A REVIEW OF BOTANY, THERAPEUTIC VALUE, PHYTOCHEMISTRY, AND PHARMACOLOGY OF CUSSONIA PANICULATA

Cussonia paniculata is a small tree widely used as herbal medicine throughout its distributional range in southern Africa. This study is aimed at providing a critical review of the botany, biological activities, phytochemistry, and medicinal uses of C. paniculata . Documented information on the botany, biological activities, medicinal uses, and phytochemistry of C. paniculata was collected from several online sources which included BMC, Scopus, SciFinder, Google Scholar, Science Direct, Elsevier, PubMed, and Web of Science. Additional information on the botany, biological activities, phytochemistry, and medicinal uses of C. paniculata was gathered from pre-electronic sources such as book chapters, books, journal articles, and scientific publications sourced from the University library. This study showed that the bark, fruits, leaves, roots, and stems of C. paniculata are used as emetic, immune booster, and herbal medicine for dysmenorrhea, intestinal parasites and worms, mental problems, boils, shingles and skin diseases, indigestion and stomach complaints, sores, and wounds. Phytochemical compounds identified from the leaves of C. paniculata include acetylated triterpene glycosides, unacetylated triterpene glycosides, flavonoid, steroidal saponin, and triterpenoid saponins. Pharmacological research revealed that C. paniculata extracts have analgesic, antibacterial, anticancer, anti-inflammatory, antiplasmodial, antiprotozoan, Aβ42 protein reduction, and cytotoxicity activities. Future research should focus on evaluating the phytochemical, pharmacological, and toxicological properties of C. paniculata crude extracts as well as compounds isolated from the species.


TAXONOMY AND BOTANICAL DESCRIPTION OF C. PANICULATA
The genus name Cussonia is in honor of Pierre Cusson (1727-1783), a French botany professor at the University of Montpellier who specialized in the plant group Umbrelliferae [50,62,63]. The specific name "paniculata" refers to the paniculate or branched inflorescence which terminates the growth of the species' branches. The English common name of C. paniculata is "mountain cabbage tree," mainly because the species is associated with dry stony hills and the thick, often blue-green leaves resemble those of a cabbage (Brassica oleracea L.) [49]. The leaves of C. paniculata are gray-green or blue-green in color which is probably due to the thick waxy layers on the leaves. These waxy layers are believed to protect the leaves from severe frost in winter [49]. Two subspecies of C. paniculata are recognized subsp. paniculata and subsp. sinuata (Reyneke and Kok) De Winter [64]. The subsp. paniculata is characterized by entire leaflet margins, confined to the southern Karoo, Eastern Cape, KwaZulu-Natal, Northern Cape, and Western Cape provinces of South Africa at an altitude ranging from 300 m to 2000 m above the sea level [41,64]. The subsp. sinuata is characterized by shallowly to deep lobed and waxy (sinuate) leaflet margins and widely distributed and recorded in Botswana, Lesotho, Swaziland, the Free State, Gauteng, KwaZulu-Natal, Limpopo, Mpumalanga, and North West provinces of South Africa at an altitude ranging from 900 m to 1980 m above the sea level [41,64]. However, most ethnobotanical and ethnopharmacological literature do not separate C. paniculata into specific subspecies but rather to C. paniculata sensu lato, and this is the approach that has been adopted in this study. Synonyms associated with C. paniculata include C. paniculata Eckl. and Zeyh. var. paniculata and C. paniculata Eckl. and Zeyh. var. sinuata Reyneke and Kok. [64].
C. paniculata is an evergreen small tree with a sturdy trunk which is sparsely branched, rarely exceeding 5 m in height [41,63,[65][66][67][68]. The stem is reddish gray to gray, rough, corky, swollen at the base and roughly 3.5 cm in diameter, the branches marked with prominent leaf scars as the species usually sheds old leaves while new flush of leaves are being produced. The branches have a mop-like crown of leathery, green, frequently blue-green leaves, composed of several leaflets on short stalks springing from the same point at the end of a stout common stalk. The leaves are bi-digitate, oblong in shape, apex and base tapering, margin Maroyi sparsely to distinctly toothed. The flowers are a branched panicle of spikes which are greenish yellow in color. The fruits are fleshy, almost globose in shape, pale purplish in color, and closely clustered along the spikes. C. paniculata has been recorded in Botswana, Lesotho, South Africa, and Swaziland [41,63,[66][67][68] in bushveld, wooded grassland, usually in rocky places at an altitude ranging from 300 m to 2000 m above the sea level [64].

MEDICINAL USES OF C. PANICULATA
The bark, fruits, leaves, roots, and stems of C. paniculata are used as herbal medicines against 32 human diseases in southern Africa (Table 1). C. paniculata is mainly used as emetic, immune booster, and herbal medicine for dysmenorrhea, intestinal parasites and worms, mental problems, boils, shingles and skin diseases, indigestion and stomach complaints, sores, and wounds ( Fig. 1). In Lesotho, the leaves of C. paniculata are mixed with those of Searsia divaricata (Eckl. and Zeyh.) Moffett and Scabiosa columbaria L. as herbal medicine for menstrual problems [69].

Analgesic activities
Adedapo et al. [95] evaluated the analgesic activities of aqueous extract of the stem bark of C. paniculata using the formalin test by treating male Wistar rats with 50 mg/kg, 100 mg/kg, and 200 mg/kg of extract; 10 mg/kg of indomethacin; and 2 ml/kg of normal saline, and the licking time and frequency of the injected paw were recorded for 30 min. In the acetic acid-induced writhing model, the extract showed a good analgesic effect characterized by reduction in the number of writhes when compared to the control. The extract caused dose-dependent decrease of licking time and licking frequency in rats injected with 2.5% formalin, signifying its analgesic effect [95].

