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\def\RunningAuthor{Alfred Maroyi}
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\articleType{Review Article}
\receivedDate{17 Jul 2020}
\acceptedDate{22 Aug 2020}
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\title{\textbf{\textit{Cussonia natalensis} Sond. and \textit{C. zuluensis} Strey (Araliaceae): A comparative analysis of their medicinal uses and pharmacological properties}}
\author{Alfred~Maroyi\textsuperscript{*}~\\[5pt]{Department of Botany, University of Fort Hare, Private Bag X1314, Alice 5700, South Africa}}

\begin{abstract}
\textit{Cussonia natalensis }Sond. and \textit{C. zuluensis } Strey have a long history of medicinal use in southern Africa. The aim of this study was to review the medicinal uses and pharmacological properties of the two species. Results of this study are based on data derived from several online databases such as Scopus, Google Scholar, PubMed and Science Direct, and pre-electronic sources such as scientific publications, books, dissertations, book chapters and journal articles. The bark, fruits and roots of \textit{C. natalensis} and \textit{C. zuluensis} are used as emetic, purgative and protective charm, and traditional medicine for diarrhoea, fever, stomach ache and swellings. This study showed that pentacyclic triterpene acids, cardiac glycosides, flavonoids, polyphenols, saponins and steroids have been identified from the leaves, roots and twigs of the species. The leaf extracts and compounds isolated from\textit{ C. natalensis} and \textit{C. zuluensis} exhibited antibacterial, antifungal, antimalarial, antiprotozoal and cytotoxicity activities. Documentation of the medicinal uses, phytochemistry and pharmacological properties of \textit{C. natalensis} and \textit{C. zuluensis} is important as this information provides baseline data required for future research and development of health-promoting and pharmaceutical products. There is need for extensive phytochemical, pharmacological and toxicological studies of crude extracts of \textit{C. natalensis } and \textit{C. zuluensis} to establish the safety profiles of different preparations of the two species. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Araliaceae,\newline Cussonia natalensis,\newline Cussonia zuluensis,\newline indigenous pharmacopeia,\newline traditional medicine
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Alfred~Maroyi~\\ Phone:\ +27406022322~\\  Email:\ amaroyi@ufh.ac.za
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\section{Introduction}
The genus \textit{Cussonia} Thunb. is one of the most important sources of herbal medicines among the Araliaceae genera. The Araliaceae family consists of approximately 55 genera and 1500 species, which are mainly woody plants with a few herbaceous plants \unskip~\citep{858621:20073839,858621:20073842}. Research by \unskip~\citep{858621:20073851} revealed that many Araliaceae species such as \textit{Acanthopanax sciadophylloide} Franch. \& Sav., \textit{A. seiboldianum} Makino, \textit{Acer mono} Maxim., \textit{Aralia cordata} Thunb., \textit{A. elata} (Miq.) Seem., \textit{A. spinosa} L., \textit{Eleutherococcus spinosus} (L. f.) S.Y. Hu, \textit{Fatsia japonica} (Thunb.) Decne. \& Planch., \textit{Gamblea innovans} (Siebold \& Zucc.) C.B. Shang, Lowry \& Frodin, \textit{Hedera helix} L., \textit{H. rhombea} (Miq.) Siebold ex Bean, \textit{Oplopanax japonicus} Nakai, \textit{Panax ginseng} C.A. Mey., \textit{P. japonicus} (T. Nees) C.A. Mey. and \textit{Schefflera heptaphylla} (L.) Frodin are noteworthy culinary and medicinal plants. Some members of the Araliaceae family have demonstrated pharmacological properties such as neuroprotective, anti-aging, immunostimulant, antiapoptotic, immunomodulatory, anticancer, antiviral, antidiabetic, antibacterial, antidiabetes, antipsoriasis, antiarthritis, antifungal, anticonvulsant, antioxidant, antiobesity and anti-inflammatory \unskip~\citep{858621:20073857}. Phytochemical studies on species belonging to the Araliaceae family revealed the presence of flavonoids, triterpenes, volatile oils, triterpenoid glycosides, saponins and tannins \unskip~\citep{858621:20073857}


