Review of Ethnomedicinal, Phytochemical and Pharmacological Properties of Lannea schweinfurthii (Engl.) Engl.

Lannea schweinfurthii is a valuable medicinal plant species among different ethnic groups in tropical Africa. The aim of the current study was to review existing literature on the ethnomedicinal uses, phytochemistry and pharmacological properties of L. schweinfurthii in an effort to evaluate the therapeutic potential of the species. The relevant information on the ethnomedicinal uses, phytochemistry and pharmacological properties of L. schweinfurthii was generated from several sources including books, book chapters, theses, scientific reports and journal articles obtained from the library and internet sources such as SciFinder, Wiley, Web of Science, American Chemical Society publications, PubMed, BMC, Elsevier, Science Direct, Scielo and Scopus. Traditionally, L. schweinfurthii is used against reproductive system disorders, respiratory disorders, injuries, headache, blood system disorders, infections or infestations and gastro-intestinal disorders. The phytochemical compounds that have been isolated from L. schweinfurthii include alkaloids, anthocyanins, flavonoids, glycosides, phenols, saponins, steroids, tannins and terpenoids. The in vitro and animal studies carried out so far from the crude extracts and compounds isolated from the species exhibited acetylcholinesterase inhibitory, anti-apoptotic, antibacterial, antiviral, anti-giardial, anti-inflammatory, antioxidant, antiplasmodial, antitrypanosomal, hepatoprotective, larvicidal and cytotoxicity activities. Detailed ethnopharmacological studies emphasizing clinical and toxicological evaluations are needed to assess efficacy and safety of the species as herbal medicine.


Introduction
Lannea schweinfurthii (Engl.) Engl. (Figure 1) is a deciduous, small to medium-sized tree which belongs to the wild currant or Anacardiaceae family. The Anacardiaceae family consists of trees and shrubs, rarely herbaceous climbers or lianas and all members of this family are characterized by resin channels and clear resinous sap that becomes dark on drying [1]. Myricetin flavonoids and cardanols are considered the chemotaxonomic markers of the Anacardiaceae family [2]. Lannea schweinfurthii is commonly referred to as "tree grape", "bastard marula", "baster-marula" or "false marula" [3,4] because the species produces fruits and seeds which have a sweet flavour resembling those of grapes, Vitis vinifera L. When L. schweinfurthii is not in flower or fruit, this species is sometimes confused with Sclerocarya birrea (A. Rich.) Hochst., commonly referred to as "marula", hence the common names "bastard marula", "baster-marula" or "false marula". The genus Lannea consists of approximately 40 species which are usually trees, shrubs, or suffrutices, occupying different habitats in sub-Saharan Africa, Arabia and tropical Asia [3][4][5][6]. Several Lannea species including L. acida A. Rich., L. discolor (Sond.) Engl., L. edulis (Sond.) Engl. and L. microcarpa Engl. & K. Krause are used in the treatment and management of bacterial infections, mental disorders, fever, viral infections, gastro-intestinal (Sond.) Engl., L. edulis (Sond.) Engl. and L. microcarpa Engl. & K. Krause are used in the treatment and management of bacterial infections, mental disorders, fever, viral infections, gastro-intestinal disorders and fungal infections in tropical Africa [7][8][9][10][11][12]. Lannea species are characterized by tetracyclic and pentacyclic triterpenes, flavonoids, phenolic lipids and cyclohexene derivatives and these phytochemical compounds and crude extracts of these species exhibited anthelmintic, antibacterial, antihypertensive, anti-inflammatory, antioxidant, antiplasmodial, antiprotozoal and lipoxygenase inhibition activities [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. Similarly, L. schweinfurthii is an important medicinal plant species among different ethnic groups in tropical Africa [27][28][29][30][31][32][33][34], not only used for human health care but also used as veterinary ethnomedicine in Tanzania [35] and Zimbabwe [36]. Lannea schweinfurthii is a popular herbal medicine in local communities in tropical Africa with the bark and leaves of the species traded as herbal medicines in informal herbal medicine markets in the Mpumalanga province in South Africa [37] and Tanzania [38,39]. Although L. schweinfurthii is an important component of the indigenous pharmacopoeia used for primary healthcare in tropical Africa, there is dearth of information on the phytochemical and pharmacological activities of the species. Despite considerable efforts over the last decades to document the medicinal uses and active ingredients of widely used medicinal plants in tropical Africa [9,13,40,41], there is still a knowledge gap on the medicinal uses, phytochemical and pharmacological activities of many plant species used as herbal medicines in the region. Therefore, L. schweinfurthii is not fully researched due to fragmented information in the literature and the current review undertaken was aimed at summarizing the medicinal uses, phytochemical and pharmacological activities of the taxon so as to provide baseline data on these aspects.

