Ethnopharmacology and Therapeutic Value of Bridelia micrantha (Hochst.) Baill. in Tropical Africa: A Comprehensive Review

Bridelia micrantha is traditionally used in tropical Africa to treat a wide range of human and animal diseases. The aim of this study was to summarise the research that has been done on the ethnomedicinal uses, phytochemistry and pharmacological properties of B. micrantha so as to understand its importance and potential value in primary healthcare systems. The literature search for information on ethnomedicinal uses and pharmacological activities of B. micrantha was undertaken using databases such as Web of Science, Scopus, Google Scholar, Science Direct, BioMed Central (BMC), PubMed and Springerlink. Other relevant literature sources included books, book chapters, websites, theses, conference papers and other scientific publications. This study showed that B. micrantha is used as herbal medicine in just over half (57.3%) of the countries in tropical Africa where it is indigenous. A total of 54 ethnomedicinal uses of B. micrantha have been recorded with a high degree of consensus on burns, wounds, conjunctivitis, painful eyes, constipation, gastric ulcers, cough, headache, rheumatism, painful joints, dysentery, ethnoveterinary medicine, malaria, sexually transmitted infections, stomach ache, tape worms and diarrhoea. Different plant parts, aqueous and organic extracts exhibited anthelmintic, antimicrobial, anticonvulsant and sedative, antidiabetic, antidiarrhoeal, antinociceptive, antioxidant, antiplasmodial, antischistosomal, hepatoprotective, insecticidal and β-lactamase inhibitory activities.


Introduction
Bridelia micrantha (Hochst.) Baill. is a small to medium sized tree belonging to the family Phyllanthaceae (formerly Euphorbiaceae), commonly known as mitzeerie or coastal golden leaf [1]. The genus name "Bridelia" was coined in honour of Samuel Elisée Bridel-Brideri (1761-1828), a Swiss-German muscologist [2]. The species name, "micrantha" means "small-flowered" [2], in reference to the species' very small flowers in auxillary clusters [3]. The genus Bridelia includes approximately 60-70 species found throughout tropical and subtropical regions of the world, particularly Africa and Asia [3,4]. Several Bridelia species are used in traditional medicine throughout the world as an anthelmintic, antiamebic, antianemic, antibacterial, anticonvulsant, antidiabetic, antidiarrhoeal, antiinflammatory, antimalarial, antinociceptive, antiviral, hypoglycemic and for abdominal pain, cardiovascular, gynecological and sexual diseases [4]. Thus it is not surprising that the bark, leaves and roots of B. micrantha are widely used as herbal medicines in tropical Africa [1], while the round and black berries of the species are widely eaten, particularly by children and can be used to make jams and juices [5,6]. B. micrantha has been identified as one of the few plant species that should be integrated in the domestication process in farming systems in sub-Saharan Africa to support medicinal, nutritional and income security of local communities through household use and marketing of its fresh or dried fruits [7]. At present, B. micrantha is domesticated as a fruit tree in Malawi [8] in Tanzania [9]. Due to its popularity as a herbal medicine, B. micrantha is sold as such edicine or "muthi" markets in Cameroon [10], Malawi [11], Nigeria [12] and South micrantha is also an important timber tree species in tropical Africa, and the species is loited as a source of wood for construction, poles, furniture, mortars, spoons and tool opia [1,14] and Kenya [1]. The present review is aimed at documenting the ethnomedicinal l activities and the correlated chemical compounds of B. micrantha with emphasis on of the ethnopharmacological uses of the species. Results of this review are expected to challenges and perspectives required to address the knowledge gaps of this important t species in tropical Africa. ethodology ha and other historical names and synonyms of the species such as Bridelia abyssinica yssinica Pax var. densiflora Gehrm., Bridelia mildebraedii Gehrm., Bridelia speciosa Mϋell. oclada Mϋell. Arg., Bridelia stenocarpa Mϋell. Arg., Bridelia zanzibarensis Vatke & Pax, crantha Hochst. as well as common names such as "Benin ironwood", "coastal golden ie" and "Yoruba ironwood" were used as the keywords in searching the major databases of Science, Scopus, Google Scholar, Science Direct, BioMed Central (BMC), PubMed nk documenting traditional uses, medicinal uses, ethnobotany, ethnomedicinal uses, ology, pharmacology, phytochemistry and therapeutic value of the species. Additional ding pre-electronic literature such as scientific articles, conference papers, books, book rtations, these and other grey material were sourced from the University of Fort Hare h Africa.