\begin{table*}[!htbp]
\caption{\boldmath {Medicinal uses of Cussonia natalensis and C. zuluensis } }
\label{tw-a1067dd34a07}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.25380000000000003\linewidth-2\tabcolsep}p{\dimexpr.31300000000000004\linewidth-2\tabcolsep}p{\dimexpr.2233\linewidth-2\tabcolsep}p{\dimexpr.20990000000000002\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Medicinal uses & Parts used & Country & Reference\\
\tblmidrule 
\multicolumn{4}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\textbf{Cussonia natalensis}}\\
Diarrhoea &
  Root decoction taken orally &
  Zimbabwe &
  \unskip~\citep{858621:20073831}\\
Emetic &
  Root decoction taken orally &
  Eswatini &
  \unskip~\citep{858621:20073846,858621:20073829}\\
Gastro-intestinal problems &
  Stem bark mixed with that of Gardenia volkensii K. Schum. subsp. spatulifolia (Stapf. \& Hutch.) Verdc. &
  Eswatini &
  \unskip~\citep{858621:20073855}\\
Protective charm &
  Bark, fruits and roots &
  Eswatini &
  \unskip~\citep{858621:20073829}\\
Purgative &
  Bark decoction taken orally &
  Eswatini &
  \unskip~\citep{858621:20073846}\\
Stomach ache &
  Bark and root decoction taken orally &
  Eswatini &
  \unskip~\citep{858621:20073846,858621:20073855}\\
\multicolumn{4}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\textbf{Cussonia zuluensis}}\\
Emetic &
  Root infusion taken orally &
  Eswatini &
  \unskip~\citep{858621:20073829,858621:20073847}\\
Fever &
  Root decoction taken orally &
  Eswatini &
  \unskip~\citep{858621:20073847}\\
Purgative &
  Root infusion taken orally &
  South Africa &
  \unskip~\citep{858621:20073833}\\
Swellings &
  Root infusion applied topically &
  South Africa &
  \unskip~\citep{858621:20073833}\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
The genus \textit{Cussonia} Thunb. comprises about 22 species which are mainly trees or shrubs or occasionally subshrubs recorded in grasslands, woodlands, and forests of sub-Saharan Africa, the Arabian Peninsula (Yemen) and the Comoro Islands \unskip~\citep{858621:20073836,858621:20073828}. \textit{Cussonia natalensis } Sond. and \textit{C. zuluensis } Strey\textit{\space } are among the species widely used as herbal medicines in southern Africa. Other \textit{Cussonia} species regarded as important medicinal plants in tropical Africa include \textit{C. arborea} Hochst. ex A. Rich., \textit{C. bancoensis} Aubr{\'e}v. \& Pellegr., \textit{C. holstii} Harms ex Engl., \textit{C. nicholsonii } Strey, \textit{C. ostinii} Chiov., \textit{C. paniculata} Eckl. \& Zeyh., \textit{S. spicata} Thunb., \textit{C. transvaalensis} Reyneke and \textit{C. zimmermannii} Harms \unskip~\citep{858621:20073852,858621:20073848}.  Apart from used as herbal medicines for similar medicinal conditions, \textit{C. natalensis } and \textit{C. zuluensis } have been recorded in overlapping geographical areas in southern Africa (Figure~\ref{f-f7e5fcf59fa1}). It is therefore, within this context that the current review was undertaken aimed at providing a comparative analysis of the botanical, medicinal, chemical and biological activities of \textit{C. natalensis } and \textit{C. zuluensis}.
    
\section{Materials and Methods}
Results of the current study are based on literature search on the botanical, medicinal, chemical and biological activities of \textit{C. natalensis } and \textit{C. zuluensis }using information derived from several internet databases. The databases included Scopus, Google Scholar, PubMed and Science Direct. Other sources of information used included pre-electronic sources such as journal articles, theses, books, book chapters and other scientific articles obtained from the University library. 
    
