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Review Article
 

Croton megalocarpus Hutch. in Tropical Africa: Phytochemistry, Pharmacology and Medicinal Potential



Alfred Maroyi
 
ABSTRACT

Croton megalocarpus (C. megalocarpus) is widely used as herbal medicine by the local people in tropical Africa. The potential of C. megalocarpus as traditional medicine, the phytochemistry and pharmacological properties of its parts used as traditional medicines are reviewed. The extensive literature survey revealed that C. megalocarpus is traditionally used to treat or manage at least 41 human and animal diseases and ailments. The species is used as herbal medicine for diseases and ailments such as colds, cough, respiratory diseases, fever and malaria, gastro-intestinal tract diseases, wounds, intestinal worms and as ethnoveterinary medicine. Multiple classes of phytochemicals such as alkaloids, clerodane diterpenoids, fatty acids, flavones, flavonoids, glycosides, phenols, reducing sugars, saponins, sterols, tannins and triterpenoids have been isolated from the species. Scientific studies on C. megalocarpus indicate that it has a wide range of pharmacological activities which include antibacterial, antifungal, anti-inflammatory, antinociceptive, antioxidant, molluscicidal, wound healing and Epstein-Barr virus-activating potency.

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Alfred Maroyi , 2017. Croton megalocarpus Hutch. in Tropical Africa: Phytochemistry, Pharmacology and Medicinal Potential. Research Journal of Medicinal Plants, 11: 124-133.

DOI: 10.3923/rjmp.2017.124.133

URL: https://scialert.net/abstract/?doi=rjmp.2017.124.133
 
Received: June 14, 2017; Accepted: September 16, 2017; Published: September 28, 2017

INTRODUCTION

Croton megalocarpus Hutch. (family Euphorbiaceae) is distributed from Eastern Democratic Republic of Congo (DRC) to Kenya and South to Malawi, Zambia and Mozambique. Croton megalocarpus is a multipurpose tree used as a source of timber, firewood, medicine and auxillary plant. The tree is commonly planted as an ornamental or shade tree in villages, also used as a shade-bearer on coffee plantations and other crops and has been used as a boundary marker of home gardens and agricultural fields for centuries1,2. Croton megalocarpus has gained interest for large-scale planting programmes as a commercial poultry feed and biofuel crop with low agro-ecological demands mainly in Kenya and Tanzania2. The ground seeds of C. megalocarpus showed good results in preliminary tests as chicken feed with no adverse effects on production and hatchability of eggs1. As traditional herbal medicine, C. megalocarpus is widely used throughout its distributional range. Croton megalocarpus is considered a priority medicinal plant species in Kenya3 and conserved on farm or deliberately allowed to persist when wild habitats are converted into agricultural lands. Croton megalocarpus is traded in herbal medicine (muthi) markets in Thika and Nairobi, Kenya4 and the bark of the species is commercially collected as traditional medicine for sale in Uganda5. It is against this background that the current study was undertaken, aimed at assessing if there is correlation between the ethnomedicinal uses of C. megalocarpus and the documented phytochemical and pharmacological properties of the species. The present review collates the fragmented information on traditional uses, phytochemistry and pharmacology of the species. It is hoped that this information will highlight the importance of C. megalocarpus as a potential source of a wide range of pharmaceutical products in tropical Africa and will provide a new direction for researchers in the future.

REVIEW

Croton megalocarpus, its synonym ‘C. elliottianus Engl. and Pax’, English common names ‘broad-leaved croton’ and ‘Kenya croton’ were used as the key words in searching the major databases including Web of Science, Scopus, Google Scholar, Science Direct, BioMed Central (BMC), PubMed and Springerlink documenting ethnomedicinal uses, ethnobotany, ethnopharmacology, pharmacology, phytochemistry and therapeutic value of the species. Chemical database sites such as ChemSpider and PubChem were used as sources of chemical structures of the documented compounds. Additional literature, including pre-electronic literature such as dissertations, theses, international journal articles, scientific reports from international, regional and national organizations, conference papers and books were sourced from the University of Fort Hare library in South Africa. This review draws heavily on the research results published in international journals (60), books (four), book chapters (three), dissertations, theses and websites (two each), conference proceedings and scientific reports from international organizations (one each).