Distribution and Botanical Description
tha has been recorded in several countries throughout tropical Africa ( Figure 1). The o been introduced on Réunion Island as a medicinal plant and is now naturalized on B. micrantha is found in a variety of habitats, ranging from savanna and woodland to ded grassland, riverine forest, swamp forest and the margins of mangrove swamps, -level in West Africa to around 2500 m altitude in East Africa [1]. B. micrantha is a s that tolerates a wide diversity of soils, different rainfall regimes and can withstand t. ha is an evergreen or deciduous, monoecious small to medium-sized tree up to 27 m rt, often twisted bole up to 100 cm in diameter and a rounded crown [3]. The bark of silver-grey to black in colour, smooth or rough with lenticels and reticulately fissured 3]. Young branches of B. micrantha often have spines and occasionally blunt spines are r branches. Leaves are simple, entire, distichous, often alternate, glabrous to slightly l to oblong in shape. Flowers occur in clusters in leaf axils, yellow in colour, unisexual r sepals and small petals [2,3]. Male flowers have stamens and filaments that are fused at the base, but free and spreading above with rudimentary ovary. Female flowers are with ovary and styles fused at the base. The fruit is a globose, fleshy drupe, black in ipe with brownish seeds [3]. medicinal tree in Tanzania [9]. Due to its popularity as a herbal medicine, B. micrantha is sold as such in the herbal medicine or "muthi" markets in Cameroon [10], Malawi [11], Nigeria [12] and South Africa [13]. B. micrantha is also an important timber tree species in tropical Africa, and the species is being overexploited as a source of wood for construction, poles, furniture, mortars, spoons and tool handles in Ethiopia [1,14] and Kenya [1]. The present review is aimed at documenting the ethnomedicinal uses, biological activities and the correlated chemical compounds of B. micrantha with emphasis on the validation of the ethnopharmacological uses of the species. Results of this review are expected to reveal research challenges and perspectives required to address the knowledge gaps of this important medicinal plant species in tropical Africa.

Research Methodology
B. micrantha and other historical names and synonyms of the species such as Bridelia abyssinica Pax, Bridelia abyssinica Pax var. densiflora Gehrm., Bridelia mildebraedii Gehrm., Bridelia speciosa Mϋell. Arg. var. trichoclada Mϋell. Arg., Bridelia stenocarpa Mϋell. Arg., Bridelia zanzibarensis Vatke & Pax, Candelabria micrantha Hochst. as well as common names such as "Benin ironwood", "coastal golden leaf", "mitzeerie" and "Yoruba ironwood" were used as the keywords in searching the major databases including Web of Science, Scopus, Google Scholar, Science Direct, BioMed Central (BMC), PubMed and Springerlink documenting traditional uses, medicinal uses, ethnobotany, ethnomedicinal uses, ethnopharmacology, pharmacology, phytochemistry and therapeutic value of the species. Additional literature, including pre-electronic literature such as scientific articles, conference papers, books, book chapters, dissertations, these and other grey material were sourced from the University of Fort Hare library in South Africa.

Occurrence, Distribution and Botanical Description
B. micrantha has been recorded in several countries throughout tropical Africa ( Figure 1). The species has also been introduced on Réunion Island as a medicinal plant and is now naturalized on the island [1]. B. micrantha is found in a variety of habitats, ranging from savanna and woodland to seasonally flooded grassland, riverine forest, swamp forest and the margins of mangrove swamps, often from sea-level in West Africa to around 2500 m altitude in East Africa [1]. B. micrantha is a pioneer species that tolerates a wide diversity of soils, different rainfall regimes and can withstand moderate frost.
B. micrantha is an evergreen or deciduous, monoecious small to medium-sized tree up to 27 m tall with a short, often twisted bole up to 100 cm in diameter and a rounded crown [3]. The bark of B. micrantha is silver-grey to black in colour, smooth or rough with lenticels and reticulately fissured and flaking [2,3]. Young branches of B. micrantha often have spines and occasionally blunt spines are found on older branches. Leaves are simple, entire, distichous, often alternate, glabrous to slightly hairy, elliptical to oblong in shape. Flowers occur in clusters in leaf axils, yellow in colour, unisexual with triangular sepals and small petals [2,3]. Male flowers have stamens and filaments that are fused into a column at the base, but free and spreading above with rudimentary ovary. Female flowers are nearly sessile with ovary and styles fused at the base. The fruit is a globose, fleshy drupe, black in colour when ripe with brownish seeds [3].
ell. Arg., Bridelia zanzibarensis Vatke & Pax, Candelabria micrantha Hochst. as well as common names such as "Benin ironwood", "coastal golden leaf", "mitzeerie" and "Yoruba ironwood" were used as the keywords in searching the major databases including Web of Science, Scopus, Google Scholar, Science Direct, BioMed Central (BMC), PubMed and Springerlink documenting traditional uses, medicinal uses, ethnobotany, ethnomedicinal uses, ethnopharmacology, pharmacology, phytochemistry and therapeutic value of the species. Additional literature, including pre-electronic literature such as scientific articles, conference papers, books, book chapters, dissertations, these and other grey material were sourced from the University of Fort Hare library in South Africa.

