LANNEA SCHIMPERI: REVIEW OF ITS BOTANY, MEDICINAL USES, PHYTOCHEMISTRY, AND BIOLOGICAL ACTIVITIES

Lannea schimperi is a well-known fruit tree and medicinal plant in tropical Africa. The current study critically reviewed the botany, medicinal uses, phytochemistry, and pharmacological activities of L. schimperi. Literature on botany, medicinal uses, phytochemical and biological activities of L. schimperi were collected from multiple internet sources including Elsevier, Google Scholar, SciFinder, Web of Science, PubMed, BMC, ScienceDirect, and Scopus. Complementary information was gathered from pre-electronic sources such as books, book chapters, theses, scientific reports, and journal articles obtained from the University Library. This study revealed that the species is used as a source of fiber, edible fruits, and herbal medicine. Phytochemical compounds identified from the species include cyclohexenones, cardanols, alkaloids, anthocyanins, anthracene glycosides, carbohydrates, cardiac glycosides, carotenoids, condensed tannins, coumarins, flavonoids, phenolic glycosides, phenols, polyoses, polyuronoids, reducing sugars, saponins, steroids, tannins, triterpenoids, and volatile compounds. Pharmacological research revealed that extracts and phytochemical constituents isolated from L. schimperi have anesthetic, antibacterial, antifungal, anticoccidial, anti-inflammatory, antinociceptive, antioxidant, antitrypanosoma, antiulcerogenic, cytotoxicity, and toxicity activities. L. schimperi should be subjected to detailed phytochemical, pharmacological, and toxicological evaluations aimed at correlating its medicinal uses with its phytochemistry and pharmacological activities of the species.


Maroyi
to Southern Africa in Zambia, Mozambique, and Malawi [17,[61][62][63][64][65]. The species has been recorded in open grassland, wooded grassland, woodland and often on rocky slopes, outcrops on volcanic limestone and basement complex or termite mounds at elevations from 800 m to 2200 m above sea level [17].

MEDICINAL USES OF L. SCHIMPERI
A bark and root decoction of L. schimperi is used as herbal medicine for abdominal pains in Kenya and Mozambique [66] while leaf decoction is used against blood diarrhea in Kenya and Tanzania [12,13,66] (Table 1). Root and bark decoction of L. schimperi is used against chest pains in Malawi, Kenya, and Tanzania [11][12][13][67][68][69] while root decoction is used against colds in Malawi and Tanzania [11][12][13]. The seed, leaf, root, and bark decoction of L. schimperi is used against cough in Rwanda and Tanzania [9,70] while root and stem bark decoction is used against diarrhea and dysentery in Burundi, Kenya, and Malawi [66][67][68][69]71]. The leaf and bark infusion of L. schimperi is used against skin infections and rashes in Ethiopia and Tanzania [16,72,73] while bark, root, and leaf infusion of the species is used against stomach problems in Kenya and Tanzania [67][68][69][70]. Bark decoction of L. schimperi is used as herbal medicine for tuberculosis in Namibia and Tanzania [16,72,74] while bark, leaf, and root decoction are used as ethnoveterinary medicine for blackleg, diarrhea, dysentery, intestinal parasites, and Texas fever in Ethiopia and Nigeria [18][19][20][21]. In Kenya, root decoction of L. schimperi is used against constipation and sore throat [66] while in Malawi, root or root bark decoction is used against syphilis [11,66]. In Ethiopia, the root decoction of L. schimperi is used against intestinal parasites [21] while in Mozambique, the bark, root, and leaf infusion is used for tussis [66]. In Tanzania, the bark, root, and leaf infusion of L. schimperi is used for anemia, mental disorders, snake bites, and tumor [70], the root decoction is used for toothache, yellow fever, and induce labor [12,13,75], the bark decoction is used for backache, chronic diarrhea, diabetes mellitus, epilepsy, general body weakness, herpes simplex, herpes zoster, and malaria [12,13,16,72,76,77]. In Kenya, the leaves of L. schimperi are mixed with roots or tubers of Cissus Phyllanthus Gilf as remedy for amoebic dysentery, diarrhea, and hiccups [78] while the bark of the species is mixed with the bark of Ficus spp. and Dalbergiellanyasae Baker f. as a remedy for dysentery in Malawi [11]. In Tanzania, the stem bark of L. schimperi is mixed with stem bark of Gymnosporia senegalensis (Lam.) Loes., Ozoroa insignis Del., and Entada abyssinica Steud. ex A. Rich. and leaves of Rhynchosia recinosa (A. Rich.) Bak. as a remedy for peptic ulcers [79].

