). Usually, the plants are soaked in water or macerated before drinking (Table 1). Anthocleista species have demonstrated antibacterial activity against disease causing microorganisms like Escherichia coli, Salmonella typhi, Staphylococcus aureus, Klebsiella pneumoniae and Corynebacterium diphtheriae. E. coli is the main causal agent of urinary tract infection, also causes food poisoning. S. aureus causes boils, impetigo cellulitis, abscesses, wound infections, toxic shock syndrome, pneumonia, and food poisoning. S. typhi is the major cause of typhoid, and sometimes accompanied with weakness, headache, abdominal pain and constipation, and in rare cases vomiting and diarrhea. K. pneumoniae causes pneumonia and infections in the urinary tract while C. diphtheriae causes diphtheria. These explain the use of Anthocleista species by locals and traditional healers in the treatment of typhoid, diarrhea, skin diseases and other infections. Studies have provided scientiﬁc evidence for the long use of these plants in the treatment of microbial infections (Table 2). A. djalonensis have been shown to possess notable growth inhibitory activities against E. coli, E. faecalis, S. typhi, S. aureus, Bacillus subtilis, Pseudomonas aeruginosa, Proteus spp., and Shigella spp. (Atindehou et al., 2002; Okoli and Iroegbu, 2004; Chah et al., 2006; Akinyemi and Ogundare, 2012; Leke, 2012), but weak antifungal activity against Candida albicans and Cladosporium cucumerinum (Atindehou et al., 2002). The folkloric claim that A. djalonensis are potent in the management of tuberculosis and leprosy was investigated in a sensitivity screening study by Esimone et al. (2009). The methanol leaf and root extracts of A. djalonensis showed antimycobacterial activity (MIC ¼125 μg/mL), while the aqueous extracts of the same parts exhibited no inhibitory activity against Mycobacterium smegmatis (Esimone et al., 2009). This suggests 658 Table 2 Pharmacological activities of Anthocleista species. Pharmacological activities Scientiﬁc name Part used Extract/fraction Dosage/duration Model used Type of effect References Antidiabetic activity Anthocleista djalonensis Leaves, stem bark and roots Same Roots Aqueous methanol (E), hexane (F), ethyl acetate (F) same Ethanol (E), methanol (F), chloroform (F), ethyl acetate (F) Isosaline (E) 1 mL of 250 mg/mL in vitro alpha-Amylase inhibitory Olubomehin et al. (2013) 1 g/kg 7 days in vivo 37,74, 111 mg/kg 7 h and in vivo 15 days 15 days in vivo Hypoglycemic Hypoglycemic Olubomehin et al. (2013) Okokon et al. (2012) Olagunju et al. (1998) Aqueous methanol (E) 1 mL of 250 mg/mL Hypoglycaemic, hypolipaemic, hypocholestero-laemic activities alpha-amylase inhibitory Methanol (E), chloroform (F), ethyl acetate (F), acetone (F) and water (F) Ethanol (E and F) Aqueous (E) Dichloromethane (E), methanol (E) 200 and 400 mg/kg in vivo 6 hrs 100, 200 and 400 mg/kg in vivo 100, 400 and 800 mg/kg in vivo Hypoglycemic Osadebe et al. (2014b) Antidiabetic/ Toxicity Hypoglycaemic α-Glucosidase inhibition Sunday et al. (2014) Abuh et al. (1990) Mbouangouere et al. (2007) Aqueous (E), Methanol (E) 1-Hydroxy-3,7,8-trimethoxyxanthone (AV) isolated from the methanol extract Ethanol (F) 0.13–8.00 mg/mL 2.50 10 2–1.60 μg/mL in vitro in vitro Spasmogenic Spasmogenic Ateufack et al. (2010) Ateufack et al. (2007) 0.06–0.31 mg/ml in vitro Spasmolytic Madubunyi and Asuzu (1996) Aqueous (E), alcohol-insoluble fraction of the aqueous extract Aqueous (E), dichloromethane (E), cardiac glycoside type compounds (F) Up to 1 mL/kg in vitro Hypotensive Activity Duwiejua (1983) in vitro Vasoconstrictor and inotropic effects Ngombe et al. (2010) in vivo Hematological and biochemical Indices Antiplasmodial activity Odeghe et al. (2012b) Antiplasmodial activity Antiplasmodial activity Antiplasmodial activity schizontocidal activity Bapela et al. (2014) Nondo et al. (2015) Bassey et al. (2009) Leaves Anthocleista vogelii Spasmogenic activity Cardiovascular effect Antimalarial Activity Olubomehin et al. (2013) Anthocleista vogelii Stem bark Stem bark Anthocleista nobilis Root bark Anthocleista nobilis Root bark Anthocleista Schweinfurthii Root bark Anthocleista grandiﬂora Stem barks Methanol (E) Stem barks Methanol (E) Stem bark Stem bark Leaf Stem bark Dichloromethane (E) and aqueous (E) Ethanol (E) Ethanol (E) Stem back Ethanol (E) 300, 500, 700 mg/kg 12 days 300, 500, 700 mg/kg 12 days 10 mg/mL 100 μg/mL 1000–3000 mg/kg/day 220–660 mg/kg/day 10 mg/mL Root 175–1 000 mg/kg; 250 and 500 mg/kg 100,200, 400 mg/kg in vivo Stem back Ethanol (E) Chloroform (F), ethyl acetate (F) and methanol (F) Ethanol (E) Leaf Petroleum ether (E) in vivo Stem bark Decussatin Ethanol (E) in vivo in vivo Antiplasmodial effect Antiplasmodial effect Alaribe et al. (2012) Gboeloh et al. (2014) Anthocleista nobilis Root Methanol (E) 100–1250 mg/kg p.o, 50–250 mg/kg i.p 10 mg/kg 100, 200, and 400 mg/ kg 125, 250 and 500 mg/kg Antiplasmodial and antipyretic activities Antiplasmodial activities (in combination with Ficus exasperata) Antiplasmodial effect in vivo Antiplasmodial effect in combination with two plants Ogbuehi et al. (2014) Anthocleista vogelii Stem bark 1-hydroxy-3,7,8-trimethoxyxanthone of Methanol 1, 2, and 5 mg/kg Anthocleista djalonensis Anthocleista vogelii Antiulcerogenic activity Root Root Root in vitro in vivo in vitro in vitro in vivo in vitro in vivo in vivo Odeghe et al. (2012a) Zirihi et al. (2005) and Zirihi et al. (2010) Akpan et al. (2012) Okon et al. (2014) Alaribe et al. (2012) Ateufack et al. (2014) G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 Anthocleista Schweinfurthii Leaves, stem bark and roots Stem bark (E) Aqueous (E), hexane (E), acetone (E), Methanol (E) 500 mg/kg in