Occurrence, Distribution and Botanical Description
B. micrantha has been recorded in several countries throughout tropical Africa ( Figure 1). The species has also been introduced on Réunion Island as a medicinal plant and is now naturalized on the island [1]. B. micrantha is found in a variety of habitats, ranging from savanna and woodland to seasonally flooded grassland, riverine forest, swamp forest and the margins of mangrove swamps, often from sea-level in West Africa to around 2500 m altitude in East Africa [1]. B. micrantha is a pioneer species that tolerates a wide diversity of soils, different rainfall regimes and can withstand moderate frost.
B. micrantha is an evergreen or deciduous, monoecious small to medium-sized tree up to 27 m tall with a short, often twisted bole up to 100 cm in diameter and a rounded crown [3]. The bark of B. micrantha is silver-grey to black in colour, smooth or rough with lenticels and reticulately fissured and flaking [2,3]. Young branches of B. micrantha often have spines and occasionally blunt spines are found on older branches. Leaves are simple, entire, distichous, often alternate, glabrous to slightly hairy, elliptical to oblong in shape. Flowers occur in clusters in leaf axils, yellow in colour, unisexual with triangular sepals and small petals [2,3]. Male flowers have stamens and filaments that are fused into a column at the base, but free and spreading above with rudimentary ovary. Female flowers are nearly sessile with ovary and styles fused at the base. The fruit is a globose, fleshy drupe, black in colour when ripe with brownish seeds [3].

Ethnomedicinal Uses of B. micrantha
The bark, leaf sap, leaves and roots of B. micrantha are reported to possess diverse medicinal properties and cure various human ailments and diseases throughout its distribution range in tropical Africa. A total of 54 ethnomedicinal uses of B. micrantha have been recorded (Table 1).
There is cross-cultural agreement among ethnomedicinal uses of B. micrantha with a high degree of consensus on burns and wounds, conjunctivitis and painful eyes, constipation, gastric ulcers, cough, headache, rheumatism and painful joints, dysentery, ethnoveterinary medicine, malaria, sexually transmitted infections (STIs), stomach ache, tape worms and diarrhoea (

Ethnomedicinal Uses of B. micrantha
The bark, leaf sap, leaves and roots of B. micrantha are reported to possess diverse medicinal properties and cure various human ailments and diseases throughout its distribution range in tropical Africa. A total of 54 ethnomedicinal uses of B. micrantha have been recorded (Table 1).
There is cross-cultural agreement among ethnomedicinal uses of B. micrantha with a high degree of consensus on burns and wounds, conjunctivitis and painful eyes, constipation, gastric ulcers, cough, headache, rheumatism and painful joints, dysentery, ethnoveterinary medicine, malaria, sexually transmitted infections (STIs), stomach ache, tape worms and diarrhoea (

Phytochemical Constituents of B. micrantha
Multiple classes of phytochemicals including alkaloids, anthocyanidin, anthraquinones, carbohydrates, cyanogenic glycoside, essential oil, ester, flavonoids, oxalate, phenolic compounds, saponins, sterols, tannins, terpenoids as well as several minerals have been isolated from the bark, fruits, leaves and roots of B. micrantha [4,36,46,69,[70][71][72][73][74][75][76][77]. Bark, fruits and leaves of B. micrantha contain a wide variety of classic nutrients, such as minerals, carbohydrates, polyol (hexahydroxy alcohol), and proteins (Table 2). Several chemical elements such as calcium, chromium, cobalt, copper, iron, lead, magnesium, manganese, nickel, phosphorus, potassium, sodium and zinc have been isolated from B. micrantha fruits ( Table 2). Shelembe [46] found that the concentrations of elements in the fruits of B. micrantha were in the decreasing order of Mg > Ca > Mn > Zn > Fe > Cu > Co > Ni ≈ Cr > Pb. The dietary reference intake (DRI) of some of the chemical elements is shown in Table 2 based on the FAO or WHO recommended dietary allowance (RDA) and tolerable upper levels (UL) [46]. Most major elements such as Mg, Ca, K and Na, and heavy metals such as Mn, Zn, Fe, Cu and Cr as determined by Shelembe [46] are within the permissible limit defined by FAO/WHO.

Anthelmintic
Waterman et al. [79] evaluated the anthelmintic activities of aqueous and organic bark extract of B. micrantha using a standard motility assay against a levamisole resistant strain of the nematode Caenorhabditis elegans. The degree of activity of extracts was presented as average percentage of worm death and statistically compared to a negative control. B. micrantha aqueous and organic bark extracts showed 89.4% and 80.7% dead worms higher than the negative control [79]. These anthelmintic evaluations are of importance in the traditional use of B. micrantha against tape worms in Cameroon [32], Ghana [34], Kenya [38,60], Nigeria [41], South Africa [2,25], Tanzania [9] and Uganda [15] and will also play an important role in future research focusing on control and management of worm infections in sub-Saharan Africa.