Research Methodology
Information on the medicinal uses, chemistry and pharmacological properties of L. schweinfurthii was collected from several sources including books, book chapters, theses, scientific reports and journal articles obtained from the University of Fort Hare library and internet sources such as SciFinder, Wiley, Web of Science, American Chemical Society publications, PubMed, BMC, Elsevier, Science Direct, Scielo and Scopus. The search for this information was carried out between June to December 2018. The keywords used in the search included "ethnobotany", "ethnomedicinal uses",

Research Methodology
Information on the medicinal uses, chemistry and pharmacological properties of L. schweinfurthii was collected from several sources including books, book chapters, theses, scientific reports and journal articles obtained from the University of Fort Hare library and internet sources such as SciFinder, Wiley, Web of Science, American Chemical Society publications, PubMed, BMC, Elsevier, Science Direct, Scielo and Scopus. The search for this information was carried out between June to December 2018. The keywords used in the search included "ethnobotany", "ethnomedicinal uses", "medicinal uses", "phytochemistry", "biological activities", "pharmacological properties",

Medicinal Uses of Lannea schweinfurthii
Herbal concoctions prepared from L. schweinfurthii are used to treat 53 human and animal diseases in south, central and east Africa (Table 1), and in terms of the plant part utilization ( Figure  2), the roots (43.0%), bark 29.0% and leaves (23.0%) are those widely used. When bark is utilized, it is usually not specified whether the bark was derived from the roots or stems ( Figure 3). The major diseases and ailments treated by L. schweinfurthii extracts include reproductive system and respiratory disorders recorded in three countries based on three literature records each (Figure 4), followed by injuries (recorded in three countries, four literature records), headache (three countries, six literature records), blood system disorders (four countries, six literature records), infections or infestations (five countries, 13 literature records) and gastro-intestinal disorders (six countries, 16 literature records). Lannea schweinfurthii is used to manage and treat the top five ailments and diseases listed by the World Health Organization [55] as the leading causes of disease burden in tropical and subtropical Africa and these include human immunodeficiency virus / acquired immune deficiency syndrome (HIV/AIDS), respiratory infections, diarrhoeal diseases and birth-related disorders (Table  1). Infectious diseases such as respiratory infections, malaria, tuberculosis, diarrhoeal diseases and HIV/AIDS are considered as a global health threat, causing the majority of mortality and morbidity with a death toll of 13.4 million per year [56]. The usage of L. schweinfurthii against bacterial, fungal and viral infections or infestations in south central and east Africa (Table 1, Figure 3) is not surprising as microbial infections or infestations are the world's leading causes of premature deaths [57]. Lannea schweinfurthii is also popular as herbal medicines against opportunistic diseases associated with HIV/AIDS which include malaria, diarrhoea, sexually transmitted infections, tuberculosis, skin infections, cancer, oral candidiasis and persistent cough in eastern and southern Africa [27,[58][59][60][61][62][63]. Herbal medicines play a vital role in primary healthcare in sub-Saharan Africa [64,65], as children in rural areas of some regions in the continent, for example in southern African often suffer from diarrhoea, bilharzia and gastro-intestinal parasites [66,67]. Eloff and McGraw [66] argued that a lack

