Ethnopharmacology, Pharmacology and Phytochemistry of Aristolochia bracteolata Lam: A Review of an Antimalarial Plant

Malaria remains one of the most common infectious diseases in the sub-Sahara African countries and other developing countries. Among the medicinal plants used in the endemic countries for the treatment of malaria is Aristolochia bracteolata Lam. due to its availability, accessibility, and traditional use. This study therefore reviewed the ethnomedicinal use, pharmacology, and the chemistry of Aristolochia bracteolata. Different electronic databases such as Medline/Pubmed, Cochrane Library, and Embase were searched to identify all published articles on Aristolochia bracteolata Lam. Key search words included ethnopharmacological use, pharmacological and phytochemical parameters of A. bracteolata. Retrieved articles were reviewed and synthesized. In addition, the reference list of retrieved articles was reviewed and articles which were not retrieved by previous search were hand searched. The review included original research articles that has investigated Aristolochia bracteolata Lam. of any study design. Only published original articles, any languages, any time of publish, and grey literature (Conference paper, theses both PhD. and Msc. technical report) were included. Those articles with full text not available, those without information of interest, e.g ethnopharmacology, pharmacology and phytochemistry of A. bracteolata were excluded. Despite having multiple use, the plant is mainly used in the treatment of malaria with a reported antiplasmodial activity. Aristolochic acids (AAs) were reported as the major and active ingredient among other components in the plant. The review revealed that A. bracteolata has various traditional use with promising pharmacological activity. However, information on its safety is limited.


INTRODUCTION
edicinal plants played a very important role in human life right from the ancient times till today. They comprise many chemical constituents with different pharmacological effects thereby regulating different biological mechanisms and treating different types of diseases 1 . They have a vital role in treating and preventing various diseases. Some of these medicinal plants have been reported for their antimalarial activities and have been the source of new lead drugs including artemisinin, quinine, etc. 2,3 . In addition to antimalarial efficacy, some of these plants have been reported to exhibit antidiuretic, antiinflammatory, anti-analgesic, anticancer, antiviral, antibacterial and antifungal activities. The use of herbal medicine (HM) has become an alternative source of treatment over the past three decades to address the gap of M high cost, resistance to conventional drugs and as alternative drug for primary healthcare (PHC) 4 . Medicinal plants have played important roles in drug discovery through phytochemicals which can be directly used as medical remedy, structural basis for chemical synthesis or act as structural model for semi-synthetic drugs 5 .
Medicinal plants are the richest bio-resource of drugs of traditional systems of medicine, modern medicines, nutraceuticals, food supplements, folk medicines, antimalarial drugs etc 4 . Many plants are useful to human lives as source of food, food supplement or therapeutic purpose, however, some have been reported to have mutagenic and genotoxic effect in vivo 6 . Plant toxicity may arise from contaminants like lead, mercury, arsenic and other that can be absorbed from the soils or from the end products of plant metabolism. Current studies have focused more on ethnomedicinal use, pharmacology and phytochemistry of medicinal plants used by humans. This is very significant in order to guarantee the safety of the consumers of plant products 7 . The plant toxicity may originate from different contaminants which may be chemical (organic pollutant, toxic metals or non-metals), biological (parasitic or microbiological) or agrochemical residues 8 . A number of bioassays are used in research to ascertain toxicity level of medicinal plants or herbal extracts which may be in vivo using laboratory animals 9 or in vitro using cell line cytotoxicity studies 10 . Identification of phytochemicals responsible either for biological activity or toxicity is important for enhancing the bioactive effect or preventing the toxic effect. In malaria endemic countries, medicinal plants are used as alternative for treatment of the different ailments including malaria, and has remained a first line source of novel drugs such as quinine, artemisinins etc. Aristolochia bracteolata is used for the treatment of various diseases in many countries including South Sudan but review on its safety, phytochemistry and efficacy is limited. This review synthesized information on ethnopharmacology, pharmacology and phytochemistry of Aristolochia bracteolata Lam.