Antibacterial
Samie et al. [80] evaluated the antibacterial activities of B. micrantha methanol, acetone and hexane bark, roots and seeds extracts against Aeromonas hydrophila, Bacillus cereus, Bacillus pumilus, Bacillus subtilis, Enterobacter cloacae, Enterococcus fecalis, Escherichia coli, Klebsiella pneumoniae, Pantoea agglomerans, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella cholerae-suis, Serratia marcescens, Staphylococcus aureus and Shigella flexneri using the disc diffusion and the micro-dilution methods. The extracts of the bark, roots and seeds of B. micrantha gave diameter of zone of inhibition ranging from 8-14 mm against all pathogenic organisms except K. pneumoniae and S. cholerae-suis [80]. The minimal inhibitory concentration (MIC) values of methanol, acetone and hexane bark, roots and seeds extracts against the tested bacteria were within the range of 1.5 mg/mL to >12 mg/mL [80]. Similarly, Steenkamp et al. [19] evaluated antibacterial activities of methanol bark extract of B. micrantha against E. coli, P. aeruginosa, S. aureus and Staphylococcus epidermidis using the plate-hole diffusion and broth micro-dilution methods. None of the extracts showed activity against E. coli and P. aeruginosa while MIC values between 1.25 mg/mL and 5.00 mg/mL were obtained against S. aureus and S. epidermidis [19]. Gangoué-Piéboji et al. [32] evaluated the antibacterial activities of B. micrantha methanol stem bark extracts against clinically proved beta-lactam-resistant bacteria Acinetobacter baumannii, Enterobacter aerogenes, E. cloacae, Enterococcus hirae, Enterococcus spp., E. coli, Klebsiella oxytoca, K. pneumoniae, P. aeruginosa, S. marcescens and S. aureus by using disc-diffusion and agar-dilution assays. The methanol extracts demonstrated broad spectrum activity against all bacteria tested with inhibition zones in the range of 14-27 mm. The MIC values of methanol extracts against the tested bacteria were found to range from 1.25 mg/mL to 10 mg/mL [32]. Adefuye et al. [81] evaluated antibacterial activities of B. micrantha dichloromethane, ethyl acetate, acetone, ethanol, methanol and methanol hydroxide stem bark extracts against Salmonella typhimurium, Shigella sonnei and S. aureus using agar-well diffusion method with ciprofloxacin as control. Zone diameters of inhibition ranged from 0 to 28 mm for the six extracts and 29 to 38 mm for ciprofloxacin. The MIC 50 values ranged from 0.078 mg/mL to 1.25 mg/mL [81]. Mabeku et al. [36] evaluated the antibacterial activities of methanol, ethanol, hexane, ethyl acetate, aqueous, mixture of methanol and water, and mixture of ethanol and water stem bark extracts of B. micrantha against B. cereus, Citrobacter freundii, E. cloacae, E. coli, K. pneumoniae, Morganella morganii, P. agglomerans, Proteus vulgaris, P. mirabilis, P. aeruginosa, Salmonella typhi, Shigella dysenteriae, S. flexneri, S. aureus and Streptococcus feacalis using the disc diffusion assay and broth micro-dilution methods. The best antibacterial activity was demonstrated against S. typhi with MIC value of 50 µg/mL and minimal bactericidal concentration (MBC) value of 400 µg/mL [36]. In a different study, Adefuye and Ndip [82] evaluated antibacterial activities of ethyl acetate extract of stem bark of B. micrantha against S. typhimurium, S. sonnei and S. aureus with ciprofloxacin as a positive control. The MIC 50 values ranged from 0.0048 mg/mL to 0.312 mg/mL [82]. Traore et al. [83] evaluated antibacterial activities of methanolic stem bark extracts of B. micrantha against E. coli, Mycobacterium chelonae and S. aureus. The methanolic extract of B. micrantha demonstrated weak activity against E. coli with IC 50 values of 64 µg/mL [83]. Douglas and Gitonga [74] evaluated antibacterial activities of methanol and ethyl acetate leaf extracts of B. micrantha against E. coli, S. typhi and S. aureus using micro-broth dilution assay. Methanol extract of B. micrantha exhibited a zone of inhibition of 7 to 19 mm against S. aureus and S. typhi respectively [74]. These documented antibacterial properties of B. micrantha corroborate the traditional uses of the species against bacterial infections such as cough in Cameroon, DRC, Nigeria and Zimbabwe [16,18,21,22,28,32,33], diarrhoea in Cameroon, DRC, Kenya, Nigeria, South Africa and Tanzania [2,9,16,22,25,32,36,[38][39][40][41], dysentery in Burundi, Cameroon, DRC, Gambia and Nigeria [16,33,36,42,43], sexually transmitted diseases in Guinea-Bissau and Kenya [47,60,63], stomach ache in Guinea-Bissau, Kenya, Nigeria, South Africa and Tanzania [38,41,47,48,51,60], syphilis in Sierra Leone and Uganda [61,65] and venereal diseases in Kenya and South Africa [2,23,25,38].