Botanical profile, taxonomy and distribution of Croton megalocarpus: The genus name "Croton" was derived from a Greek word "kroton", a tick, referring to thick smooth seeds, a common feature of most Croton species which belong to the Crotonoideae subfamily of the Euphorbiaceae family6-8. The specific name "megalocarpus" is in reference to the species’ relatively large fruits9,10. The synonym of C. megalocarpus is C. elliottianus Engl. and Pax and the species is known by several vernacular names as shown in Table 1. Croton megalocarpus has been recorded in Burundi, DRC, Kenya, Malawi, Mozambique, Rwanda, Tanzania, Uganda and Zambia11,12. Research by Maroyi2 revealed that C. megalocarpus is a canopy tree of evergreen rainforest, riverine gully forest and in high rainfall Brachystegia woodland from 350 m upto 2400 m altitude.

Croton megalocarpus is a medium sized to a fairly large monoecious or occasionally dioecious tree up to 35 m tall with a cylindrical, branchless bole up to 20 m tall and 1 m in diameter with a spreading and flat crown11,12. The bark is pale to dark grey in colour and smooth when young, slightly rough, cracking and longitudinally fissured in older trees11,12. The leaf blade is elliptic-ovate to ovate-lanceolate in shape, shortly acuminate, entire at the apex and cordulate at the base with two to four sessile or shortly stipitate basal glands on the under surface or near the petiole apex10,11. The inflorescence is an upright, terminal raceme, 7.5-30 cm long, completely male or with a few female flowers at the base11,12. The fruit is ellipsoid-ovoid to subglobose with a woody endocarp, 3-4.5 cm long and seeds are ellipsoid-ovoid or oblong-ellipsoid in shape, 2.2-2.4 cm long and 1.2-1.4 cm wide, slightly shiny and yellowish-grey in colour11,12.

Ethnomedicinal uses of Croton megalocarpus: The bark, leaves and roots of C. megalocarpus are reported to possess diverse medicinal properties and used to treat or manage various human and animal ailments and diseases throughout the distributional range of the species (Table 2). A total of 41ethnomedicinal uses of C. megalocarpus are documented in literature (Table 2) with 87.5% of the ethnomedicinal uses recorded in Kenya based on 19 literature records.

Table 1:Vernacular names of Croton megalocarpus in tropical Africa

Table 2:Ethnomedicinal uses of Croton megalocarpus in tropical Africa39

Fig. 1:Major ethnomedicinal uses of Croton megalocarpus in tropical Africa. An ethnomedicinal use is only counted once per publication

Croton megalocarpus is mainly used to treat colds, cough, respiratory diseases (ten citations), fever, malaria, ethnoveterinary diseases, ailments (with nine citations each), gastro-intestinal tract diseases (eight citations), wounds (four citations) and intestinal worms with three citations (Fig. 1). Some of these diseases or ailments treated by C. megalocarpus are a major concern in tropical Africa, particularly colds, cough, respiratory diseases32 and gastro-intestinal tract diseases33.

In Kenya, the root decoction of C. megalocarpus is used as purgative24 and herbal medicine for backache, chest problems, malaria and stomach problems14,19 while bark decoction is used for arthritis, bile release, chest pains, colds, cough, diarrhoea, dysentery, fever, induce vomiting, intestinal worms, malaria, stomach ache and whooping cough13,15,22,34-37. Leaf decoction is used as herbal medicine for diabetes, intestinal worms, pneumonia, respiratory problems and whooping cough21,23,37, while root bark decoction or leaf sap or a mixture of bark and leaves is applied on wounds19,20,25. Bark and leaf decoction of C. megalocarpus is used as herbal medicine for amoebiasis, influenza, menstrual problems, pneumonia, protozoan infections and typhoid25, while root bark or a mixture of bark and roots is used as herbal medicine for anaplasmosis, cough, diarrhoea, fever, malaria and tonsils17,20, a mixture of bark, leaves and roots is used for diarrhoea20. In Tanzania, bark decoction of C. megalocarpus is used as herbal medicine for constipation, fever, gall bladder problems, intestinal worms, malaria, spleen problems and whooping cough26,28,29 while in Uganda, root decoction is used to induce labour30.

