Not ordinary antimalarial drugs: Madagascar plant decoctions potentiating the chloroquine action against Plasmodium parasites
Graphical abstract
Section snippets
Current strategies in the fight against malaria
Mosquito vector-borne diseases pose a major threat to millions of people worldwide. They include malaria, yellow fever, dengue, chikungunya, Japanese encephalitis, St. Louis encephalitis, filariasis and, more recently, outbreaks of Zika virus (Mehlhorn, 2015, Benelli, 2016a, Benelli, 2016b, Benelli et al., 2016a, Benelli et al., 2016b, Ward and Benelli, 2017). Furthermore, Culicidae transmit key pathogens and parasites that dogs and horses are very susceptible to, including the dog heartworm,
Imaging future trends
Recently, there have been signs that the efficacy of artemisinin-based combination therapy and monotherapy have declined in western Cambodia (Dondorp et al., 2009). After these first reports, artemisinin resistance spread and has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria (Elizabeth et al., 2014). Artesunate (Fig. 2) is replacing quinine for the treatment of severe malaria. To face the phenomenon, a new strategy is emerging. Artemisinin-based
Malagasy plants as sources of chloroquine-potentiating agents
Malaria is known by Malagasy population since ancient times (Blanchard, 1901). Ethnobotanical knowledge acquired from one generation to another allowed the majority of population living in rural areas to currently use natural remedies as primary health care. Also in urban areas, where malaria revealed to be resistant or incurable by modern scientific medicines, people have turned to traditional treatments. It is therefore of paramount importance to preserve and transmit this ethnobotanical
Efficacy of Malagasy medicinal plants: from traditional medicine to scientific evidence
Forty-six medicinal plants that are traditionally used in Madagascar for the treatment of malaria and other diseases were subjected to biological screening for the determination of the most active compounds against P. falciparum FCM29/Cameroon (Rasoanaivo et al., 1999). Ethanol and chloroform extracts were prepared and the most active ones were subjected to a bioassay-guided fractionation. The in vitro antimalarial activity of plant extracts, based on [3H]-hypoxanthine uptake, was determined
Bisbenzylisoquinoline alkaloids
Benzylisoquinoline alkaloids (BBIQ) (Fig. 4) are derived from the couple of aromatic aminoacids phenylalanine/tyrosine. BBIQs can generate dimers (bisbenzyisoquinoline alkaloids, BBIQ). BBIQ have been reported as an important source of new potential antimalarial drugs with reversing resistance phenomenon (Ratsimamanga-Urverg et al., 1992). Some of them showed promising efficacy against both CQ-sensitive and CQ–resistant strains of P. falciparum and important synergism with CQ and artemisinin (
Hazomalania voyronii (Jum.) Capuron (Hernandia voyronii Jum.)
Hazomalania voyronii (Jum.) Capuron (syn. Hernandia voyronii Jum.) (Hernandiaceae) is a tree endemic to Madagascar, where is easily recognized by the repulsive and stinking odour of its stem bark and known under the vernacular names ‘hazomalany’ and ‘hazomaimbo’. Notably, local population of the south-west regions used to drink a decoction of H. voyronii stem bark together with intake of one or two tablets of CQ (2–4 ppm) (Ratsimamanga-Urverg et al., 1994a). This species has become endangered in
Strychnopsis thouarsii Baill. and Spirospermum penduliflorum DC
Strychnopsis thouarsii Baill. and Spirospermum penduliflorum DC. are endemic Malagasy plants belonging to the Menispermiaceae family. As traditional herbal remedies, these two plants are used as an adjuvant to CQ to potentiate its curative effects and avoid resistance phenomenon. The in vitro antimalarial activity and the CQ-potentiating effects of the two plant active compounds on a resistant strain of P. falciparum FCM29 from Cameroon were evaluated (Ratsimamanga-Urverg et al., 1992). The
Indole alkaloids
To appreciate the novelty of Malagasy Strychnos alkaloids, a further consideration concerning their stereochemistry is necessary. Stereochemistry is a fundamental feature in natural products. Plant secondary metabolites are rich in stereogenic centers, and their biological activity is strictly related to the configurations of functional groups, since the receptors of the target organisms are stereoselective (Dewick, 2009). On the contrary, conformational movements are restricted by the presence
Strychnos myrtoides Gilg & Busse
Phytochemical analysis on Strychnos species used in Madagascar as adjuvant of CQ evidenced the presence of complex indole alkaloids, which resulted active in vitro and in vivo tests against CQ-resistant Plasmodium strains, attesting the potential use of the mix of CQ and medicinal plants or compounds therein present. As previously evidenced, among indole alkaloids, a prominent position must be assigned to Strychnos alkaloids. Strychnos is a pantropic genus, with in total about 200 species, that
Tabernaemontana sessilifolia Baker
Tabernaemontana sessilifolia Baker (syn. Muntafara sessilifolia (Baker) Pichon), belonging to Apocynaceae family, is a plant endemic to Madagascar. Apocynaceae are taxonomically related to Loganiaceae, being insert in Gentianales order, and from phytochemical point of view both are a good source of indole alkaloids (Gottlieb, 1982). The stem bark of this species is used traditionally to treat fever and the analysis of the stem bark allowed the identification of vobasinyl-iboga bisindole
Vernoniopsis caudata (Drake) Humbert
Vernoniopsis caudata (Drake) Humbert, belonging to Asteraceae, a family were alkaloids are rare, whereas terpenes and phenols are dominant. It is an herb endemic to Madagascar where is used traditionally to treat respiratory diseases (Rasoanaivo et al., 2004). A bioassay-guided fractionation of ethyl acetate extract of leaves led to the isolation of three pseudoguanolide sesquiterpene lactones named helenalin-[2-(1-hydroxyethyl)acrylate], helenalin-[(2-hydroxyethyl-3-methyl)acrylate] and 11
Entada pervillei (Vatke) R. Vig.