Anticonvulsant and Sedative
Bum et al. [84] evaluated the anticonvulsant effects of crude stem bark extracts of B. micrantha using mice model maximal electroshock (MES), strychnine (STR), pentylenetetrazol (PTZ), picrotoxin (PIC), isonicotinic hydrazide acid (INH)-induced convulsions and diazepam-induced sleep in assessing the sedative effects. Results showed that B. micrantha stem bark extracts at the doses of 34 and 67 mg/kg protected 100%, 80%, 80% and 80% of mice from PIC, STR, PTZ and MES-induced seizures, respectively [84]. B. micrantha also delayed the onset to seizures in the INH test. The decoctions of B. micrantha possess sedative and anticonvulsant activities and these results corroborate the use of the species as herbal medicine for epilepsy and insomnia in Cameroon [55].

Antidiabetic
Adika et al. [85] evaluated the antidiabetic activities of methanol leaf extract of B. micrantha using alloxan-induced diabetic mice in vivo and in vitro. The methanol leaf extract at the dose of 250, 500, and 1500 mg/kg showed remarkable time-dependent decrease in blood glucose level in alloxan-induced diabetic mice. Adika et al. [85] found that there was no significant difference between the extract-treated groups and the groups treated with 10 mg/kg of distilled water and glibenclamide (2 mg/kg) respectively. Adika et al. [85] found that after six hours posttreatment, the blood glucose level for the groups treated with 250 mg/kg of B. micrantha and glibenclamide (2 mg/kg) were lower than the normal blood glucose level for the groups before the induction of diabetes. Even in its crude form, the effects were comparable to that of glibenclamide, an oral sulfonylurea with proven antidiabetic activity. These findings demonstrate that B. micrantha has antidiabetic effects on experimental model of diabetes in mice and validate its use in Cameroon, Guinea and Nigeria as a traditional medicine for the treatment of diabetes mellitus [34][35][36][37]. This finding suggests that the leaf extract could be a potential source of a novel antidiabetic for the management of diabetes mellitus.

Anti-Helicobacter pylori
Adefuye et al. [81] evaluated anti-Helicobacter pylori activities of B. micrantha dichloromethane, ethyl acetate, acetone, ethanol, methanol and 40% methanol hydroxide stem bark extracts against Helicobacter pylori using agar-well diffusion method with ciprofloxacin as control. Zone diameters of inhibition ranged from 0 to 18 mm for the extract and 29 to 38 mm for ciprofloxacin. The MIC 50 values ranged from 0.312 mg/mL to 0.625 mg/mL [81]. Okeleye et al. [70] evaluated anti-Helicobacter pylori activities of ethyl acetate, acetone, aqueous and methanol extracts of stem bark of B. micrantha against Helicobacter pylori using clarithromycin, metronidazole and amoxicillin as controls. The inhibition zone diameters ranged from 0-23 mm for all the extracts in comparison to 0-35 mm observed for clarithromycin [70]. Marked susceptibility of H. pylori strains (100%) was observed for the acetone extract, followed by ethyl acetate extract at 93.5% and clarithromycin had susceptibility of 58.1% [70]. The MIC 50 values ranged from 0.0048 to 0.313 mg/mL while the MIC 90 values ranged from 0.0048 to 2.5 mg/mL for the acetone and ethyl acetate extracts [70]. Adefuye and Ndip [82] evaluated anti-Helicobacter pylori activities of ethyl acetate extract of stem bark of B. micrantha against H. pylori with ciprofloxacin as positive control. B. micrantha extracts showed some activity with MIC 50 values ranging from 1.25 mg/mL to 5.0 mg/mL [82]. The ethyl acetate extract could thus be a potential source of lead molecules for the design of new anti-Helicobacter pylori therapies. These findings are significant since bark, leaf and root decoctions of B. micrantha are widely used as traditional remedies for gastric ulcers in Cameroon [32], DRC [16] and South Africa [46].