The resource limited farmers in East Africa, use bark, leaf and root decoctions of C. megalocarpus as ethnoveterinary medicine as a solution to their animal health problems. In Kenya, bark decoction of C. megalocarpus is used as ethnoveterinary medicine for anthrax, diarrhoea, East Coast fever and swollen head38,39 while a mixture of bark, leaves and roots is used to repel and control ticks40. In Tanzania, bark decoction of C. megalocarpus is used as anthelmintic, conditioner and laxative26,27.

Phytochemistry: Many researchers have investigated the phytochemical constituents of C. megalocarpus in an effort to identify compounds responsible for a wide range of ethnomedicinal uses of the species. Phytochemical screening of C. megalocarpus leaves and stem bark revealed the presence of alkaloids, flavones, flavonoids, glycosides, reducing sugars, saponins, sterols, tannins and terpenoids41-44. Research by Addae-Mensah et al.45-47, revealed the presence of clerodane diterpenoids, namely chiromodine and epoxy-chiromodine from C. megalocarpus stem bark. The clerodane diterpenoids have been evaluated for many pharmacological principles and have been found to be potentially useful as antitumor, antiviral, antimicrobial, antipeptic ulcer, antifungal, antifeedant, insecticidal and psychotropic properties48. Other compounds isolated from the stem bark of C. megalocarpus by Addae-Mensah et al.45-47, include β-sitosterol, betulin, lupeol, 3-β-O-acetoacetyllupeol, O-acetylaleuritolic acid and E-ferulic acid. Croton megalocarpus has an oil content of about 32%49,50 and protein content of about 50%49.

Table 3:Phytochemical compounds isolated from seed oil and stem bark of Croton megalocarpus
GC: Gas chromatography, MS: Mass spectrometry, NMR: Nuclear magnetic resonance spectroscopy and NOE: Nuclear overhauser effect

Croton megalocarpus seed oil contain saturated fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid (Table 3). Monounsaturated fatty acids isolated from seed oil of C. megalocarpus included palmitoleic acid, oleic acid and erucic acid, while polyunsaturated fatty acids included linoleic acid and linolenic acid (Table 3). Some of the monounsaturated fatty acids isolated from C. megalocarpus, for example erucic acid is characterized by more than 22 carbon atoms (Table 3), termed very long fatty acids which are rarely found in nature51. Very long fatty acid chains present in C. megalocarpus seed oil makes it a good candidate for use as biodiesel50,52 and other non-conventional energy and protein sources for poultry feeds1,52, corroborating an observation that seeds of the species are traditionally known to be eaten by birds and squirrels53.

Pharmacological activities: A number of pharmacological activities of C. megalocarpus have been reported in literature justifying some of its ethnomedicinal uses. Such pharmacological activities include antibacterial54,55, antifungal42, anti-inflammatory54, antinociceptive56, antioxidant54, molluscicidal43,57, wound healing44 and Epstein-Barr virus-activating potency58.