vivo in vivo in vivo Anthocleista vogelii Root bark Root bark Ethanol (E) Ethanol (E) 500 mg/kg 28 days 500 mg/kg 28 days Antiobesity Liver function, antioxidant activity Anyanwu et al. (2013) Anyanwu Sangodele et al. (2014) Analgesics properties Anthocleista vogelii Anthocleista djalonensis Stem bark Root Aqueous (E) Methanol (E) 125, 250 and 500 mg/kg in vitro 200, 400 and 800 mg/kg in vivo Analgesic effect Analgesic effect Mbianctha et al. (2013) Kagbo and Simon (2015) Antimicrobial effects Anthocleista vogelii Leaf Stem Leaves Anthocleista Schweinfurthii Anthocleista liebrechtsiana Anthocleista djalonensis stem bark and leaves stem bark and leaves Leaves Aqueous (E), ethanol (E), chloroform (E) Aqueous (E), Ethanol (E) Acetone (E), ethanol (E), methanol (E), methylenedichloride (E), methanol:chloroform: water (E), water (E) n-hexane (F), dichoromethane (F), ethyl acetate (F), and methanol (F) n-hexane (F), dichoromethane (F), ethyl acetate (F), and methanol (F) Methanol (E), Petroleum ether (E), Aqueous (E) 12.5–100 mg/kg ni in vitro in vitro in vitro Typhoid fever Antimicrobial effect Antimicrobial effect Musa et al. (2010) Olukoya et al. (1993) Eloff (1998) 250–1.95 μg/mL in vitro Antibacterial Ngbolua et al. (2014b) 250–1.95 μg/mL in vitro Antibacterial Ngbolua et al. (2014c) 30–5.0 mg/mL in vitro Antidiarrhoeal effect in vitro Antimicrobial effect Akinyemi and Ogundare (2012) Leke et al. (2012) in in in in in in Antibacterial and antifungal Antibacterial Antibacterial Treatment of STDs Anti-mycobacterial Antibacterial and antifungal Atindehou et al. (2002) Ikegbunam et al. (2014) Chah et al. (2006) Okoli and Iroegbu (2004) Esimone et al. (2009) Atindehou et al. (2002) in vivo in vitro Newcastle disease virus Antibacterial Ayodele et al. (2013) Annan and Dickson (2008) Oladimeji Igbalaye and Coleshowers (2014) Muanya and Odukoya (2008) Root Anthocleista nobilis Fertility Anti-inﬂammatory activity Antioxidant assay vitro vitro vitro vitro vitro vitro Anthocleista vogelii Leaves Ethanol (E) 100, 200 mg/kg in vivo Improve female fertility Anthocleista djalonensis Root Ethanol (E) 1 mL in vivo Improve male fertility Anthocleista djalonensis Root Aqueous ethanol (E) and sweroside 100, 200 and 400 mg/kg in vivo Root Stem bark Methanol (E) Methanol (E) 0.2 mL of 20 mg/mL 33.3% w/w in vitro in vivo Aqueous (E), ethanol (E) 2.5–40.0 mg/mL in vitro Abu et al. (2009) Anthocleista djalonensis Anthocleista nobilis Leaf, stem and root Stem back Ethanol (E) 500–0.07 g/mL in vitro Atindehou et al. (2004) Root bark Ethanol (E) 80, 67, 40 mg/kg, i.p. In vivo Madubunyi and Asuzu (1996) Anthocleista Schweinfurthii Anthocleista liebrechtsiana Anthocleista stem bark and leaves stem bark and leaves Leaves Methanol (F) 0.1–1 mg/mL in vitro DPPH radical scavenging assay Ngbolua et al. (2014b) Methanol (F) 0.1–1 mg/mL in vitro DPPH radical scavenging activity Ngbolua et al. (2014c) Methanol (E) 100 μL/ various conc. in vitro Free radical scavenging activity Awah et al., (2010) Anthocleista nobilis Antitrypanosomal activity Hexane (F) Methanol (F), Chloroform (F), Aqueous Full length and 10% (F) dilution Stem bark Ethanol (E) ni Leaves Methanol (E) 3000.00–21.87 mg/mL Root Methanol (E) 0.1 mL of 20 mg/mL Root Ethanol (E), cold and hot water (E) 100 μL l of 25 mg/mL Leaves Root Aqueous (E) Methanol (E) 20 mg/mL Stem bark, root Ethanol (E) ni bark Root Ethanol (E) 0.5 mg/100 g for 28 days Stem bark Methanol (E) 20 μL aliquot of extract Anthocleista vogelii Baba and Usifoh (2011) Wound healing properties Wound healing activity G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 Antiobesity activity Ateufack et al. (2006) Chah et al. (2006) Annan and Dickson (2008) 659 Anyanwu et al. (unpublished thesis, 2015) Nweze and Ngongeh (2007) in vivo 250–500 mg/kg Ethanol (E) Anthocleista vogelii Diuretic and Laxative activity Root bark Anthocleista djalonensis Anthelmintic activity Root in vitro 25–200 mg/mL Ethanol (E) TBA reactivity DPPH radical scavenging activity in vitro in vitro – 50 μL of 10–100 μg/mL djalonensis Anthocleista nobilis Bark Stem bark Ethanol (E) Methanol (E) Type of effect Model used Dosage/duration Extract/fraction Part used Scientiﬁc name Pharmacological activities Table 2 (continued ) Odukoya et al. (2012) Annan and Dickson (2008) G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 References 660 that the active principles in A. djalonensis are better extracted or much more concentrated in alcoholic extracts. Aqueous, ethanol and chloroform extracts of A. vogelii leaf and stem bark have revealed antibacterial activity against S. typhi, K. pneumoniae and C. diphtheriae (Olukoya et al., 1993; Musa et al., 2010), while the methanol stem bark extracts of A. nobilis inhibited the growth of S. aureus, B. subtilis, M. ﬂavus, E. coli and P. aeruginosa (Annan and Dickson, 2008). The extracts of the leaves and stem barks of A. schweinfurthii and A. liebrechtsiana have shown antibacterial activity against S. aureus, but they were less sensitive to E. coli (Ngbolua et al., 2014b, 2014c). Species like A. schweinfurthii and A. liebrechtsiana have only been screened for fewer microorganisms, there is need to experiment with more microorganisms in order not to limit the effect of the plants. Traditionally, A. schweinfurthii is used to treat bronchitis and mycosis, but there is yet to be scientiﬁc evidence to this practice. Irlbacholine, isolated from A. djalonensis, revealed potent in vitro activity against three pathogenic fungi: C. albicans, C. neoformans, and A. fumigatus, with minimum inhibitory concentrations (MIC) of 1.25, 0.04 and 0.08 pg/mL respectively (Biere et al. 1995). Similarly, Irlbacholine showed potent activity (MIC¼ 0.04 pg/mL) against