Medicinal Uses of Lannea schweinfurthii
Herbal concoctions prepared from L. schweinfurthii are used to treat 53 human and animal diseases in south, central and east Africa (Table 1), and in terms of the plant part utilization (Figure 2), the roots (43.0%), bark 29.0% and leaves (23.0%) are those widely used. When bark is utilized, it is usually not specified whether the bark was derived from the roots or stems ( Figure 3). The major diseases and ailments treated by L. schweinfurthii extracts include reproductive system and respiratory disorders recorded in three countries based on three literature records each (Figure 4), followed by injuries (recorded in three countries, four literature records), headache (three countries, six literature records), blood system disorders (four countries, six literature records), infections or infestations (five countries, 13 literature records) and gastro-intestinal disorders (six countries, 16 literature records). Lannea schweinfurthii is used to manage and treat the top five ailments and diseases listed by the World Health Organization [55] as the leading causes of disease burden in tropical and subtropical Africa and these include human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), respiratory infections, diarrhoeal diseases and birth-related disorders (Table 1). Infectious diseases such as respiratory infections, malaria, tuberculosis, diarrhoeal diseases and HIV/AIDS are considered as a global health threat, causing the majority of mortality and morbidity with a death toll of 13.4 million per year [56]. The usage of L. schweinfurthii against bacterial, fungal and viral infections or infestations in south central and east Africa (Table 1, Figure 3) is not surprising as microbial infections or infestations are the world's leading causes of premature deaths [57]. Lannea schweinfurthii is also popular as herbal medicines against opportunistic diseases associated with HIV/AIDS which include malaria, diarrhoea, sexually transmitted infections, tuberculosis, skin infections, cancer, oral candidiasis and persistent cough in eastern and southern Africa [27,[58][59][60][61][62][63]. Herbal medicines play a vital role in primary healthcare in sub-Saharan Africa [64,65], as children in rural areas of some regions in the continent, for example in southern African often suffer from diarrhoea, bilharzia and gastro-intestinal parasites [66,67]. Eloff and McGraw [66] argued that a lack of easy access to the Western healthcare facilities and the expense of orthodox medicines result in the use of herbal medicines against diarrhoea, gastrointestinal parasites and bilharzia. Eloff and McGraw [66] also argued that parasitic infestations and infections caused by helminth parasites are prevalent in poor peri-urban, rural and marginalized areas of southern Africa and these parasites are often treated with herbal medicines. Similarly, Palombo [68] also argued that diarrhoeal disease is a major cause of mortality and morbidity worldwide, especially in children in third world countries, usually as a result of infections or infestations by protozoal parasites, viruses, fungi and bacteria. Over the years, there have been several studies that have validated the use of herbal medicines as a strategy to treat or prevent gastro-intestinal disorders, infectious diseases and malaria [31,67,69]. Lannea schweinfurthii is also used in multi-therapeutic applications when the bark is taken, mixed with roots of Plectranthus barbatus Andrews and Solanum incanum L. as herbal medicine for blood pressure and diarrhoea in Kenya [34]. There is therefore a need to validate the ethnomedicinal applications of L. schweinfurthii through phytochemical and pharmacological evaluations of both the crude extracts and compounds associated with the species.

Phytochemistry of Lannea schweinfurthii
Chhabra et al. [87] isolated alkaloids and anthocyanins from the stem bark of L. schweinfurthii while Oyugi [88] identified alkaloids, flavonoids, glycosides, phenols, saponins, steroids, tannins and terpenoids from leaves and roots of L. schweinfurthii. The nutritional value of L. schweinfurthii which included classic nutrients such as carbohydrates, fibres, lipids, proteins, micro-and macro-nutrients

Medicinal Use Parts of the Plant Used Country References
Animal diseases (coccidiosis, corridor disease and prophylactic measure against poultry diseases) Roots Tanzania and Zimbabwe [35,36] Birth-related disorders (induce labour, pre, intra and post-partum, post-partum haemorrhage, pregnancy anaemia and retained after birth) Bark, leaves and roots Kenya and Tanzania [27,70,71] Blood pressure and diarrhoea Bark mixed with roots of Plectranthus barbatus Andrews and Solanum incanum L.
Kenya [34] Blood system disorders (anaemia and blood pressure) Bark

Acetylcholinesterase Inhibitory Activities
Adewusi and Steenkamp [93] determined the acetylcholinesterase inhibitory (AChEl) of the ethyl acetate and methanol extracts of L. schweinfurthii roots using the Ellman's colorimetric method with galantamine as a positive control. Acetylcholinesterase inhibitory activities were observed to be dose-dependent with IC 50 values of 0.0003 mg/mL for the ethyl acetate extract [93]. Further research is required on this aspect as these preliminary findings support the traditional use of L. schweinfurthii for treating and managing fits in Zambia [29], mental disorders in Mozambique [28], headache in Kenya, South Africa and Tanzania [27,51,52,75,76,78] and as sedative in South Africa and Swaziland [8,82,85].