Anesthetic activities
Haule et al. [79] evaluated anesthetic activities of the methanolic leaf extracts of L. schimperi using intracutaneous wheal test in guinea pigs for infiltration anesthesia and guinea pig corneal reflex method of surface anesthesia using lidocaine and normal saline as positive and negative controls, respectively. The extracts exhibited dose-dependent local anesthetic activities with faster onset and longer duration of action at 24 mg/ml than at 12 mg/ml of the extract. Additions of 5 µg of adrenaline into the 24 mg/ml preparation also prolonged the duration of local anesthetic activities of the extract. The extract at 24 mg/ml significantly inhibited corneal reflex [79].

Phytochemical composition Formula
Alkenyl cyclohexenones   [86] also evaluated the modulation effects when sub-inhibitory concentrations of plant extracts were combined with the standard antibiotic, ciprofloxacin using the checkerboard assay. The combinatorial cases yielded biologically significant modulation factors causing more than two-fold reduction of the MIC of the standard drug, ciprofloxacin [86].

Antifungal activities
Kisangau et al. [87] evaluated antifungal activities of dichloromethane and aqueous stem bark extracts of L. schimperi against Candida albicans, Cryptococcus neoformans, and Aspergillus niger using agar well and disk diffusion methods with fluconazole (2 µg/mL) as the positive control. Dichloromethane extracts showed activities against all tested fungi with a zone of inhibition ranging from 7.0 mm to 16.5 mm. The MIC and minimum fungicidal concentration values of dichloromethane crude extracts and semi-purified fractions ranged from 12.5 µg/mL to 50.0 µg/mL [87]. Ekuadzi et al. [86] evaluated antifungal activities of ethanol stem bark extracts of L. schimperi against Candida albicans using the broth microdilution method. The extract showed activities with MIC value of 3.0 mg/mL. Ekuadzi et al. [86] also evaluated the modulation effects when sub-inhibitory concentrations of plant extracts were combined with the standard drug, ketoconazole using the checkerboard assay. The combinatorial cases yielded biologically significant modulation factors causing more than two-fold reduction of the MIC of the standard drug, ketoconazole [86].

Anticoccidial activities
Mikail et al. [88] evaluated the anticoccidial activities of the methanolic leaf extracts of L. schimperi against oocysts of Eimeria tenella with amprolium (1 mg/ml) as a positive control. The extract was tested at concentrations of 25 mg/ml, 50 mg/ml, and 100 mg/ml against E. tenella isolated from infected chicks. The extracts showed activities against unsporulated and sporulated oocysts of E. tenella in a dose-dependent manner, the extract at concentration of 100 mg/ml inhibited oocyst sporulation (98 %) and inhibited the viability of sporulated oocysts (97%) similar to that recorded by the standard drug amprolium after 72 h of incubation [88].

Anti-inflammatory activities
Egbe et al. [82] evaluated the anti-inflammatory activities of the methanolic leaf extracts of L. schimperi at doses of 12 mg/kg and 24 mg/kg using the egg albumin-induced acute inflammation model in rat with aspirin at dose of 80 mg/kg used as a positive control while the drug vehicle was used as a negative control. The extracts showed activities at both doses, and there were no significant differences between the extract treated rats with those rats treated with the standard drug, aspirin [82]. The exhibited anti-inflammatory activities of the methanolic leaf extracts of L. schimperi could be beneficial in alleviating painful inflammatory conditions.

Antinociceptive activities
Egbe et al. [82] evaluated the antinociceptive activities of the methanolic leaf extracts of L. schimperi at doses of 12 mg/kg and 24 mg/kg using acetic acid-induced writhing model in mice with aspirin at dose of 80 mg/kg used as a positive control while the drug vehicle was used as a negative control. The extracts showed activities at both doses, decreasing the acetic -nduced writhing reflex in mice when compared with the negative control [82]. The exhibited antinociceptive activities of the methanolic leaf extracts of L. schimperi could be beneficial in alleviating painful inflammatory conditions.

Antioxidant activities
Sherfi et al. [83] evaluated antioxidant activities of methanolic leaf, root, and stem extracts of L. schimperi using 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH) free radical scavenging assay with propyl gallate as a positive control. The extracts showed high effective free radical scavenging in the DPPH assay with a scavenging rate ranging from 86.0% to 92.0% and half maximal inhibitory concentration (IC 50 ) values ranging from 0.04 mg/ml to 1.2 mg/ml and these values were comparable to 91.0% and 0.03 mg/ml exhibited by propyl gallate, the standard drug [83].

Anti-trypanosomal activities
Mikail [8] evaluated the anti-trypanosomal activities of the methanolic extracts against Trypanosoma brucei brucei at concentrations of 3 mg/ml, 6 mg/ml, 12 mg/ml, and 24 mg/ml with 5% dextrose and 0.9% saline as controls. Complete mortality of the organism was observed at the concentrations of 24 mg/kg, 12 mg/kg, 6 mg/kg, and 3 mg/kg within 30 min, 60 min, 180 min, and 330 min, respectively, in a dose-dependent manner [8]. These findings suggest that the methanolic leaf extracts of L. schimperi possess some trypanocidal principles which may require further scientific elucidations.