the dermatophyte Trichophyton rubrum. Tene et al. (2008) evaluated the antibacterial and antifungal activities of anthocleistenolide, 1-hydroxy-3,7-dimethoxyxanthone,1-hydroxy-3,7,8-trimethoxyxanthone and sitosterol 3-Oβ-D-glucopyranoside isolated from the stem bark of A. vogelii. The results showed relatively low activity against Staphylococcus aureus (MIC ¼200 μg/mL) and against Enterococcus faecalis (MIC¼ 100 μg/mL) for anthocleistenolide, while compounds 1-hydroxy-3,7-dimethoxyxanthone and 1-hydroxy-3,7,8-trimethoxyxanthone were active against Candida parapsilosis with MIC of 200 μg/mL and 25 μg/mL respectively. Sitosterol 3-O-β-D-glucopyranoside was inactive against all the bacterial and fungal species used. Although, the traditional use of Anthocleista species for the treatment of STDs and skin diseases still remains to be proven scientiﬁcally, their use in the treatment of bacterial and fungal diseases have been sufﬁciently supported by the above scientiﬁc studies. However, more work is essential to isolate the biologically active components in the numerous extracts for antibacterial and antifungal activities. Studies on antiviral activities of this species were not found to be reported. 5.4. Antihypertensive and antihypotensive activities In Nigeria and Togo, the leaf, bark and root of A. djalonensis and A. vogelii are used to treat hypertension (Table 1). The root of A. djalonensis is also macerated in combination with three other plants (Crematogaster pilosa, Securidaca londepedunculata and Nauclea latifolia) and one tea spoon is taken three times daily to treat hypertension in Nigeria (Olorunnisola et al., 2015). Although, no comprehensive ethnobotanical use of A. nobilis and A. schweinfurthii for the management of hypertension was found, Burkill (1985a and 1985b) had earlier documented the traditional use of the leaf of A. nobilis for the treatment of spasm, and the leaf, bark and root of A. schweinfurthii as medicines for arteries and veins. The reason behind the tradition use of Anthocleista species in the treatment of hypertension might not be farfetched as studies have suggested their action on adrenergic receptors, direct or indirect activation of L-type calcium channels, antispasmodic effect, vasodilator action, inhibition of the Naþ pump, ganglionblocking and muscarinic effect (Lafon, 1966; Duwiejua, 1983; Ignesti et al., 1988; Ngombe et al., 2010). The pharmacological effects of the aqueous extract and the alcohol-insoluble fraction (crystalline compound) of the aqueous extract of the root bark of Anthocleista nobilis was investigated on G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 the arterial blood pressure of anaesthetized cat and on isolated perfused rabbit heart by Duwiejua (1983). A dose-dependent depressor effect, which was slightly antagonized by atropine, was observed in both models (in vitro and in vivo). The extract exerted a resultant lowered tone of the muscles which could cause a drop in the blood pressure. The hypotensive action of the root extract of A. nobilis was reported to be due to a direct muscarinic effect, ganglion-blocking effect and a non-speciﬁc depressant action on both smooth and skeletal muscles. Previously, Lafon (1966) reported that the aqueous and alcohol extracts of A. nobilis possess antispasmodic effect, hypotensive activity, neurotropic activity and vasodilator action. Also, aqueous extract of A. nobilis has been reported to have inhibited the contraction induced by noradrenalin in the rat ductus deferens (Ignesti et al., 1988). Vasodilation involves the widening of arterial and/or venous vessels, thus reducing systemic vascular resistance and consequently leading to reduced blood pressure. The vasodilator effect of A. nobilis validates its traditional use for the management of hypertension or spasms. Ngombe et al. (2010) investigated the cardiovascular effect of three extracts (aqueous extract, dichloromethane extract and a fraction enriched in cardiac glycoside type compounds) from the root bark of A. schweinfurthii. The bolus injection of extracts produced a positive inotropic effect in isolated perfused frog heart. Other results indicated that A. schweinfurthii contains substances that promote vasoconstriction and increase cardiac contraction. The effect of dichloromethane extract was only partially mediated by inhibition of the Na þ pump while the mechanism of action of aqueous extract and cardiac glycoside type compounds was distinct from the inhibition of the Na þ , K þ -ATPase pump, but could involve adrenergic receptors, or either direct or indirect activation of L-type calcium channels. The rise in concentration of Ca2 þ ions within vascular smooth muscle cells results in vasoconstriction (Capponi et al., 1985). Drugs/agents that cause vasoconstriction, that is the narrowing of blood vessels (large arteries and small arterioles) help to elevate blood pressure. Therefore, the vasoconstrictor effect of A. schweinfurthii suggests its possible use for the treatment of hypotension. Scientiﬁc reports supporting the traditional use of A. djalonensis and A. vogelii for the management of hypertension was not available. Recent studies on the hypotensive properties of Anthocleista species is lacking, and neither past nor the reported studies have gone beyond fractions in their investigation of the species. This spells out clearly that more work on the pharmacological activities of the extracts, fractions and their isolated compounds is necessary. 