Entada pervillei (Vatke) R.Vig. (syn. Piptadenia pervillei Vatke) is a plant endemic to Madagascar, where uses in the traditional medicine are not reported (Ramanandraibe et al., 2008). Previous studies highlighted that the ethyl acetate extract obtained from leaves showed relevant antiplasmodial activity (IC50 = 0.5 μg/ml) on the CQ-resistant P. falciparum FCM29 with minor effects on human cells (Rasoanaivo et al., 2004). The ethyl acetate extract was subjected to bioassay-guided fractionation
Evodia fatraina H. Perrier
Evodia fatraina H.Perrier (Rutaceae), locally known as ‘afatraina’ or ‘fatraina’, is an endemic tree of Madagascar where it occurs in the eastern rainforest. The aqueous extract of its stem bark is used by local populations in the treatment of malaria. The polar extract obtained from E. fatraina stem bark was tested in vitro against three CQ resistant strains of Plasmodium falciparum and in vivo on P. berghei yoelii N67 in mice (Ratsimamanga-Urverg et al., 1991b). The initial extraction with
The pharmacological approach
The CQ mechanism of action is well known. When CQ enters the red blood cell infected with the malaria parasite, it interacts with hemozoin and prevents further biocrystallization of heme leading to heme build-up. The CQ complex with heme is highly toxic to the Plasmodium cell and disrupts membrane function, resulting in cell lysis and ultimately parasite cell autodigestion (Hempelmann, 2007). Resistant strains of the parasite Plasmodium evolved to neutralized antiplasmodial drug activity. They
Conclusions
A challenging problem about the utilization of natural products is that the quantity of plants to be studied, as well as the possible activities, are too high to be faced with the current technology, and therefore ethnobotanical information have been and still are of great utility, as evidenced in this review. Besides any necessary pharmacological test on cell and animal models and clinical trials, popular medicine practiced by rural populations is an open laboratory directly performed on
Conflict of interest
The Authors declare no competing interests.
Acknowledgements
We are grateful to M. Berti for inviting this Review. This work is dedicated to the memory of our friend P. Rasoanaivo, who started working on the manuscript with us and suddenly died before to see it published. G. Benelli is sponsored by PROAPI (PRAF 2015) and University of Pisa, Department of Agriculture, Food and Environment (Grant ID: COFIN2015_22). Funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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2022, Green Sustainable Process for Chemical and Environmental Engineering and Science: Biomedical Application of Biosurfactant in Medical SectorInsecticidal and mosquito repellent efficacy of the essential oils from stem bark and wood of Hazomalania voyronii
2020, Journal of EthnopharmacologyCitation Excerpt :For this reason, it is employed to make shelters, coffins, dugouts, buildings, paddles and food boxes (Allorge and Ikor, 2003; Boiteau et al., 1999; CFPF, 2008). The intensive exploitation of the wood also led to reduction of local populations of H. voyronii trees (Benelli et al., 2017a). In the Malagasy traditional medicine, H. voyronii enjoys a longstanding use.
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2020, Insect-Borne Diseases in the 21st CenturyIn vitro antiplasmodial, antitrypanosomal and antileishmanial activities of selected medicinal plants from Ugandan flora: Refocusing into multi-component potentials
2019, Journal of EthnopharmacologyCitation Excerpt :A considerable number of their extracts and isolated compounds have been shown to possess significant anti-parasitic activities (Kuete and Efferth, 2010). So far only very few whole extracts and pure natural molecules have been tested to demonstrate the hidden and promising chemosensitizing properties they posses towards some of the drug-resistant protozoan parasites (Benelli et al., 2017). Evidence from recent Artemisia leaf studies demonstrate the therapeutic superiority of the combined effect of active molecules in multicomponent plant extracts, clearly corroborating ethnopharmacological claims (Rasoanaivo et al., 2011; Weathers et al., 2014).
- 1
These authors contributed equally to this manuscript.
- 2
P. Rasoanaivo, who collaborated to the writing of this manuscript, suddenly died on July 13th 2016. The other authors are presenting this Review as homage to his contribution to ethnopharmacology.