Anti-Apoptotic Activities
Seoposengwe et al. [93] evaluated anti-apoptotic activities of ethyl acetate and methanol extracts of L. schweinfurthii root bark in SH-SY5Y neuroblastoma cells. In vitro assays employed included intracellular redox state, reactive oxygen species (ROS), intracellular glutathione content, mitochondrial membrane potential (MMP) and caspase-3 activity of the extracts. The methanol extract produced LC 50 value of 78.9 µg/mL, while ethyl acetate extract produced LC 50 value of 36.0 µg/mL. Both the methanol and ethyl acetate extracts demonstrated cytoprotective properties in cells exposed to concentrations of 10 nM of rotenone, however, the same extracts did not show any significant cytoprotective effects at rotenone concentrations of 50 nM and 100 nM. Both the methanol and ethyl acetate extracts countered the decrease in intracellular ROS caused by rotenone exposure. The extracts produced significant increases in glutathione content in a dose-dependent manner. Pre-treating cells with the extracts caused a further reduction in MMP, when compared to rotenone exposure alone. The extracts significantly reduced rotenone-induced caspase-3 activity with methanol extract being more effective than ethyl acetate extract [93].

Antiviral Activities
Maregesi et al. [95] evaluated antiviral activities of methanol extract of L. schweinfurthii stem bark against Herpes Simplex Virus type 1, Vesicular Stomatitis Virus T2, Coxsackie B2 and Semliki Forest A7 using of 50% end point titration technique (50% EPPT) with acyclovir as a positive control. The extract showed strong antiviral activities with reduction factor (RF) values of 101 and 103 at concentrations of 25 µg/mL and 50 µg/mL, respectively against Semliki Forest virus A7 [95]. Similarly, Maregesi et al. [97] evaluated the anti-HIV activities of aqueous and 80% methanol extract of L. schweinfurthii stem bark against human immunodeficiency virus type 1 (HIV-1, III B strain) and type 2 (HIV-2, ROD strain) using the micro dilution assay. The 80% methanol extract exhibited the best activities with IC 50 values ranging from 7.1 µg/mL to 9.9 µg/mL while aqueous extract exhibited weaker activities with IC 50 values ranging from 53.2 µg/mL to 89.4 µg/mL [97]. There is need for further research as L. schweinfurthii bark leaves and roots are traditionally used as herbal medicines against viral infections and coughs in Kenya [75], herpes simplex and zoster in Namibia and Zambia [59,62], smallpox in Zambia [29], tussis in Mozambique [28] and venereal diseases in Kenya and Mozambique [70,75,80].

Anti-giardial Activities
Johns et al. [98] evaluated anti-giardial activities of methanol extract of L. schweinfurthii root bark using a bioassay of the growth inhibition of Giardia lamblia trophozoites with metronidazole as a positive control. The methanolic extract were lethal or inhibited growth of Giardia lamblia trophozoites at 1000 ppm [98].

Anti-inflammatory Activities
Lawal et al. [99] evaluated anti-inflammatory activities of acetone extracts of L. schweinfurthii bark against lipoxygenase (15-LOX) enzyme. The extract exhibited activities with IC 50 value of 43 µg/mL [99]. Yaouba et al. [100] evaluated in vivo anti-inflammatory activities of methanol extract of L. schweinfurthii roots using the carrageenan-induced rat paw edema assay in adult Wistar rats, where 200 mg/kg body weight of the extract was administrated orally to different groups of rats with indomethacin (10 mg/kg) as the positive control. The extract showed moderate activities at 60 min and 120 min post-carrageenan administration and showed the smallest increase in paw volume observed at any time point [100]. The observed in vivo anti-inflammatory activity of L. schweinfurthii extract of the roots partially support the reported traditional use of L. schweinfurthii the relief of pain and inflammation such as abdominal pain in Tanzania [27], body pains in South Africa [83], sores in Swaziland and Tanzania [27,58,82] swellings in Kenya [75] and wounds in Tanzania [81].