661 polar fraction of the extract. The spasmolytic activity of A. nobilis supports its traditional use in the treatment of colic, stomachaches, diarrhea and constipation. Although, neither the compound nor mechanism by which A. nobilis produces spasmolysis have been investigated. Ateufack et al. (2010) have reported the spasmogenic effect of A. vogelii stem bark, where it’s aqueous and methanol extracts produced a dose-dependent effect on the tone and force of the spontaneous contraction of the rat ileal and stomach smooth muscle fragments at concentrations ranging from 0.13 to 8.00 mg/mL. Also, xanthone, 1-hydroxy-3,7,8-trimethoxyxanthone isolated from the methanol extract of the stem bark of A. vogelii produced a dose-dependent effect on the tone and force of the spontaneous contraction of the rat ileal and stomach smooth muscle fragments at concentrations ranging from 2.50 10 2 to 1.60 mg/mL (Ateufack et al., 2007). These results point to a possible stimulation of these muscle fragments through muscarinic receptors which increase Ca2 þ mobilization from both extra and intramuscular medium, that is, the plant extracts or isolated compound interfere with calcium metabolism in smooth muscle to exert its effect. The spasmogenic activity of A. vogelii validates their use in African traditional medicine for gastro-intestinal disorders, stomach ache and as a purgative, and most especially for the treatment of abdominal pains in Cameroon. The suggestion by the authors that the spasmogenic effect of aqueous and methanol extracts of A. vogelii is by stimulation of muscarinic receptors needs further investigation to ascertain which muscarinic receptor subtypes (M1–M5) and their location is responsible for this function. Also, it is imperative to determine if the stimulation of muscarinic receptors extends to other smooth muscles like the heart, mesenteric arteries, veins, etc. This is important because, for instance, activation of M1 and M3 are known to mediate a direct smooth muscle vasocontrictive effect which consequently leads to elevated blood pressure (Medina et al., 1997; Grekin and Hamlyn, 2003). But it is also possible that the aqueous and methanol extracts of A. vogelii might act by stimulating M2 muscarinic receptors in the heart and aorta of animals thereby producing hypotension. If such is the case, this action may also lend support to the use of A. vogelii in the management of hypertension by traditional healers and locals (Table 1). The evidences above support the use of A. nobilis and A. vogelii for their folkloric use against stomach disorders, but no evidence was available to support the traditional use of A. djalonensis for diarrhea or dysentery; A. schweinfurthii for stomach aches or A. grandiﬂora for stomach amoeba infections (Table 1). 5.6. Anti-obesity activity 5.5. Spasmolytic and spasmogenic activities The traditional use of Anthocleista species in the treatment of stomach disorders such as stomach ache, abdominal pains, ulcer, diarrhea and dysentery has been reported (Dalziel, 1955; Akubue et al., 1983; Adjanohoun et al., 1986; Nweze and Ngongeh, 2007; Adongo et al., 2012; Odukoya et al., 2012; Christophe et al., 2015). Generally, the relevant parts of A. djalonensis, A. vogelii, A. nobilis, A. schweinfurthii, and A. grandiﬂora are prepared by decoction and taken orally in Nigeria, Cameroun and Kenya (Table 1). In evaluating the pharmacological properties of defatted ethanol root bark extract A. nobilis, Madubunyi and Asuzu (1996) tested its spasmolytic effect on smooth muscle, the isolated guineapig ileum. Out of six fractions obtained by chromatographic separation of the ethanol extract, only one fraction, which showed one main compound (Rf 0.4) in chloroform:acetone:formic acid (9:2:1) relaxed the guinea-pig ileum in a concentration-dependent manner. This indicated that the active principle responsible for the relaxation effect on the guinea-pig ileum was contained in the The impact of ethanol extract of A. vogelii root bark on weight reduction in high carbohydrate diet (HCD) induced obesity in male wistar rats had been investigated. The ethanol extract of A. vogelii of 500 mg/kg b.w signiﬁcantly decreased food intake, body weight, total fat mass, adiposity index, low density lipoprotein cholesterol, glucose and leptin levels (Anyanwu et al., 2013). In an anti-lipideamic study in hyperglycemic rats, the ethanol root extracts (100, 200 and 400 mg/kg) and fraction (200 mg/kg) of A. vogelii exerted a dose dependent signiﬁcant decrease (Po 0.05) in TC, TG, LDL-C, ALT, AST and an increase in HDL-C when compared to the control (Sunday et al., 2014). The ethanol extract of A. vogelii root bark showed positive effect on liver function and antioxidant status of obese rats (Anyanwu et al., 2014). The extract of 500 mg/kg b.w signiﬁcantly decreased ALT, AST and ALP activities; while it increased the catalase and superoxide dismutase activities, and glutathione level, with no signiﬁcant difference in MDA level compared to the high fat diet and high carbohydrate diet obese controls. Also, the numerous 662 G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 prominent fat deposits in the livers appeared relatively reduced among the groups treated with the extract (Anyanwu et al., 2014). These indicated that the ethanol extract of A. vogelii root bark was helpful in preventing the progress of oxidative stress, fatty liver and eventually obesity. Although, the results of the antiobesity studies which were limited to A. vogelii seemed interesting, none of the studies have determined the antiobesity effect of Anthocleista species based on the 5 categorized mode of action for antiobesity agents from natural products. This means that the species need to be tested for their ability to decrease energy intake, increase energy expenditure, decrease lipid absorption, decrease lipogenesis and increase lipolysis, and lastly to decrease pre-adipocyte differentiation and proliferation. Also, studies need to go beyond crude extracts and fractions of plants, beginning with in vitro studies which are lacking if any meaningful antiobesity agents have to be discovered from this species. 