Antibacterial: Matu and van Staden54 evaluated antibacterial activities of aqueous, hexane and methanol extracts of leaves, roots and stem bark of C. megalocarpus against Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Micrococcus luteus and Staphylococcus aureus using the disc-diffusion assay with neomycin as positive control. The antibacterial activity of hexane and methanol stem bark extracts at a concentration of 100 mg mL–1 exhibited activity values ranging from 0.12±0.02-0.14±0.0 against Bacillus subtilis and Staphylococcus aureus. Similarly, Kariuki et al.55, evaluated in vitro antibacterial activities of aqueous, chloroform and ethanol extracts of C. megalocarpus against Escherichia coli, Klebsiella pneumonaie, Pseudomonas aerugenosa, Salmonella typhi and Staphylococcus aureus. The activity of the water extracts was the highest, followed by ethanol and chloroform extracts, respectively55. The documented antibacterial activities of C. megalocarpus may be due to the presence of compounds such as betulin, lupeol, ferulic acid, lauric acid and palmitoleic acid which are known to have antibacterial activities59-61. Ouattara et al.59, found lauric acid and palmitoleic acid to exhibit antibacterial activities against Brochothrix thermosphacta, Carnobacterium piscicola, Lactobacillus curvatus, Lactobacillus sake, Pseudomonas fluorescens and Serratia liquefaciens with minimum inhibitory concentrations (MIC) ranging from 250-500 μg mL–1. Research by Borges et al.60, revealed antibacterial activity of ferulic acid with minimum bactericidal concentration (MBC) value of 2500 mg mL–1 against Escherichia coli, for Staphylococcus aureus MBC was 5000 mg mL–1, for Listeria monocytogenes MBC was 5300 mg mL–1 and MBC value of 500 mg mL–1 was recorded for Pseudomonas aeruginosa. Duric et al.61, documented antibacterial activities of betulin and lupeol isolated from the bark of Betula pendula Roth against Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. These results support the traditional use of C. megalocarpus in treating bacterial infections such as diarrhoea, dysentery and wound infections18,20,22,25,36.

Antifungal: Kiswii et al.42, evaluated antifungal activities of methanolic bark and leaf extracts of C. megalocarpus against Aspergillus flavus using the micro-dilution method with miconazole as the control. Both extracts showed antifungal activity with minimum inhibition concentration (MIC) and minimum fungicidal concentration (MFC) values of 12.50 mg mL–1. The documented antifungal activities of C. megalocarpus may be due to the presence of phytosterol and triterpenoids such as β-sitosterol, betulin and lupeol which are known to have antifungal activities62. Lall et al.62, evaluated antifungal activities of β-sitosterol, betulin and lupeol isolated from Euclea natalensis A. DC. root bark which showed different antifungal activities against Aspergillus flavus, Aspergillus niger, Cladosporium cladosporioides and Phytophthora spp. Similarly, Nisar et al.63, documented antifungal activities of betulin and lupeol isolated from the bark of Rhododendron arboreum Sm. against Aspergillus flavus, Aspergillus niger, Candida albicans, Candida glaberata, Fusarium solani and Microsporum caris.