METHODS
Different electronic databases searches were performed in Medline/Pubmed, Cochrane Library, Google scholar, proquest library and Embase to identify all published articles on Aristolochia bracteolata Lam. The key words included ethnopharmacological use, pharmacological and phytochemical parameters of Aristolochia bracteolata. In addition, the reference list of retrieved articles was reviewed and articles which were not retrieved by previous search were hand searched. The review included original research articles that has investigated Aristolochia bracteolata Lam. of any study design. Only published original articles, any languages, any time of publish, and grey literature (Conference paper, theses both PhD. and MSc., technical report) were included. Full text not available, those without information of interest, e.g. ethnopharmacology, pharmacology and phytochemistry of A. bracteolata were excluded.

Search results
After searching the data bases and hand searching a total of 215 articles were obtained. After reviewing articles for relevance, 73 were excluded. Since 23 full text were not available, 5 were reviewed articles, and the remaining does not have the information of interest. Therefore, 42 articles were finally included in this review.  11 . Aristololochia bracteolata is a climbing perennial plant with cordate leaves and dark-purple colour tubular flowers widely distributed in tropical Asia, Africa and South America 12 . It is commonly known as worm killer and classification details are provided in Table 1.  13 . Apart from treating malaria, A. bracteolata is also used for treatment of various diseases and ailments in South Sudan traditional health system. These uses include dysentery, headache, fever, general body pain, snake bites, scorpion bites, high blood pressure, diabetes, diarrhea and stomach ache 13 . The whole plant has been reported to be of medicinal importance 13 . The plant A. bracteolata Lam. is the most commonly used as an antimalarial plant and sold in the markets as a source of income for the local inhabitants in South Sudan. The whole plant is either administered fresh or after sun dried. For the topical use, the plant paste is applied in the affected area and seeds are swallowed for the treatment of malaria and other stomach conditions. Its root is also powdered, infused in water and administered orally for the treatment of malaria, fever, headache, general body pain, stomachache, diarrhea and flu 13 .

Root
Root paste as vulnerary agent: 100g of fresh roots taken processed and ground to paste. It is mixed with 1 spoonful of turmeric powder, warmed and applied on wounds 16 Root and Leaf Roots used for Scorpion stings and anti-inflammatory, leaves for malaria 17 The Whole Plant For the treatment of malaria and other conditions like, fever, headache, general body pain, stomachache, diarrhea and flu. 13 Pharmacological activity of Aristolochia bracteolata Lam. Aristolochia bracteolaae Lam. has been reported to have antibacterial, antifungal 18 , anti-arthritis 19 , hypotensive, hypothermia, antioxidant, anti-inflammatory, antihyperglycemic and antihyperlipidemic 20 activities. Hexane extract of A. bracteolata showed in vitro antiplasmodial activity on chloroquine sensitive P. falciparum MRC-2 strain with IC50 of 16 µg/mL. 21 . In another study, methanol extract of seed and root of A. bracteolata showed in vitro antiplasmodial activity on chloroquine resistant and pyrimethamine sensitive strain with IC50 less than 5 µg/mL. Likewise, petroleum ether/chloroform extract of whole plant of A. bracteolata showed in vitro antiplasmodial activity of 100% inhibition against P. falciparum at 50 μg/mL concentration 17,22 . This confirms local community claim that the plant has effect on malaria parasite. Antimicrobial activity 23 anti-arthritis activity 24 , anti-allergic activity 19 and anti-oxidant property 25 were also exhibited by the plant. The ethyl acetate, acetone and methanol extracts of the root showed promising antibacterial activity on Gram positive and Gram negative bacteria, with ethyl acetate extract being the most effective 14 . Aristolochia bracteolata showed a promising hyperuricemia in a metabolic arthritis rat model 1 and showed a potent in vitro wound healing action through anti-inflammatory and proliferative effect on human dermal fibroblasts and keratinocytes 26 .