Antimycobacterial
Green et al. [86] evaluated the antimycobacterial activities of acetone, methanol, hexane and ethanol leaf extracts of B. micrantha against Mycobacterium tuberculosis using a tetrazolium microplate assay to determine the minimum inhibitory concentration (MIC). Acetone extract was active against M. tuberculosis with a MIC value of 25 µg/mL [86]. In another study, Green et al. [78] evaluated the antimycobacterial activities of the n-hexane sub-fraction of ethyl acetate fractions from acetone extracts of B. micrantha stem barks using the resazurin microplate assay against M. tuberculosis. The n-hexane fraction showed 20% inhibition of M. tuberculosis H37Ra and almost 35% inhibition of M. tuberculosis isolate resistant to all first-line drugs at 10 µg/mL [78]. The primary ethyl acetate fraction showed MIC value of 8.25 µg/mL against H37Ra M. tuberculosis strain [78]. The fraction also inhibited the growth of M. tuberculosis isolate resistant to isoniazid (INH), ethambutol (EMB), streptomycin (STM) and rifampicin (RIF) at a concentration of 50 µg/mL [78]. These preliminary evaluations done by Green et al. [78,86] serve as scientific validation for the use of B. micrantha in traditional medicine for treatment of respiratory systems such as chest complaints and cough in Cameroon [21,28,32], DRC [16,22], Nigeria [33] and Zimbabwe [18].

Antinociceptive
Onoja et al. [87] evaluated the antinociceptive effects of the hydromethanolic extract of B. micrantha stem bark. The antinociceptive effects of B. micrantha extracts at the doses of 50, 100 and 200 mg/kg were investigated using male Wistar rats via acetic acid-induced writhing reflex and tail flick methods and the effects of B. micrantha on thiopentone-induced narcosis was also investigated. The B. micrantha extracts produced a significant dose-dependent decrease in the mean number of abdominal constriction in the acetic acid-induced writhing reflex when compared to the negative control. Both the extract (200 mg/kg) and paracetamol (400 mg/kg) produced 61.85% and 73.08% inhibition of writhing reflex, respectively [87]. B. micrantha and pentazocine (3 mg/kg) caused a significant increase in the pain reaction time (PRT) in treated rats when compared to the negative control group in tail flick method. The pretreatment of the rats with B. micrantha at different doses increased the normal sleeping time of thiopentone from 69.33 ± 7.31 min to an average of 105.33 ± 11.88 min [87]. The results of the effect of the extract on acetic acid-induced writhing reflex suggest that the extract may have a peripheral pain relieving effect mediated through the inhibition of cyclooxygenase and prostaglandin synthesis. These findings support the traditional use of B. micrantha in the management of pain, for example as remedy for abdomninal pain in DRC and Uganda [15,16], epigastric pain and sore eyes in Tanzania [45], muscle pain in Cameroon [55], painful eyes, joints and as pain killer in South Africa [2,23,25,39,46,54] and wounds in DRC, Sierra Leone and South Africa [2,16,[23][24][25]65].

Antioxidant
Nwaehujor and Udeh [88] evaluated the antioxidant activities of the methanolic leaf extracts of B. micrantha using the DPPH (2,2-diphenyl-1-picrylhydrazyl) and ferric reducing antioxidant power (FRAP) assay methods. The DPPH assay showed 98% antioxidant activity at concentration of 400 µg/mL while FRAP values were 0.016, 0.39, 0.455, 0.601 and 1.382 µM at 10, 50, 100, 200 and 400 µg/mL respectively [88]. Adika et al. [85] evaluated antioxidant activities of methanol leaf extracts of B. micrantha using DPPH spectrophotometric assay at the concentration of 400 µg/mL. The ferric reducing antioxidant power showed a significant concentration-dependent increase in the total antioxidant power. Nwaehujor et al. [89] evaluated antioxidant activities of the methanolic leaf extracts of B. micrantha using the DPPH and FRAP assay methods with ascorbic acid as reference standard. The methanol extracts of B. micrantha leaves gave 98% antioxidant activity at a maximal test concentration of 400 µg/mL while ascorbic acid produced a comparatively reduced percentage value of 79% at the same concentration [89]. In the FRAP assay, B. micrantha leaf extracts produced 1.39 µM at 400 µg/mL but 1000 µg/mL of ascorbic acid had a standard FRAP value of 2.0 µM [89]. Onoja et al. [87] evaluated the antioxidant activities of the hydromethanolic extract of B. micrantha stem bark using 2,2-diphenyl-1-picrylhydrazyl (DPPH) photometric assay. B. micrantha extract produced concentration-dependent increase in percentage antioxidant activity in DPPH photometric assay. The B. micrantha extract demonstrated a potent antioxidant activities with 50% inhibitory concentration (IC 50 ) of <25 µg/mL concentration in DPPH photometric assay [87]. These results suggest that B. micrantha has antioxidant potential. Shelembe et al. [77] evaluated the antioxidant activities of fruit methanol extracts of B. micrantha using the DPPH stable free radical method using ascorbic acid as control. The IC 50 value for the methanol extract of the stem bark of B. micrantha was 150 µg/mL while that of the standard ascorbic acid was 41 µg/mL indicating the high antioxidant potential of the plant, especially the stem bark [77]. The scavenging effect of fruit extract increased with increasing concentrations, with the extract exhibiting appreciable scavenging activity at 1000 µg mL −1 with the scavenging ability 85.5% [77]. These antioxidant activities are probably due the presence of flavonoids and phenolic compounds [100].