Antiulcerogenic activities
Haule et al. [79] evaluated the ability of ethanol extract of L. schimperi mixed with R. recinosa and stem bark of O. insignis, G. senegalensis, and E. abyssinica to protect Sprague Dawley rats from gastric ulceration at doses of 100 mg/kg, 200 mg/kg, 400 mg/kg, and 800 mg/kg body weight. The cytoprotective effect was assessed by comparison with a negative control group given 1% tween 80 in normal saline and a positive control group given 40 mg/kg body weight pantoprazole. The combined ethanolic extracts of the five plant species caused dose-dependent protection against ethanol/hydrochloric acid-induced ulceration of rat gastric mucosa, reaching 81.7% mean protection as compared to 87.5% protection by 40 mg/kg body weight pantoprazole [79].

Cytotoxicity activities
Moshi et al. [77] evaluated the cytotoxicity activities of ethanol stem bark extract of L. schimperi using the brine shrimp lethality test with cyclophosphamide, a standard anticancer drug as a positive control. The extract exhibited weak activities with the median lethal concentration (LC 50 ) value of 110.8 µg/ml which was higher than LC 50 value of 16.3 µg/ml exhibited by cyclophosphamide, a standard anticancer drug [77]. Kisangau et al. [90] evaluated the cytotoxicity activities of dichloromethane stem bark extracts against K562 Leukemia cell line using the CellTiter-Blue™ cell viability assay. In the CellTiter-Blue™ cell viability assay, the mean percentage of cell vitality growth for the extracts was 52.3% [90]. Haule et al. [79] evaluated the cytotoxicity activities of L. schimperi bark extracts using the brine shrimp lethality test with cyclophosphamide as the positive control. The extract exhibited weak activities with an LC 50 value of 128.4 µg/ml which was higher than an LC 50 value of 16.3 µg/ml exhibited by cyclophosphamide, a standard anticancer drug [79]. Okoth and Koorbanally [81]

Toxicity activities
Haule et al. [79] evaluated acute toxicity activities of L. schimperi ethanol bark extracts using both male and female Theiler's albino mice. A dose of 1000 mg/kg, 2000 mg/kg, 3000 mg/kg, 4000 mg/kg, and 5000 mg/kg body weight were administered to a group of six mice (three male and three female), and the mice observed for signs of immediate toxicity and/or death for 72 h. Extracts were solubilized in 1% tween 80 and administered at a single oral dose volume of 5 ml/kg body weight or two separate 5 ml/kg body weight doses given within an hourly interval, depending on solubility. A control group was run for each plant extract Maroyi which was administered a single 5 ml or two 5 ml/kg body weight of 1% tween 80 to match with the volume of plant extracted ministered. The extract caused increased defecation or diarrhea, but it did not kill any mice up to 2000 mg/kg body weight. Mortality to mice occurred at doses of 3000 mg/kg body weight and above [79]. Mikail [8] evaluated the toxicological activities of methanolic leaf extracts of L. schimperi in mice using the Lorke's assay. The mice were treated at doses of 10 mg/kg, 100 mg/kg, and 1000 mg/kg with extracts intraperitoneally and observed for 24 h for any signs of toxicity including death. Acute toxicity test indicated that the extracts produced 100% mortality at doses of 370 mg/kg, 600 mg/kg, and 1000 mg/kg. At these doses, the rats showed signs of toxicity including inactiveness, rough hair coat, dullness, depression, and death, and the median lethal dose of the extract was determined to be 288.5 mg/kg [8]. Therefore, the methanolic leaf extract of L. schimperi is considered to be moderately toxic.

CONCLUSION
The present review summarizes the botany, medicinal uses, phytochemistry, and pharmacological properties L. schimperi. In the past 40 years, L. schimperi has been the subject of phytochemical and pharmacological research, but there is not yet enough data correlating the ethnomedicinal uses of the species with its phytochemical and pharmacological properties. Detailed studies on the pharmacokinetics, in vivo and clinical research involving both extracts and compounds isolated from the species, are required. Therefore, future research should focus on the molecular modes or mechanisms of action, pharmacokinetics, and physiological pathways for specific extracts of the species including identification of the bioactive compounds of the species and their associated pharmacological activities.

ACKNOWLEDGMENTS
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.

AUTHOR'S CONTRIBUTIONS
The author declares that this work was done by the author named in this article.

CONFLICTS OF INTEREST
The author declares that there are no conflicts of interest regarding the publication of this paper.