Phytochemistry of Aristolochia bracteolata Lam.
Phytochemical screening of Aristolochia bracteolata Lam. showed that it contains presence of alkaloids, saponins, flavonoid, phenol and tannin 16 . Methanol extract of A. bracteolata subjected to phytochemical screening has shown the presence of phenolic compounds, flavonoids, triterpenoids, alkaloids, steroids, cardiac glycosides, saponins and aristolochic acids A-D 4 . The stem and the root were reported to contain the alkaloid and aristolochic acids. The chief active principle of the drug is aristolochic acid, though aristolic and p-coumaric acids also appear to contribute to the activities of the drug. Aristolochic acid is 8-methoxy-3; 4-methylenedioxy -10nitrophenanthrene -1-carboxylic acid. It is intensely bitter and is optically inactive. It is the same as iso-aristolochic acid, aristolochia yellow, aristinic and aristolochic acids, but is different from aristolochine now identified as 1-curine. The aristolochic acids were host of phenanthrene derived metabolites in which the aristolactams also possessed the similar skeleton 27 . Both aristolochic acids (AAs) I and II are the major components of the plant in aristolochia genus. Phytochemical screening East Africa Science 2020 | Volume 2 | Issue 1 26 of A. bracteolata using different solvents is presented in Figures 1 and 2 and Table 3 depict structures of aristolochic acid I and II respectively. However, in another study, methanolic extract of A. bracteolata Lam was purified and toxic compounds identified as AAs were isolated using different purification techniques. It was noted in previous studies that the whole plant (200g) was defatted to produce dark green oily residue (5.35%). High performance liquid chromatography (HPLC) data also showed that AA-ΙΙ was represented in a higher calculated quantity of 49.03 g/kg compared to AA-Ι (12.98 g/kg) in A. bracteolata L. whole plant 31,32 . Although evidence of the presence of aristolochic I and II in A. bracteolata Lam. is reported by Achenbach and Fischer 33 , Kumar 34,35 reported absence of Aristolochic II in this plant. Variation in their results may be explained by the different techniques and methods of analysis used.

Toxicity of Aristolochia bracteolata Lam.
Most of the plant family Aristolochiaceae are said to contain aristolochic acids (AAs) 15 . Pure AAs from A. bracteolata plant has been reported for nephrotoxic, mutagenic and carcinogenic in the tested animals after a prolong administration. In experimental animals, high doses of aristolochic acids administered either orally or intravenously caused severe necrosis of the renal tubules 36 . However, there is limited evidence in human on the carcinogenicity of the plant. The acute oral toxicity study on A. bracteolata extract showed no mortality and any sign of toxicity after dosing at 2000 mg/kg 7 . In a similar study, 29,32 the ethanol extract of A. bracteolata administered orally at 1000, 2000, 3000, 4000, and 8000 mg/kg did not produce any sign of toxicity and mortality in rats when observed for 14 days postadministration, which could be safety-acutely.
The kidney is an important organ required by the body to perform several important functions including the maintenance of homeostasis, power of hydrogen (PH), blood pressure (BP), regulation of the extracellular environment, such as detoxification, and excretion of toxic metabolite and drugs. Kidney is also a major site of organ damage caused by drug toxicity 37 . Nephron is a basic unit structure in the kidney which functions to remove waste products, stray ions and excess water from the blood. Therefore, the kidney can be considered as a major target organ for exogenous toxicants due to nephrotoxicity [38][39][40] .
Aristolochic acid administered orally on rats at 50 mg/kg for three days neoplastic lession on the kidneys were reported 41 .
In another study, aristolochic acids administered through intraperitoneal injection on rabbits at 0.1 mg/kg for 17-21 months reported kidney tumors, ulcers, and peritoneal cavity 34 .
However, it is important to recognize that safety concerns must be incorporated into a general 'risk-benefit' analysis and that toxicity of a drug does not necessarily mean that it should not be developed or approved. The aminoglycoside antibiotics, the cancer drug cisplatin and the antiviral tenofovir were some of the few mentioned examples of drugs which are proved to be nephrotoxic but efficacious in terms of treatment 42 .

CONCLUSION
This review study has shown that Aristolochia bracteolata Lam. is used as remedy for different ailment and unlike pure aristolochic acids which is toxic, the extracts did not show any sign of toxicity from the literature. The plants have also shown a promising antiplasmodial activity which could be recommended for antimalarial study in vivo. It could be concluded that the plant contains different chemical constituents with aristolochic acids being the marker which is reported for a degenerative effect on the organs. This plant however has shown a promising pharmacology which could be explored in the development of future drugs development.