\section{Results and Discussion}
\textbf{Botanical description of \textit{Cussonia natalensis } and \textit{C. zuluensis }}

The genus name ``\textit{Cussonia}'' is in honour of Pierre Cusson (1727-1783), a French Professor of botany at the University of Montpellier who specialized in Apiaceae family \unskip~\citep{858621:20073849}. The specific name ``\textit{natalensis}'' means ``of Natal'', part of KwaZulu-Natal province in South Africa where the type specimen of the species was collected \unskip~\citep{858621:20073854}. \textit{Cussonia natalensis } is commonly referred to as ``rock cabbage tree'', ``simple-leaved cabbage tree'' and ``Natal cabbage tree''. \textit{Cussonia natalensis } is a sturdy, small to medium-sized deciduous tree with a rounded crown which can grow up to a height of 11 metres \unskip~\citep{858621:20073856}.\ensuremath{^{}} The bark of \textit{C. natalensis} is dark grey to brown in colour, deeply rectangularly fissured and corky. The leaves of \textit{C. natalensis} are simple, deeply lobed, leathery, glossy green, hairless, apex tapering to a point, base lobed with bluntly toothed leaf margins. The flowers are greenish yellow in colour, occurring in terminal heads of radiating cylindrical spikes. The fruit is a cone-shaped drupe, fleshy and purple in colour when ripe and closely crowded along the spikes. \textit{Cussonia natalensis} has been recorded in Eswatini, South Africa and Zimbabwe at an altitude ranging from 100 m to 1640 m above sea level \unskip~\citep{858621:20073853}. \textit{Cussonia natalensis } has been recorded in bushveld, usually in rocky places, hills, hillsides and mountain sides.


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\caption{\boldmath {Geographical distribution of \textit{Cussonia natalensis} and \textit{C. zuluensis}}}
\label{f-f7e5fcf59fa1}
\end{figure}
\egroup
The specific name ``\textit{zuluensis}'' refers to Zululand (part of KwaZulu-Natal province in South Africa) from where the type specimen of the species was collected \unskip~\citep{858621:20073835}. \textit{Cussonia zuluensis} is commonly referred to as ``Zulu cabbage tree''. \textit{Cussonia zuluensis} is a small, multi-stemmed, sparsely branched tree with a spindly shape, growing to a height of six metres \unskip~\citep{858621:20073853}. The bark is grey-green in colour, smooth to flaking. The leaves of \textit{C. zuluensis} are multi-digitate, clustered near ends of branches or arranged spirally at the ends of branches. The leaves are leathery, glossy dark green above, dull green below, apex tapering with a hair-like tip, base tapering with sparsely to distinctly toothed leaf margins. Flowers occur in terminal simple umbels and are greenish yellow in colour. The fruit is a goblet-shaped drupe, fleshy and mauve in colour when ripe and closely crowded along the axes. \textit{Cussonia zuluensis } has been recorded in Eswatini, Mozambique and South Africa at an altitude ranging from 10 m to 1000 m above sea level \unskip~\citep{858621:20073853}. \textit{Cussonia zuluensis } has been recorded in sandy soils and river valleys in bushveld, dry coastal scrub and forest.\ensuremath{^{}}

\textbf{Medicinal uses of } \textit{\textbf{Cussonia natalensis }} \textbf{and \textit{C. zuluensis }} \textit{\textbf{\space }}

In Eswatini and Zimbabwe, the bark, fruits and roots of \textit{C. natalensis} are used as emetic, purgative and protective charm, and traditional medicine against diarrhoea and stomach ache (Table~\ref{tw-a1067dd34a07}). In Eswatini, the stem bark of \textit{C. natalensis} is mixed with that of \textit{Gardenia volkensii } K. Schum. subsp. \textit{spatulifolia} (Stapf. \& Hutch.) Verdc. as herbal medicine for gastro-intestinal problems \unskip~\citep{858621:20073855}. In Eswatini and South Africa, the root infusion of \textit{C. zuluensis} is used as emetic and purgative, and herbal medicine for fever and swellings \unskip~\citep{858621:20073829,858621:20073847}.