Antioxidant Activities
Adewusi and Steenkamp [93] determined the antioxidant activities of the ethyl acetate and methanol extracts of L. schweinfurthii roots using the DPPH and 2,2´-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays. The methanol extract of both the DPPH and ABTS methods showed activities with IC 50 values of 0.01 mg/mL and 0.004 mg/mL, respectively [93]. Okoth [2] determined the antioxidant activities of the methanol extract of L. schweinfurthii roots using the DPPH radical scavenging assay with ascorbic acid as the standard. The extract showed activities with IC 50 value of 22.8 µg/mL which was comparable to IC 50 value of 5.0 µg/mL exhibited by ascorbic acid, the standard drug [2]. Sobeh et al. [101] evaluated antioxidant activities of methanol extract of L. schweinfurthii bark using the DPPH radical scavenging and ferric reducing antioxidant power (FRAP) assays. The extract of the DPPH method showed activities with EC 50 value of 5.6 µg/mL which was comparable to EC 50 value of 2.9 µg/mL exhibited by ascorbic acid, the standard drug. The extract of the FRAP method showed activities with 18.3 mM FeSO 4 equivalent/mg of sample which was comparable to 24.0 mM FeSO 4 equivalent/mg of sample exhibited by quercetin, the standard drug. In in vivo experiments where antioxidant capacity (TAC) of the extract was examined in male Wistar rats treated with toxic D-galactosamine where TAC was determined as well as lipid peroxidation product, malondialdehyde (MDA) in liver tissues as markers for oxidative stress. The extract was able to counteract the D-galactosamine-intoxication and caused an increase in TAC of liver tissues, the low dose levels of 100 mg/kg body weight were able to attenuate the MDA increase [101].

Antiplasmodial Activities
Gathirwa et al. [95] evaluated the antiplasmodial activities of aqueous and methanol extracts of L. schweinfurthii stem bark using an in vitro semi-automated micro-dilution assay technique that measures the ability of the extracts to inhibit the incorporation of [G-3 H]hypoxanthine into the malaria parasite Plasmodium falciparum chloroquine sensitive (D6) and chloroquine resistant (W2). The in vivo anti-plasmodial activities of aqueous and methanol extracts of L. schweinfurthii roots were evaluated on male Balb C mice. The Plasmodium berghei strain maintained by serial passage of infected blood through interperitonial injection was used based on the four-day suppressive test. Gathirwa et al. [95] also evaluated the in vitro and in vivo drug interactions of aqueous and methanol stem bark extracts of L. schweinfurthii in combination with Boscia salicifolia Oliv., Searsia natalensis (Bernh. ex C. Krauss) F. A. Barkley, Turraea robusta Gürke and Sclerocarya birrea (A. Rich.) Hochst. against W2. The methanol and aqueous extracts exhibited low activities with IC 50 values of 36.3 µg/mL and 75.9 µg/mL, respectively against W2. The aqueous and methanol extracts exhibited moderate activities with IC 50 values of 10.6 µg/mL and 11.4 µg/mL, respectively against D6. The methanol and water extracts were active in interperitonial injection treatment with chemo-suppression of 91.4% and 83.1%, respectively and the chemo-suppression of malaria parasites by extracts was not significantly different from that of chloroquine. Moderate to weak synergism was observed in most combinations of L. schweinfurthii and Turraea robusta except towards equal proportion of each extract (50:50) where moderate additive interaction was noted. The interaction of L. schweinfurthii and Searsia natalensis was additive at all tested ratios. All combinations of L. schweinfurthii and Boscia salicifolia extracts gave additive interaction except at 70:30 where synergistic behaviour was observed and at a high amount of L. schweinfurthii while blended with Sclerocarya birrea, additive behaviour was observed which changed to antagonism at the high amount of the latter. The combination of aqueous extracts of Turraea robusta and L. schweinfurthii (10:90) also exhibited antagonistic interaction with chemo-suppression of the combination (57.5%) being lower than that of the single extracts (63.8 and 83.1%, respectively). The combination of Turraea robusta and L. schweinfurthii exhibited high chemosupression of 94.4%. Testing these combinations in vivo demonstrated enhanced anti-malarial activities compared to the single L. schweinfurthii extracts with some giving chemosuppression close to that of chloroquine. The mean survival times of mice treated with blends of L. schweinfurthii and Boscia salicifolia were not significantly different from the control group treated with chloroquine [95]. Maregesi et al. [97] evaluated the antiplasmodial activities of 80% methanol extracts of L. schweinfurthii stem bark against Plasmodium falciparum using twofold serial dilutions method with chloroquine diphosphate as a positive control. The extracts exhibited activities with IC 50 values ranging from 62.3 µg/mL to 125 µg/mL and MIC value of 125 µg/mL [97]. Gathirwa et al. [33] evaluated in vitro antiplasmodial activities of methanol leaf extracts of L. schweinfurthii by measuring the ability of the extracts to inhibit the incorporation of radio-labelled hypoxanthine into the malaria parasite Plasmodium falciparum chloroquine sensitive (D6) and chloroquine resistant (W2) with chloroquine as a positive control. The extracts were tested singly and then in combination with leaves of Searsia natalensis using the standard fixed ratio analysis to evaluate synergism. In vivo bioassay was done in mice using Peter's 4-days suppressive test. The extracts showed activities with IC 50 values of 38.9 µg/mL and 54.2 µg/mL against D6 and W2, respectively. When tested in vivo in a mouse model, L. schweinfurthii extract alone and in combination with Searsia natalensis showed percent parasite clearance and chemo-suppression of 83.5% and 87.7%, respectively which was comparable to 95.2% exhibited by the positive control, chloroquine (5 mg/kg). Evaluating the effect of combining L. schweinfurthii extracts with Searsia natalensis leaves against a multidrug resistant W2 revealed synergism with the sum of fractional inhibition concentration (SFIC) values ranging from 0.4 to < 1.0 [33]. Muthaura et al. [103] evaluated antiplasmodial activities of aqueous and methanol extracts of L. schweinfurthii stem bark against chloroquine sensitive (D6) and resistant (W2) Plasmodium falciparum using the semi-automated micro-dilution technique that measures the ability of the extracts to inhibit the incorporation of (G-3 H) hypoxanthine into the malaria parasite. The aqueous and methanol extracts exhibited low activities with IC 50 values of 36.3 µg/mL and 75.9 µg/mL, respectively against W2. The aqueous and methanol extracts exhibited moderate activities with IC 50 values of 10.6 µg/mL and 11.4 µg/mL, respectively against D6 [103]. These documented antiplasmodial activities support the use of L. schweinfurthii bark as herbal medicine against malaria in Tanzania [58].