5.7. Antiulcerogenic/analgesics, wound healing and anti-inﬂammatory activities The antiulcerogenic effect of a drug often times is as a result of its combined effect of decreasing both pain and inﬂammation. The ethnomedicinal uses of A. vogelii in the treatment of stomach pain have been validated by the ﬁndings that both aqueous and organic extracts of the stem bark of A. vogelii possess potent antiulcer properties. The aqueous and methanol extracts showed 87.91% and 100% inhibition respectively at a dose of 500 mg/kg when screened for antiulcerogenic activity using HCl/ethanol gastric necrotizing solution (Ateufack et al., 2006). Similarly, the aqueous extract at a dose of 500 mg/kg signiﬁcantly reduced indomethacin-induced gastric lesions by 78.62% while the methanol extract at the same dose completely inhibited the action of indomethacin (Ateufack et al., 2006). Further investigations on the action of the xathone (1-hydroxy-3,7,8-trimethoxyxanthone) obtained from the methanol extract of the A. vogelii stem bark prevented in a dose-dependent manner ulcers induced by HCl/ethanol (60.90–93.22%), Indometacin (46.86–89.68%), and pylorus ligation (0.00–70.69%) at the doses of 1, 2, and 5 mg/kg respectively (Ateufack et al., 2014). Anti-inﬂammatory agents/drugs make up about half of analgesics, because they remedy pain by reducing inﬂammation or swelling. Traditionally, a cold infusion of the stem bark of A. djalonensis with 8 other plants is prepared and two table spoons is taken daily for the treatment of Asthma in Nigeria (Sonibare and Gbile, 2008; Borokini et al., 2013). For swellings, rheumatism and wounds, the area affected is poulticed to relieve the soreness and inﬂammation, and to cleanse the wound (Musa et al., 2010). The action of A. djalonensis at central and peripheral sites to inhibit neurogenic and inﬂammatory pains has been proposed by Kagbo and Simon (2015), after investigation of the analgesic properties on the methanol root extract of A. djalonensis in albino rats using chemical, mechanical and thermal models of pain. The response to neurogenic and inﬂammatory pains by the formalin hind paw licking test was used to study chemically induced pain. Mechanical pain was induced by exertion of pressure on inﬂamed and hyperalgesic rat paw with an Analgesy-meter while thermally induced pain was assessed by the supraspinally mediated tail ﬂick test. The extract showed a signiﬁcant, dose dependent inhibition of nociception in all the models of pain used. The aqueous extract of A. vogelii stem barks at 125, 250 and 500 mg/kg, reduced the number of abdominal constrictions induced by acetic acid with 40.42%, 65.62% and 68.75% respectively demonstrating its analgesics properties (Mbianctha et al., 2013). In the formalin test of the same study, extract provoked 56.48%, 59.49% and 89.93% of inhibition respectively with the same doses; while the second phase was marked by a higher activity of the extract, with 94.16%, 97.47% and 100% of inhibition. The ethanol-water (1:1) extract of A. djalonensis root showed signiﬁcant activity (p o0.05) at 400 mg/kg comparable to the reference drug, while the pure compound (sweroside) isolated from the extract revealed signiﬁcant anti-inﬂammatory activity (p o0.05) at 100 mg/kg in animal model (Baba and Usifoh, 2011). Chah et al. (2006) determined the wound healing properties of methanol root extracts of A. djalonensis using the excision wound model, and the extract proved wound healing properties (98.84%) s comparable with that of the standard drug cicatrin (100%) by the 17th day post-surgery in rats. Also, the methanol extracts of A. nobilis revealed potent wound healing activity as evident from the wound contraction, increased tensile strength and hydroxyproline content in male rats using the excision wound model (Annan and Dickson, 2008). These ﬁndings support the traditional use of Anthocleista species, particularly A. djalonensis, A. vogelii and A. nobilis as pain killers and in the treatment of wounds and inﬂammatory diseases. Although, scientiﬁc evidence supporting the traditional use of A. grandiﬂora and A. schweinfurthii for treatment of chest pains and wounds respectively is lacking, based on evidence of other Anthocleista species as anti-inﬂammatory agents, there is need to research their mode of action for reducing pain and/or inﬂammation, likewise the bioactive agents mediating these effects. 5.8. Antioxidant activity Antioxidants are needed to prevent the formation and reduce the level of reactive oxygen and nitrogen species, which are produced in vivo and cause damage to DNA, proteins, lipids, and other biomolecules. Antioxidants are widely used in dietary supplements and have been investigated for the prevention of diseases such as cancer, coronary heart disease and even altitude sickness (Baillie et al., 2009). Plants produce a number of antioxidants for their own protection and some that may also be useful to humans such as vitamin E, vitamin C, carotenoids, ﬂavonoids, etc. The Anthocleista species are potential source of antioxidants which could be responsible for their health beneﬁts. The methanol extract of A. djalonensis leaves showed a very potent DPPH and O2 anion radical scavenging activities (IC50¼ 8.69 70.95 μg/mL and 5.32 71.05 μg/mL respectively). Also, the extract displayed signiﬁcantly higher OH radical and nonenzymatic lipid peroxidation inhibitory potentials than that of standard antioxidants (IC50 ¼33.06 75.65 μg/mL and 59.147 4.64 μg/mL respectively), likewise, it