Anti-inflammatory: Matu and van Staden54, evaluated anti-inflammatory activities of aqueous, hexane and methanol extracts of C. megalocarpus using the cyclooxygenase (COX-1) assay. All the extracts showed some anti-inflammatory activities, with methanolic root extract displaying the highest inhibition of cyclooxygenase at a level of 81.0±1.4% at a test concentration of 500 μg mL–1. The anti-inflammatory activities of C. megalocarpus documented by Matu and van Staden54 may be due to the presence of β-sitosterol, betulin, lupeol, linoleic acid and linolenic acid which are known to have anti-inflammatory activities64-67. Lin et al.66, examined the analgesic effects of betulin using models of acetic acid-induced writhing response and its anti-inflammatory effects using model of λ-carrageenan-induced paw edema. The authors revealed that betulin (30 and 90 mg kg–1), inhibited the acetic acid-induced writhing response and formalin-induced licking time during both the early and late phases and decreased the paw edema at the 4th h after λ-carrageenan injection. Lin et al.66, also observed that betulin 4 (30 and 90 mg kg–1) increased the activities of superoxide dismutase (SOD), glutathione reductase (GR) and glutathione peroxidase (GPx) in the liver while decreasing the level of malondialdehyde (MDA) in the edema paw and caused considerable reduction of nitric oxide (NO) level in the edema paw. This study therefore, demonstrated that betulin possess analgesic and anti-inflammatory effects which may be related to decreasing the levels of MDA and NO in the edema paw by increasing the activities of antioxidant enzymes in the liver. Nirmal et al.67, evaluated analgesic and anti-inflammatory activities of β-sitosterol isolated from leaves of Nyctanthes arbortristis L. using hot plate test, acetic acid-induced writhings and carrageenan-induced hind paw edema method at the dose of 50 mg kg–1. Nirmal et al.67, found β-sitosterol(5, 10 and 20 mg kg–1) to exhibit dose-dependent analgesic and anti-inflammatory activities comparable with the standard extract. Singh et al.64, evaluated anti-inflammatory activities of lupeol isolated from Crateva religiosa G. Forst. bark in rats and mice. Lupeol exerted dose dependent effect on acute and chronic inflammatory processes with oral LD50 greater than 2 g kg–1 in rats and mice65. Research by Zhao et al.65, showed that linoleic acid and linolenic acid exhibited dose-dependent anti-inflammatory effects, decreasing interleukin (IL)-6, interleukin (IL)-1β, tumor necrosis factor-α (TNFα) and nuclear factor (NF)-κB DNA-binding activity and increased peroxisome proliferator-activated receptor-γ (PPARγ) DNA-binding activities. These findings by Zhao et al.65, show that linoleic acid and linolenic acid have anti-inflammatory effects probably due to the inhibition of NF-κB activation via activation of PPARγ. The documented anti-inflammatory activities of C. megalocarpus reported by Matu and van Staden54, support the traditional use of the species in various inflammatory ailments and diseases ranging from microbial infection to injury that result in cell injury and death.

Antinociceptive: Gichui56 evaluated the antinociceptive activities of C. megalocarpus using animal models of pain. The nociceptive tests used by Gichui56 were the writhing, tail flick and the formalin tests using Swiss albino mice of both sexes in a randomized design. In the tail flick test, the mice were injected intraperitoneally with doses of the plant extract, morphine and the vehicle. In the tail flick test, the mice were injected intraperitoneally with doses of the plant extract, morphine and the vehicle. In the formalin test, the mice were injected with doses of the plant extract, morphine, aspirin and the vehicle. In the writhing test, all the doses of the plant extract exhibited antinociceptive effects compared to the vehicle. In the tail flick test the 50, 100 and 200 mg kg–1 doses of the plant extract exhibited antinociceptive effects compared to the vehicle56. In the formalin test, the 50 mg kg–1 dose of the extract did not exhibit significant antinociceptive effects on Swiss albino mice in comparison with the vehicle whereas the 100 and 200 mg kg–1 doses exhibited antinociceptive effects in the early phase compared to the vehicle. In the late phase, all the doses of the plant extract exhibited antinociceptive effects compared to the vehicle56. The observed antinociceptive properties of C. megalocarpus documented by Gichui56 could be due to the presence of lupeol, oleic acid, linoleic acid and linolenic acid which are known to exhibit antinociceptive activities68,69. These results showed that the extracts of C. megalocarpus exhibited peripheral, chronic and central antinociceptive activity hence the species may be of value in development of novel pharmaceutical drugs and health products for analgesia.