Antibacterial activities
De Villiers et al. [104] evaluated antibacterial activities of aqueous and methanol leaf extracts of C. paniculata subsp. paniculata and C. paniculata subsp. sinuata against Enterococcus faecalis, Escherichia coli, Neisseria gonorrhoeae, Staphylococcus aureus, and Pseudomonas aeruginosa using the microplate bioassay with ciprofloxacin (0.01 mg/mL) as a positive control. The extract exhibited activities with minimum inhibitory concentration values ranging from 0.3 mg/mL to 16.0 mg/mL [104].

Anticancer activities
Fouché et al. [105] evaluated anticancer activities of dichloromethane leaf extracts of C. paniculata against sixty human cancer cell lines organized into subpanels representing leukemia, melanoma and cancer of the lung, colon, kidney, ovary, and central nervous system. The extracts exhibited a moderate growth inhibition of above 50% for two or more of the cell lines (GI 50 ) with values ranging from >0 µg/mL to 1.1 µg/mL [105]. Similarly, Fouché et al. [106] evaluated anticancer

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being the highest inhibition [52,75]. Adedapo et al. [95] evaluated the anti-inflammatory activities of aqueous extract of the stem bark of C. paniculata using the carrageenan-induced rat paw edema and histamine-induced rat paw edema assays with indomethacin and cyproheptadine as positive controls. The extract at 50 mg/kg, 100 mg/kg, and 200 mg/kg body weight reduced significantly, the formation of edema induced by carrageenan and histamine [95].

Antiplasmodial activities
Tetyana [52] and Tetyana et al. [75] evaluated antiplasmodial activities of the bark ethanolic, ethyl acetate and water extracts of C. paniculata against Plasmodium falciparum in an in vitro assay, a slightly modified version of the parasite lactate dehydrogenase assay with chloroquine as a positive control. The extracts exhibited weak inhibitory activities ranging from 10% to 35% at a concentration of 200 mg/ml [52,75]. De Villiers et al. [104] evaluated antiplasmodial activities of aqueous and methanol leaf extracts of C. paniculata subsp. paniculata and C. paniculata subsp. sinuata using the (G-3 H) hypoxanthine incorporation assay against the chloroquine-sensitive (3D7) strain of P. falciparum as the test organism. The extracts exhibited moderate antiplasmodial activities with half maximal inhibitory concentration (IC 50 ) value of >50.0 mg/mL [104].

Antiprotozoan activities
De Villiers et al. [104] evaluated antiprotozoan activities of aqueous and methanol leaf extracts of C. paniculata subsp. paniculata and C. paniculata subsp. sinuata against protozoan pathogen associated with urogenital or sexually transmitted infections, Trichomonas vaginalis using the microplate bioassay with ciprofloxacin     activities of dichloromethane: methanol (1:1) leaf extracts of C. paniculata against sixty human cancer cell lines organized into subpanels representing leukemia, melanoma and cancer of the lung, colon, kidney, ovary, and central nervous system. The extracts exhibited activities against leukemia RPMI-8226, colon HCT-116, and colon KM12 with total growth inhibition (TGI) values of 1.0 µg/ml, 1.5 µg/ml, and 2.7 µg/ml, respectively [106].

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(0.01 mg/mL) as a positive control. Only methanol extract exhibited activities with MIC value of 1.0 mg/mL and 1.3 mg/mL against C. paniculata subsp. paniculata and C. paniculata subsp. sinuata extracts, respectively, and these values were higher than 0.001 mg/mL exhibited by the control [104].

Aβ42 protein reduction activities
Thakur et al. [76] evaluated the Aβ42 protein reduction activities of dichloromethane: methanol (1:1) leaf and stem extracts of C. paniculata using ELISA -sAPPα, sAPPβ, and Aβ peptide assays. The extract reduced the secreted level of Aβ42 in a dose-dependent manner compared to the control by 57.5%. The extract also decreased the levels of Aβ40, sAPPβ-sw, and sAPPα in a dose-dependent manner [76].

Toxicity activities
Adedapo et al. [95] evaluated acute toxicity activities of aqueous extract of the stem bark of C. paniculata by oral administration of graded doses of the extract of 200 mg/kg, 400 mg/kg, 800 mg/kg, 1600 mg/kg, and 3200 mg/kg body weight in Wistar male rats. All the rats were allowed free access to food and water and observed over a period of 48 h for signs of acute toxicity and deaths within this period. Acute toxicity test showed that the extract caused 80% mortality in rats, and hence, C. paniculata can be regarded as toxic [95].

CONCLUSION
The diverse medicinal uses of C. paniculata documented in southern Africa, and the scientific evidence of its phytochemistry and biological activities indicates its potential as herbal medicine. However, there is a need for detailed phytochemical and pharmacological studies aimed at correlating its documented ethnomedicinal uses with the phytochemical and pharmacological properties of the species. There is a need for clinical and toxicological evaluations since preliminary acute toxicity studies by Adebapo et al. [95] indicated that aqueous extract of the stem bark of C. paniculata contains potentially toxic compounds. Therefore, future research should focus on the identification of toxic compounds, the possible side effects caused by taking C. paniculata as herbal medicine, and mechanisms of how potential toxic components of the species can be managed when the species is used as herbal medicine.

ACKNOWLEDGMENTS
I would like to express my 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.

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

CONFLICTS OF INTEREST
The author declares that he has no conflict of interest.