inhibited the accumulation of nitrite in vitro (Awah et al., 2010). Annan and Dickson (2008) reported the inhibition of lipid peroxidation, DPPH radical scavenging activity and protection against oxidant injury to ﬁbroblast cells as indications of A. nobilis potent antioxidant activity. A. Schweinfurthii and A. liebrechtsiana had been shown to possess DPPH free radical scavenging activities (IC50 o 10 μg/mL) (Ngbolua et al., 2014b, 2014c). And the ethanol extract of Anthocleista nobilis bark showed TBA reactivity by decreasing levels of MDA and a reduction in lipid peroxides both in the raw and cooked ﬁsh homogenate, but the antioxidant capacity was low compared to other plants tested (Odukoya et al., 2012). The extract of A. schweinfurthii showed no inhibition of microsomal lipid peroxidation using rat hepatic microsomes, but revealed inhibition of carbonyl-group formation on bovine serum albumin (BSA), that is, against protein oxidation. The results indicated that the antioxidant activities of A. schweinfurthii may be due to their ability to scavenge free radicals involved in protein oxidation, but not in microsomal lipid peroxidation (Njayou et al., 2008). Nonetheless, the compounds within the plants that are responsible for its antioxidant properties are yet to be identiﬁed. G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 5.9. Antitrypanosomal activity The antitrypanosomal activity of 101 crude ethanol extracts derived from 88 medicinal plants from Cote d’Ivoire was determined in vitro using Trypanosoma brucei rhodesiense by Atindehou et al. (2004). A. djalonensis was one of the 56 plants that did not show any activity at all (IC50 values 4 25 g/mL). Similarly, in a previous study, the defatted ethanol root bark extract of A. nobilis did not reduce the level of parasitaemia in mice infected with Trypanosoma brucei brucei (Madubunyi and Asuzu, 1996). However, a different result was obtained in the in vitro antitrypanosomal studies of crude extracts of some Nigerian medicinal plants by Abu et al. (2009). It was discovered that both aqueous and ethanol extracts of the root bark of A. vogelii showed activity at 40 and 20 mg/mL, but the stem bark had no activity at the test concentrations. This could be indicative of species difference with respect to presence or concentration of the bioactive components in the part of the plants used. 5.10. Anthelmintic activity Anthelmintic is any drug used in the treatment of infections caused by parasitic worms (helminths). Helminths include tapeworms, roundworms and ﬂukes. The Anthocleista species have been used to kill or ﬂush out worms in Tanzania, Nigeria, Cameroun and Kenya (Table 1). Majorly, the roots and stem barks of the A. djalonensis, A. vogelii, A. nobilis, A. schweinfurthii, and A. grandiﬂora are prepared as a decoction and taken orally (Akubue et al., 1983; Kerharo, 1974; Madubunyi et al., 1994; Burkill, 1995; Fowler, 2006; Nweze and Ngongeh, 2007; Dibong et al., 2011; Adongo et al., 2012; Christophe et al., 2015). The in vitro anthelmintic activity of the ethanol extract of A. djalonensis was studied against L larvae of Heligmosomoides polygyrus (roundworm) at 25, 50, 100 and 200 mg/mL concentrations (Nweze and Ngongeh, 2007). The extract had a concentrationdependent lethal action on H. polygyrus larvae. At a concentration of 100 mg/mL, the extract recorded 98.45% mortality which was equivalent to that of levamisole (the positive control) at 10 mg/mL. This is indicative of the validity of its use traditionally against worms and other internal parasites in the body, and thus, the mode of action of the species on the worms needs to be investigated. 5.11. Fertility activity The Anthocleista species, particularly A. djalonensis, A. vogelii, A. nobilis and A. schweinfurthii are a source of traditional recipes for treatment of male and female fertility problems in Togo, Nigeria, Ghana, Cameroon, Gabon, Equatorial Guinea and Congo (Table 1). Traditionally, A. djalonensis is used in South West Nigeria to boost libido, induce erection, increase sperm count and consequently male fertility (Olowokudejo et al., 2008). Other examples include the use A. vogelii for the treatment of menstrual dysfunction (Omobuwajo et al., 2008) and A. schweinfurthii for ovarian problems (Kerharo, 1974; Christophe et al., 2015). In contrast to the use of Anthocleista species to enhance fertility, the roots of A. vogelii and bark/leaf of A. nobilis are reported to be used as contraceptives or to induce abortion (Kadiri, 2009; Diame, 2010). Reactive oxygen species are important mediators of sperm dysfunction (Wang et al., 1997; Bansal and Bilaspuri, 2011). Production of MDA, an end product of lipid peroxidation, has been reported in spermatozoa. Muanya and Odukoya (2008) studied the effect of 9 medicinal plants on lipid peroxidation as an index of male fertility. Lipid peroxidation in raw and cooked ﬁsh homogenates was measured as the amount of thiobabituric acid reactive sample (TBARS) in nmol/mg. The A. djalonensis extract was the 663 most active in the inhibition of lipid peroxidation among the 9 plants tested. This indicates that A. djalonensis possess the ability to improve sperm function thereby increasing male fertility, and hereby it gives support to its traditional use in the treatment of male fertility problems. The ethanol extract of A. vogelii showed a statistically signiﬁcant increase of estradiol concentration in the female rats, from (184.65 730.06 pg/mL) in the control group compared to (288.29 7 30.06 pg/mL) in the extract treated group (Oladimeji Igbalaye, Coleshowers, 2014). In female reproductive system, estrogen plays a very important role especially in ovulation. The evidence by Oladimeji Igbalaye and Coleshowers (2014) that A. vogelii can induce estrogen production supports the claim on the traditional use of the plant to enhance fertility in females. The traditional use of A. djalonensis for the treatment of female infertility has not been reported, likewise no report was found for A. nobilis and A. schweinfurthii vis-à-vis its folkloric use for improving female fertility. Nevertheless, the evidence that A. djalonensis and A. vogelii improves male and female fertility respectively should trigger further investigation on the bioactive compounds in these plants in order to develop them into useable therapeutic agents of fertility enhancers. 