Antischistosomal
Waiganjo et al. [92] evaluated the antischistosomal activities of hexane, methanol and water extract of B. micrantha bark on Swiss white mice infected with Schistosoma mansoni with praziquantel as control. There were no significant differences between praziquantel which showed worm reduction percentages of 75.2% against 48.7% and 63.4% demonstrated by hexane and water extracts respectively [92]. These findings demonstrated that B. micrantha extracts were able to protect the mice from schistosomiasis infection.

Antiviral
Bessong et al. [39] evaluated B. micrantha leaf methanol extracts against human immunodeficiency type 1 reverse transcriptase by assessing inhibition of the RNA dependent DNA polymerase activity by measuring the degree of incorporation of methyl-3H thymidine triphosphate using polyadenylic acid. Ribonuclease H activity was evaluated by measuring the extent of degradation of a radiolabelled RNA in an RNA/DNA hybrid by reverse transcriptase. The methanol extract of the leaves of B. micrantha inhibited the polymerase with IC 50 value of 23.5 µg/mL and the ribonuclease H with IC 50 value of 18.9 µg/mL [39]. In another study, Bessong et al. [40] evaluated antiviral activities of B. micrantha root methanol extracts for activity against HIV-1 reverse transcriptase (RT) and integrase (IN). The n-butanol fraction obtained from the crude methanol extracts of B. micrantha inhibited the RNA-dependent-DNA polymerization (RDDP) activity of HIV-1 RT with an IC 50 of 7.3 µg/mL. More pharmacological evaluations are required as B. micrantha is widely used against viral infections such as HIV/AIDs in Kenya [52], yellow fever in Tanzania [20] and other infectious diseases such as diarrhoea, dysentery, sexually transmitted infections (STIs) and skin infections.

Hepatoprotective
Nwaehujor and Udeh [88] evaluated hepatoprotective activities of the methanolic leaf extracts of B. micrantha on paracetamol induced liver damage in Wistar rats through measuring alanine aminotransaminase (ALT), aspartate aminotransferase (AST), alkaline phosphate (ALP), bilirubin and total protein. B. micrantha extract significantly decreased the level of AST in the rats given PCM, reduced ALP and total bilirubin while total protein was significantly increased [88]. Nwaehujor and Udeh [88] also found that the ethyl acetate extract of B. micrantha had better hepatoprotective effects on the Wistar rats than the known silymarin especially at 300 mg/kg. Therefore, B. micrantha has the ability to help in the regeneration of damaged hepatic cells and can be useful in the treatment and management of hepatic diseases.

Insecticidal
Adesina et al. [93] evaluated the insecticidal activities of aqueous leaf extracts of B. micrantha against Podagrica uniforma (Jacoby) and Nisotra dilecta (Jacoby) insect pests of okra (Abelmoschus esculentus (L.) Moench) with synthetic insecticide cypermethrin as control. Yield parameters such as number of fruits and fruit weight were collected on insect population before treatment application and three days after spraying of insecticides at 28, 35, 42, 56 days after planting (DAP). There were no significant differences between mean number of P. uniforma and N. dilecta counted on okra plants after 56 DAP which were 0.80 ± 0.10 and 0.47 ± 0.17 for B. micrantha and cypermethrin respectively. There were no significant differences in mean yield of okra fruits after application of B. micrantha and cypermethrin which stood at 0.93 ± 0.3 and 2.20 ± 0.23 respectively [93]. Results obtained showed that B. micrantha extracts exhibited effectiveness in reducing the insect population and improved A. esculentus fruit yield compared to cypermethrin. Therefore, B. micrantha crude extracts could be explored as promising insecticidal agents to provide valuable alternatives to chemical control of insect infestation on A. esculentus [93]. These findings indicate that B. micrantha has insecticidal properties corroborating traditional use of the bark and leaf decoction as insecticide in Tanzania [51].