Antitrypanosomal Activities
Nibret et al. [104] evaluated in vitro antitrypanosomal activities of dichloromethane and methanol extracts of L. schweinfurthii roots using quantitative colorimetric assay via the oxidation-reduction indicator resazurin against Trypanosoma brucei brucei with diminazene aceturate as the standard drug. The extracts exhibited activities with IC 50 values of 22.2 µg/mL and 44.2 µg/mL against dichloromethane and methanol extracts, respectively which were higher than 0.09 µg/mL exhibited by diminazene aceturate, the standard drug [104].

Hepatoprotective Activities
Sobeh et al. [101] evaluated hepatoprotective activities of L. schweinfurthii bark extracts in male Wistar rats treated with the toxic D-galactosamine that causes liver damage through evaluation of both the biochemical and histopathological changes in rats. The extracts reduced the elevated levels of serum aspartate aminotransferase (AST) and total bilirubin and significantly attenuated the deleterious histopathologic changes in liver after D-galactosamine-intoxication [101].

Larvicidal Activities
Okoth [2] evaluated the larvicidal activities of ethyl acetate, hexane and methanol extracts of L. schweinfurthii leaf, root and stem against the malaria vector, Anopheles gambiae which was bio-assayed following WHO susceptibility protocols [111]. The extracts exhibited activities with LC 50 values ranging between 6.3 µg/mL to 240.4 µg/mL which were higher than 3.1 µg/mL exhibited by pylarvex, the standard drug used as control [2]. The results suggest that the investigated leaf, root and stem extracts of L. schweinfurthii are promising as larvicides against Anopheles gambiae mosquitoes and could be useful leads in the search for new and biodegradable plant derived larvicide products.