5.12. Diuretic and laxative activities Traditionally, A. djalonensis, A. vogelii, and A. liebrechtsiana are used as purgative by locals/natives in Nigeria, Cameroun and other African regions (Dalziel, 1955, Okorie, 1976; Adjanohoun et al., 1986; Igoli et al., 2005; Olowokudejo et al., 2008; Lawal et al., 2010; Ariwaodo et al., 2012). The leaf, bark or roots are usually boiled with water and drank to obtain its purgative/laxative effect. The root of A. vogelii is traditionally used as a diuretic (Burkill, 1985c), however, Lawal et al. (2010) reported the use of A. djalonensis as an antidiuretic. The diuretic and laxative activity of ethanol extracts of A. vogelii root bark was studied in vivo in male wistar rats (Anyanwu et al unpublished thesis, 2015). The extracts increased the volume of urine excreted compared to the negative control at 250 mg/kg and 500 mg/kg oral doses after 5 and 18 h. Diuretics promote the production and excretion of urine from the body. A. vogelii proved to be a potent diuretic as it promoted the excretion of urine from the rats, although the effect was not more than the positive control (25 mg/kg of Furosemide). Thus, the traditional use of A. vogelii for forced diuresis and hypertension is valid. In the laxative studies, ethanol extracts of A. vogelii root bark signiﬁcantly increased the fecal output of rats compared to the positive and negative control at 500 mg/kg oral dose after 8 and 16 hours (Anyanwu et al unpublished thesis, 2015). A. vogelii was shown to be a potent laxative at 500 mg/kg, but not at 250 mg/kg concentration of the extract. As common with all laxatives, A. vogelii increased bowel movement and loosened feces. Therefore, the results supported its traditional use as a laxative or purgative. Apart from A. vogelii, the diuretic and laxative effect of other Anthocleista species has not yet been reported. The dose, that is, 500 mg/kg at which the diuretic and laxative effect of A. vogelii was recorded seems high considering the use by humans, the biodiversity of the plant will greatly be affected. Also, considering that the diuretic effect of A. vogelii at 500 mg/kg was not more than that 25 mg/kg of Furosemide, there is need to research the bioactive component of the plant, possibly its effect may be comparable or more than the available standard diuretic drugs. 6. Toxicity studies There are several acute toxicity studies in different animals showing different safety levels or varying LD50 of the different 664 G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 parts of Anthocleista species. The acute toxicity study of aqueous extract of the stem bark of A. vogelii did not provoke a death until the dose of 20 g/kg p.o in mice (Mbianctha et al., 2013). The acute toxicity (LD50) of the ethanol stem bark extract was estimated to be 3162 mg/kg p.o in mice (Gboeloh et al., 2014). In another toxicity study on pet ether leaf extract of A. vogelii, no lethality was observed at 2000 mg/kg body weight i.p. in mice (Alaribe et al., 2012). Sunday et al. (2014) reported the LD50 of A. vogelii ethanol root extract as Z5000 mg/kg p.o in rats, while in an earlier study, the ethanol extract of A. vogelii root bark revealed no lethality at 6400 mg/kg p.o in rats (Anyanwu et al., 2013). The LD50 of the defatted ethanol root bark extract of A. nobilis was 200 mg/kg, i.p. in mice (Madubunyi and Asuzu, 1996). The acute toxicity study of the stem bark of A. grandiﬂora indicated that extract did not cause mortality of mice up to 1000 mg/kg p.o. (Okoye et al., 2014). Acute toxicity using a single dose of 2000 mg/ kg of aqueous extract of A. schweinfurthii bark administered orally to mice showed neither death nor signiﬁcant changes in the behavioral and morphological parameters after 14 days of observation (Christophe et al., 2015). In a subacute toxicity study, the aqueous extract of the stem bark of A. vogelii tested at the doses of 0, 250, 500 and 1000 mg/kg p.o. once daily for 28 days revealed decreases in the body weight and water consumption, and increases in food consumption without any signiﬁcant difference in the relative organ weight in mice (Mbianctha et al., 2013). The serum and hepatic level of ALT increased signiﬁcantly, but that was not the case in the levels of AST, proteins and creatinine in all the treated animals compared with the animals of the group controls. Also, the aqueous extract of A. vogelii showed reno-protective and hepatoprotective effect as compared with the control following ethanol-induced toxicity in rats (Ayoka et al., 2014). Ogbonnia et al. (2011) reported the evaluation of the acute and subacute toxicities of a Nigerian polyherbal tea remedy, prepared with A. vogelii, Ficus exasperata and Viscum album in Swiss albino mice and wistar rats of both sexes. The acute toxicity (LD50) of the polyherbal tea was determined to be 8.970 g/kg p.o in mice. The tea signiﬁcantly reduced plasma glucose, LDL-cholesterol, AST and creatinine levels, but increased HDL-cholesterol with no signiﬁcant increase in the body weight and ALT levels. The