β-Lactamase Inhibitory
Gangoué-Piéboji et al. [94] evaluated the anti-β-lactamase activities of methanolic stem bark extracts of B. micrantha by assessing the inhibition activities (over 90%) against four classes of β-lactamases, namely TEM-1, OXA-10, IMP-1 and P99. B. micrantha extracts had strong inhibition activities of 99.2% and 92.0% against OXA-10 and P99 respectively. After elimination of tannins, the extracts of B. micrantha were tested further for anti-β-lactamase activities with OXA-10 demonstrating potent inhibitory activity with 50% inhibitory concentration (IC 50 ) value of 0.02 mg/mL [94]. Further research aimed at isolating and elucidating the chemical structure of the active constituents of B. micrantha will provide useful leads in the search and development of β-lactamase inhibitors.

Toxicity and Cytotoxicity
Ajaiyeoba et al. [95] reported the cytotoxicity effects of 20 plants used in Nigeria as antimalarials. The 50% lethal concentration (LC 50 value) at 95% confidence interval was calculated with the brine shrimp lethality assay for each plant methanol extract. B. micrantha leaf extract showed the least LC 50 value of >9.0 × 10 6 µg/mL [95]. Moshi et al. [97] evaluated toxicity of dichloromethane and/or ethanol root extracts of B. micrantha using brine shrimp toxicity with dimethyl sulphoxide (DMSO) and seawater as negative controls. B. micrantha ethanol root extract was found to be mildly toxic with concentration killing fifty percent of the larvae (LC 50 ) of 30 µg/mL [97]. Onoja et al. [87] assessed oral acute toxicity of hydromethanolic stem bark extract of B. micrantha using the OECD guideline, the up-and-down-procedure by orally dosing five male Wistar rats with 2000 mg/kg of B. micrantha and observing the rats for 48 h for signs of toxicity and death. Oral administration of the B. micrantha extract was well tolerated at the dose of 2000 mg/kg and no death and clinical signs of toxicity were observed [87]. Similarly, Osebe et al. [99] evaluated toxicity of water stem bark extract of B. micrantha using brine shrimp lethality test for the determination of LC 50 and the water extract with LC 50 of 77 µg/mL was deemed toxic.
Steenkamp et al. [96] evaluated the cytotoxicity of B. micrantha using human adenocarcinoma cells of the cervix (HeLa), human breast cells (MCF-12A), lymphocytes (both resting and stimulated) and primary porcine hepatocytes. Steenkamp et al. [96] also determined acute systemic toxicity of B. micrantha extracts using the luminescent bacteria Vibrio fischerii and the vertebrate Poecilia reticulata (guppy). The 50% inhibition of proliferation (IC 50 ) of B. micrantha in HeLa cells was 8.9 µg/mL, IC 50 was 24.2 µg/mL in MCF-12A cells and the positive control, cisplatin had IC 50 value of 1.14 µg/mL and 0.21 µg/mL for the HeLa and MCF-12A cells respectively. Toxicity was found to be concentration dependent when HeLa and MCF-12A cells were exposed to B. micrantha extracts. B. micrantha extracts resulted in 100% mortality of the guppies [96]. Similarly, Omosa et al. [98] evaluated the cytotoxicity of dichloromethane and methanol (1:1) extract of B. micrantha leaves and stem bark using the resazurin reduction assay against CCRF-CEM leukemia cell line. The dichloromethane and methanol extract of B. micrantha leaves and stem bark displayed cytotoxicity towards leukemia CCRF-CEM cells with IC 50 value of 9.43 µg/mL and 23.5 µg/mL respectively [98]. These studies show that B. micrantha extracts are cytotoxic and possess acute systemic toxicity. According to Verdcourt and Trump [101], B. micrantha is poisonous as death of a patient has been reported, four hours after the ingestion of a cough mixture made from B. micrantha herbal concoction in Kenya.

Conclusions
The historical traditional usage of B. micrantha as herbal medicine throughout its distribution range, the documented phytochemistry and pharmacological properties call for detailed pharmacokinetics and clinical research on the species and its pharmaceutical and food products. At the moment there is insufficient evidence to interpret the documented ethnomedicinal uses with specific chemical mechanisms associated with some of the documented pharmacological properties. Future research should identify the bioactive compounds, details of their molecular modes or mechanisms of action, pharmacokinetics and physiological pathways for specific bioactives of B. micrantha. B. micrantha has been categorized as poisonous by Verdcourt and Trump [101], toxicity and cytotoxicity studies conducted by Steenkamp [96], Moshi et al. [97], Omosa et al. [98] and Osebe et al. [99] appear to suggest that the species is toxic and may cause damage to genetic material and therefore, has potential to cause long-term damage in patients when administered as herbal medicines. There is need for rigorous toxicological and clinical studies aimed at identification of poisonous compounds, associated pharmacological activities and the side effects that are likely to be caused when B. micrantha is used as herbal medicine. Therefore, future research should focus on dosage range that is safe for humans and evaluation of target-organ toxicity.