\textbf{Phytochemical and biological activities of \textit{Cussonia natalensis } and \textit{C. zuluensis }}

There is very little information available concerning the phytochemistry of the crude extracts of \textit{C. natalensis } and \textit{C. zuluensis}. However, \unskip~\citet{858621:20073837} identified pentacyclic triterpene acids, 23-hydroxy-3-oxo-urs-12-en-28-oic acid and oleanolic acid from the leaves and twigs of \textit{C. natalensis}. Preliminary research by \unskip~\citet{858621:20073837} showed that the triterpene acid, 23-hydroxy-3-oxo-urs-12-en-28-oic acid isolated from the leaves and twigs of \textit{C. natalensis} has anti-ulcer properties. Similarly, \unskip~\citet{858621:20073847} identified cardiac glycosides, flavonoids, polyphenols, saponins and steroids from the roots of \textit{C. zuluensis}. Some of these chemical compounds may be responsible for the pharmacological properties of the species.\ensuremath{^{}} The phytochemical compounds like triterpenes are associated with antioxidant, antimicrobial, antimalarial, anti-inflammatory, anticancer, \ensuremath{\alpha }-glucosidase inhibitors and antidiabetic properties \unskip~\citep{858621:20073832,858621:20073844}. Many flavonoids, polyphenols, saponins and steroids have anti-inflammatory, anticancer, antioxidant, antiparasitic, antiphlogistic, antiallergic, immunomodulating, antihepatotoxic, antiviral, hypoglycemic, antifungal and molluscicidal activities \unskip~\citep{858621:20073845,858621:20073843}.

\unskip~\citet{858621:20073841} evaluated the antibacterial activities of methanol and water extracts of \textit{C. natalensis} leaves against \textit{Pseudomonas aeruginosa, Neisseria gonorrhoeae, Enterococcus faecalis, Staphylococcus aureus} and \textit{Escherichia coli} using the microdilution method with ciprofloxacin (0.01 mg/mL) as positive control. Both extracts exhibited activities against all the tested pathogens with the minimum inhibitory concentrations (MIC) values ranging from 0.3 mg/mL to 8.0 mg/mL. Similarly, \unskip~\citet{858621:20073841} evaluated the antibacterial activities of methanol and water extracts of \textit{C. zuluensis} leaves against \textit{Pseudomonas aeruginosa, Neisseria gonorrhoeae, Enterococcus faecalis, Staphylococcus aureus} and \textit{Escherichia coli} using the microdilution method with ciprofloxacin (0.01 mg/mL) as positive control. Both extracts exhibited activities against all the tested pathogens with the MIC values ranging from 0.2 mg/mL to 9.3 mg/mL \unskip~\citep{858621:20073841}. \unskip~\citet{858621:20073827,858621:20073834} evaluated the antibacterial activities of acetone, dichloromethane and n-hexane extracts of \textit{C. zuluensis} leaves against \textit{Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli} and \textit{Staphylococcus aureus} using the microdilution method with gentamicin as a positive control. The extracts exhibited activities against the tested pathogens with MIC values ranging from 0.3 mg/ml to 2.5 mg/ml and total activity ranging from 8.0 ml to 267.0 ml \unskip~\citep{858621:20073827,858621:20073834}.

\unskip~\citet{858621:20073840} evaluated the antifungal activities of ethanol extracts of \textit{C. natalensis} leaves against \textit{Candida krusei} and \textit{Candida albicans} using the agar disc diffusion and broth dilution methods with miconazole as positive control. The extract exhibited activities against \textit{Candida albicans} with zone of inhibition value of 16.0 mm, MIC and minimum fungicidal concentration (MFC) values of 0.3 mg/ml and 1.3 mg/ml, respectively. The zone of inhibition exhibited by miconazole, the control ranged from 20.0 mm to 22.6 mm, and the MIC and MFC values ranged from 0.3 mg/ml to 0.6 mg/ml \unskip~\citep{858621:20073840}. \unskip~\citet{858621:20073827,858621:20073834} evaluated the antifungal activities of acetone, dichloromethane and n-hexane extracts of \textit{C. zuluensis} leaves against \textit{Cryptococcus neoformans, Aspergillus fumigatus, Candida albicans, Micrococcus canis} and \textit{Sporothrix schenckii} using the microdilution method with amphotericin B as positive control. The extracts exhibited activities against tested pathogens with MIC values ranging from 0.06 mg/ml to 2.5 mg/ml and total activity ranging from 8.0 ml to 133.0 ml \unskip~\citep{858621:20073827,858621:20073834}. \unskip~\citet{858621:20073830,858621:20073838} evaluated the antifungal activities of hexane, dichloromethane, acetone and methanol leaf extracts of \textit{C. zuluensis} against \textit{Cryptococcus neoformans } using the two-fold serial dilution microplate and microdilution methods. The extracts exhibited activities against the tested pathogen with MIC values ranging from 0.02 mg/mL to 0.6 mg/mL and total activity ranging from 9.0 mL/g to 496.0 mL/g \unskip~\citep{858621:20073830,858621:20073838}.