subacute toxicity of the aqueous extract of A. schweinfurthii bark at doses 250 mg/kg, 500 mg/kg and 1000 mg/kg showed no signiﬁcant variation in the evaluated parameters on male and female rats for 28 days (Christophe et al., 2015). The cytotoxic activity of the crude methanol extracts obtained from the stem, roots and leaves of A. djalonensis and three natural plant constituents (djalonenol, sweroside (1) and djalonensone (27) respectively) isolated from these extracts were evaluated in vitro against ST-57 brain tumor transformed ﬁbroblasts (Onocha et al., 2003). Comparatively, the three crude extracts as well as djalonenol and sweroside (1) exhibited low cytotoxicity (ED50 40– 70 μg/mL) while djalonensone (27) was not signiﬁcantly cytotoxic against the brain tumor transformed ﬁbroblasts (Onocha et al., 2003). The ethanol extracts of A. grandiﬂora showed little to no toxicity to brine shrimps (Mosh et al., 2010). Similar, the activity of A. djalonensis on brine shrimps lethality was not signiﬁcant (Awachie and Ugwu, 1997). The effect of aqueous ethanol extract of A. vogelii leaves against CCl4 induced toxicity in wistar albino rats restored the liver function to near normal indicating the protection of hepatic cells, also the extract increased the rate of erythropoiesis and antioxidant activity (Iroanya et al., 2015). The extract showed dose dependent signiﬁcant increase in the levels of catalase, glutathione peroxidase, superoxide dismutase, reduced glutathione and glutathione-S-transferase with decrease in the level of MDA compared to the normal and toxin control groups. The administration of 800 mg/kg of extract reduced the levels of ALP, AST and ALT levels almost the same as Silymarin. Also, the extract stimulated signiﬁcant (p o0.05) increase in PCV, Hb, platelet and MCH levels compared to the toxin control group. The oral administration of 67 mg/kg of defatted ethanol root bark extract of A. nobilis reduced pentobarbitone-induced sleep in CCl4-poisoned mice, and effect was comparable to that of Silibinin (Madubunyi and Asuzu, 1996). Elevation of serum ALT and AST induced by CCl4 intoxication in rats were also signiﬁcantly attenuated by the defatted ethanol root bark extract of A. nobilis (Madubunyi and Asuzu, 1996). Overall, the Anthocleista species are safe and not toxic at considerably high doses. The toxicity studies revealed that the genus possess hepatoprotective, reno-protective, free radical scavenging, and antioxidant properties. The above ﬁndings imply and validate the safety and tolerability of the plant various extracts in animals models. The 41 g/kg LD50 implies drug safety and tolerability in animal models. Additionally, subacute toxicity studies have shown safety and tolerability attributable partly to the hepatoprotective and antioxidant effects of the plant. The subacute toxicity studies have shown considerable safety and tolerability on over all parameters of health and imply safe usage, as practiced and experienced folklorically. 7. Conclusion Six of the fourteen accepted species of Anthocleista have been reported for their traditional medicinal uses in Africa. Scientiﬁc studies on Anthocleista have given credence to their use by traditional healers or locals in the treatment/management of various ailments such as diabetes, pain, inﬂammations, wounds, malaria, hypertension, stomach disorders, infertility, obesity, typhoid and worm infestations. However, its use as a contraceptive, antidote for snake bite, ear and eye treatments or in the treatment of asthma, STDs, jaundice, hemorrhoid, hernia, cancer, etc. had not been scientiﬁcally researched or proven. Forty chemical compounds were shown to have been isolated belonging to the groups of secoiridoids, nor-secoiridoids, xanthones, phytosterols, triterpenes, alkaloids, and others. The chemical structures of 29 isolated chemical compounds were displayed. Majority of the studies on Anthocleista species were on crude extract, few on fractions and very few on isolated compounds. There were no reports of mechanisms of action of the extracts/fractions/compounds of these plants on any of the disease conditions indicating that most of the studies were basic or preliminary and no clinical trial studies were found. Generally, the plants of this genus are considered to be safe and non-toxic as practiced and believed folklorically even at higher concentrations and subsequently validated in experimental animals. This review has provided for the ﬁrst time a repository of ethnopharmacological information while critically evaluating the relation between the traditional medicinal uses, chemical constituents and pharmacological activities of the Anthocleista species. Therefore, researchers have to move quickly and deeply in the investigations of this species, particularly for antidiabetic and antimicrobial agents. Also, there is need for substantial advanced research on their chemistry and pharmacological properties (both in vivo and in vitro), the determination of the mode of action of the active principles for new and already known pharmacological activities and commencement of clinical studies of some Anthocleista species which will hopefully lead to newer, more effective and less toxic drugs. G.O. Anyanwu et al. / Journal of Ethnopharmacology 175 (2015) 648–667 Acknowledgments We wish to thank The World Academy of Sciences (TWAS) and COMSATS Institute of Information Technology (CIIT) for giving the lead author the Award of 2014 CIIT-TWAS Sandwich Postgraduate Fellowship in CIIT, Abbottabad, Pakistan. Thanks to Dr. Ethelbert Chukwuagozie and Dr. Opeolu Ojo who assisted in sourcing some materials for the writing of this paper. 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