Wound healing: Wambugu and Waweru44 evaluated wound healing potential of ethanolic extract of C. megalocarpus leaves by applying different doses of 50, 100 and 150 mg mL–1 topically to excision wounds in Wistar albino rats with neomycin sulphate and normal saline as positive and negative controls, respectively. Percentage wound contraction was determined at 3 day intervals and a histopathology examination of wound tissue was done on day 10 of post application of the extracts to evaluate the different stages of wound healing in the different treatment groups. Histopathology examination of section showed almost complete healing in the groups treated with 100 and 150 mg mL–1 while there were signs of early stages of wound healing for the group treated with 50 mg mL–1. The observed wound healing properties of C. megalocarpus documented by Wambugu and Waweru44 could be due to the presence of betulin, lupeol and linolenic acid which are known to exhibit wound healing activities70,71. Ebeling et al.70, demonstrated positive wound healing effects of betulin and lupeol isolated from the bark of Betula alba L. in scratch assay experiments with primary human keratinocytes and in a porcine ex-vivo wound healing model (WHM). Mechanistical studies carried out by Ebeling70 showed that betulin and lupeol transiently upregulated pro-inflammatory cytokines, chemokines and cyclooxygenase-2 on gene and protein level. For cyclooxygenase-2 (COX-2) and IL-6 the increase of mRNA is due to an mRNA stabilizing effect of betulin and lupeol, a process in which p38 MAPK and HuR (human antigen R) are involved. In a previous research, Lewinska et al.71, attributed wound healing activities demonstrated by linseed and rapeseed oils to linolenic acid which were taken up by the cells and promoted cell proliferation. Linolenic acid ameliorated the process of wound healing as judged by improved migration of fibroblasts to the wounding area71. Wound healing properties of C. megalocarpus documented by Wambugu and Waweru44, provide a scientific basis for the traditional use of the species as herbal medicine for wounds in Kenya18,20,25,35.

Molluscicidal: Waiganjo et al.57, evaluated the anti-schistosomal activity of water, dichloromethane/methanol bark extract of C. megalocarpus on Swiss white mice infected with Schistosoma mansoni with praziquantel as control. The water and dichloromethane/methanol extracts of C. megalocarpus showed low worm reduction percentages (38.7-47.7%) against 75.2% demonstrated by praziquantel. Similarly, Kindiki et al.43, evaluated the molluscicidal activities of aqueous and ethanol extracts of C. megalocarpus against adult and juveniles of Biomphalaria pfeifferi snails. Both aqueous and methanol extracts of C. megalocarpus were moderately toxic on adult snails with LD50 values of between 100 and 500 mg L–1. Based on the molluscicidal activities demonstrated by C. megalocarpus, the species could be used in control of schistosomias is, a disease which remains a public health concern in many third world countries72.

Other activities: Mwangi et al.73, evaluated biological activities of methanol and petroleum ether extracts of C. megalocarpus using the brine shrimp lethality test. Croton megalocarpus was active with LC50 value <250 μg mL–1. Preliminary evaluation of C. megalocarpus seed oil showed that it possessed Epstein-Barr virus-activating potency58.

CONCLUSION

There are several gaps in the understanding of correlation between ethnomedicinal uses and pharmacological properties of C. megalocarpus. Although contemporary research involving C. megalocarpus is promising, the documented scientific evidence is too preliminary to be used to explain and support the documented ethnomedicinal uses. There is not yet enough systematic data regarding the phytochemistry, pharmacological properties, pharmacokinetics and clinical research on C. megalocarpus. Clinical research should be carried out to evaluate the possible therapeutic effects and investigate any side effects and toxicity of C. megalocarpus and its constituents to the target organs. The antibacterial, antifungal, anti-inflammatory, antinociceptive, molluscicidal, wound healing, toxicity and Epstein-Barr virus-activating potency of C. megalocarpus discussed in this paper shows that the species is worth further investigation, particularly linking these pharmacological properties to certain compounds that have been isolated from plant extracts.

SIGNIFICANCE STATEMENT

Croton megalocarpus exhibit several ethnomedicinal uses throughout its distributional range in tropical Africa. Croton megalocarpus demonstrated several pharmacological activities. Further research on the phytochemistry, pharmacological properties, pharmacokinetics and clinical studies of C. megalocarpus will enhance the ethnopharmacology of the species and also create awareness on the species’ ethnomedicine, thereby improving primary health care and knowledge of local communities in tropical Africa.

ACKNOWLEDGMENTS

The author would like to express his gratitude to the National Research Foundation (NRF) grant number T398 and Govan Mbeki Research and Development Centre (GMRDC) grant number C169, University of Fort Hare for financial support to conduct this research.

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