Cytotoxicity and Toxicity Activities
Moshi et al. [58] evaluated toxicity activities of methanol extract of L. schweinfurthii stem using the brine shrimp lethality test. The extract exhibited activities with LC 50 value of 67.9 µg/mL [58]. Gathirwa et al. [102] evaluated cytotoxicity activities of methanol extract of L. schweinfurthii roots on Vero cells using the plaque reduction assay. The methanol extract exhibited weak activities with CC 50 value of 225.3 µg/mL and selectivity index of 6.2 against W2 [101]. Gathirwa et al. [101] evaluated in vivo acute toxicity activities of methanol root extract of L. schweinfurthii using Swiss mice. The groups of five starved mice were given increasing dosages of test sample, 250 mg/kg body weight, 500 mg/kg body weight, 750 mg/kg body weight, 1000 mg/kg body weight, 1500 mg/kg body weight and 5000 mg/kg body weight orally and the number of deaths occurring within 24 h to 48 h were noted. In the acute toxicity assay, no deaths were observed at the highest concentration tested and the LD 50 values for both extracts were above 5000 mg/kg body weight when tested by oral administration [102]. Nibret et al. [104] evaluated cytotoxicity of dichloromethane and methanol extracts of L. schweinfurthii roots against the human cancer cell line HL-60 cells with diminazene aceturate as the standard drug. The dichloromethane extract was the most cytotoxic extract with IC50 value of 27.2 µg/mL and selectivity index of 1.2 which was much higher than IC 50 value of >128.9 µg/mL and selectivity index value of >1464.0 exhibited by diminazene aceturate, the standard drug [104]. Maregesi et al. [97] evaluated cytotoxicity activities of aqueous and 80% methanol extracts of L. schweinfurthii stem bark on MT-4 cells. Both extracts exhibited activities with CC 50 values of 72.3 µg/mL and >125 µg/mL for 80% methanol and aqueous extracts, respectively [97]. Gathirwa et al. [33] evaluated cytotoxicity activities of aqueous extracts of L. schweinfurthii leaves using growth inhibition of Vero E6 cells.
The extract exhibited mild cytotoxicity with CC 50 values of 76 µg/mL and a selectivity index of 1.4 [33]. Adewusi et al. [105] evaluated cytotoxicity activities of methanol extracts of L. schweinfurthii roots against SH-SY5Y (human neuroblastoma) cells which were untreated, as well as toxically induced with amyloid-beta peptide (Aβ) using the MTT and neutral red uptake assays. Exposure of the SH-SY5Y cells to Aβ25-35 at 2.5 µM, 5 µM, 10 µM and 20 µM for 72 h, resulted in a concentration-dependent decrease in cell survival. The extracts exhibited low cytotoxicity with IC 50 values exceeding 100 µg/mL from both the neutral red and MTT assays. The pre-treatment with extract resulted in an optimum dose for inhibition of Aβ25-35 induced cell death at 25 µg/mL, while still maintaining 80% viability [105]. Yaouba et al. [100] evaluated cytotoxicity activities of root extracts of L. schweinfurthii using the assay on the mammalian African monkey kidney (Vero) and DU-145 prostate cancer cell lines. The extracts showed activities with CC 50 values of 7.4 µg/mL and 74.0 µg/mL against the Vero cell line and DU-145 prostate cancer cell lines, respectively [100].

Conclusions
In this article, the ethnomedicinal uses, phytochemistry and pharmacological activities of L. schweinfurthii were reported emphasizing its acetylcholinesterase inhibitory, anti-apoptotic, antibacterial, antiviral, anti-giardial, anti-inflammatory, antioxidant, antiplasmodial, antitrypanosomal, hepatoprotective, larvicidal and cytotoxicity activities. The diverse uses of L. schweinfurthii among different ethnic groups in tropical Africa and the scientific evidence of its phytochemistry and pharmacological properties indicate therapeutic potential of the species. However, there is need for clinical evaluation of crude extracts and compounds isolated from the species using in vivo models. Therefore, further studies of L. schweinfurthii should focus on comprehensive phytochemical analyses of the species and to more accurately define its biological activities so that biological activities can be correlated to phytochemical components. Additionally, new biological evaluations are still needed to scientifically validate some of its ethnopharmacological applications so that the species can be used as a future resource for disease treatment and management. Lannea schweinfurthii is also not fully evaluated regarding its safety as herbal medicine. Further studies should therefore, evaluate the toxicity of the species on humans.
Funding: The author would like to express his gratitude to the National Research Foundation, South Africa and Govan Mbeki Research and Development Centre, University of Fort Hare for financial support to conduct this study.

Conflicts of Interest:
No conflict of interest is associated with this work.