\unskip~\citet{858621:20073841} evaluated the antiprotozoal activities of methanol and water extracts of \textit{C. natalensis} against the protozoan pathogen associated with urogenital or sexually transmitted infections, \textit{Trichomonas vaginalis} using the microdilution method with ciprofloxacin (0.01 mg/mL) as positive control. The methanol extract exhibited activities against the tested pathogen with MIC value of 1.0 mg/mL which was higher than the MIC value of 0.001 mg/mL exhibited by the positive control. \unskip~\citet{858621:20073841} evaluated the antiprotozoal activities of methanol and water extracts of \textit{C. zuluensis} leaves against the protozoan pathogen associated with urogenital or sexually transmitted infections, \textit{Trichomonas vaginalis} using the microdilution method with ciprofloxacin (0.01 mg/mL) as positive control. The methanol extract exhibited activities against the tested pathogen with MIC value of 0.8 mg/mL which was higher than the MIC value of 0.001 mg/mL exhibited by the positive control \unskip~\citep{858621:20073841}. 

\unskip~\citet{858621:20073841} evaluated the antimalarial activities of methanol and water extracts of \textit{C. natalensis} leaves using the [G-\ensuremath{^{3}}H] hypoxanthine incorporation assay using chloroquine-sensitive (3D7) strain of Plasmodium falciparum as the test organism. The extracts exhibited weak activities with half maximal inhibitory concentration (IC\ensuremath{_{50}}) values {\textgreater}50.0 \ensuremath{\mu }g/mL. \unskip~\citep{858621:20073841} also evaluated the antimalarial activities of methanol and water extracts of \textit{C. zuluensis} leaves using the [G-\ensuremath{^{3}}H] hypoxanthine incorporation assay using chloroquine-sensitive (3D7) strain of \textit{Plasmodium falciparum} as the test organism. The extracts exhibited weak activities with IC\ensuremath{_{50}} values {\textgreater}50.0 \ensuremath{\mu }g/mL \unskip~\citep{858621:20073841}.

De Villiers \textit{et al.} (2010) evaluated the cytotoxicity activities of methanol and water extracts of \textit{C. natalensis} against the human T-cell leukemia (Jurkat) cell line using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) calorimetric assay with (S)-(+)- camptothecin as a positive control. The extracts exhibited weak cytotoxicity activities with IC\ensuremath{_{50}} values {\textgreater}50.0 \ensuremath{\mu}g/mL in comparison to IC\ensuremath{_{50}} value of 0.07 \ensuremath{\mu}g/mL exhibited by the positive control. \unskip~\citet{858621:20073833} also evaluated the cytotoxicity activities of methanol and water extracts of \textit{C. zuluensis} leaves against the human T-cell leukemia (Jurkat) cell line using the MTT calorimetric assay with (S)-(+)- camptothecin as a positive control. The methanol and water extracts exhibited moderate cytotoxicity activities with IC\ensuremath{_{50}} values of 37.0 \ensuremath{\mu}g/mL and {\textgreater}50.0 \ensuremath{\mu}g/mL, respectively in comparison to IC\ensuremath{_{50}} value of 0.07 \ensuremath{\mu}g/mL exhibited by the positive control \unskip~\citep{858621:20073828}. 
    
\section{Conclusions}
The present review summarizes the botanical, medicinal, chemical and biological activities of \textit{C. natalensis } and \textit{C. zuluensis}. Based on the presented information, these two species are closely related and deemed as potent traditional medicines for treating and managing fever, heart problems, headache, earache, skin disorders, fatigue and respiratory problems. \textit{Cussonia natalensis } and \textit{C. zuluensis} should be subjected to detailed phytochemical, pharmacological and toxicological evaluations aimed at correlating their medicinal uses with their phytochemistry and pharmacological properties. 
    
\section{Acknowledgement}
I am grateful to the reviewers who kindly commented on my manuscript.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest for this study.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.
    

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