Elsevier

Industrial Crops and Products

Volume 103, September 2017, Pages 19-38
Industrial Crops and Products

Not ordinary antimalarial drugs: Madagascar plant decoctions potentiating the chloroquine action against Plasmodium parasites

https://doi.org/10.1016/j.indcrop.2017.03.032Get rights and content

Highlights

  • Resistance-modifiers restore chloroquine sensitivity in chloroquine-resistant Plasmodium.

  • Malagasy populations use plant decoctions and low doses of chloroquine to boost its action.

  • 12 plants contain complex alkaloids effective against chloroquine-resistant Plasmodium.

  • Correspondence between ethnobotanical reports and scientific studies was highlighted.

Abstract

Malaria mortality rates have fallen by 47% globally since 2000 and by 54% in the African region, but they are still a major problem. Malaria is caused by Plasmodium parasites, vectored to people through Anopheles mosquitoes, which mainly bite between dusk and dawn. Currently, a growing number of Plasmodium species and strains developed resistance to the most commonly used anti-malarial drugs. Chloroquine (CQ), the most commonly used anti-malarial drug, actually is not effective in a number of cases, and growing Plasmodium resistance has been already observed to artemisinin. New approaches are necessary to face this challenge. One of the strategies to overcome the drug resistance in different Plasmodium species is the search for compounds known as resistance-modifiers or chemosensitizers. These compounds may restore the CQ sensitivity in CQ-resistant strains of Plasmodium. The studies started from the knowledge that some Madagascar populations use decoctions of some local plants in association with low doses of CQ to complement the CQ action against chronic malaria. In such way, resistance insurgence is lowered, as well as collateral effects. Phytochemical analyses on twelve plant species commonly used by local populations to treat malaria evidenced the presence of complex alkaloids, which showed in vitro and/or in vivo efficacy against CQ-resistant Plasmodium strains, attesting the potential use of the mix of CQ and medicinal plant preparations or compounds therein present. The approach, in accordance with recent tendencies on multidrug resistance control, is based on mixtures of natural products and classic antimalarial drugs, with a relevant coincidence between the ethnobotanical reports and the scientific evidence.

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.

References (101)

  • S. Munagala et al.

    Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication

    Bioorg. Med. Chem.

    (2014)
  • H. Rafatro et al.

    Reversal activity of the naturally occurring chemosensitizer malagashanine in Plasmodium malaria

    Biochem. Pharmacol.

    (2000)
  • D. Ramanitrahasimbola et al.

    Malagashanine potentiates chloroquine antimalarial activity in drug resistant plasmodium malaria by modifying both its efflux and influx

    Mol. Biochem. Parasitol.

    (2006)
  • P. Rasoanaivo et al.

    Medicinal plants used to treat malaria in Madagascar

    J. Ethnopharmacol.

    (1992)
  • P. Rasoanaivo et al.

    Screening of plant extracts from Madagascar for the study of antimalarial activity and potential effect of chloroquine. [Criblage d'extraits de plantes de Madagascar pour recherche d'activité antipaludique et d'effet potentialisateur de la chloroquine]

    J. Ethnopharmacol.

    (1999)
  • P. Rasoanaivo et al.

    The co-occurrence of C(3) epimer Nb, C(21)-secocuran alkaloids in Strychnos diplotricha and Strychnos myrtoides

    Phytochemistry

    (2001)
  • S. Ratsimamanga-Urverg et al.

    Antimalarial activity and cytotoxicity of Evodia fatraina stem bark extracts

    J. Ethnopharmacol.

    (1991)
  • C. Vadivalagan et al.

    Exploring genetic variation in haplotypes of the filariasis vector Culex quinquefasciatus(Diptera: Culicidae) through DNA barcoding

    Acta Tropica

    (2017)
  • J. Achan et al.

    Plant-derived antimalarial agents: new leads and efficient phythomedicines. Part I. Alkaloids

    An. Acad. Bras. Ciánc.

    (2009)
  • B.O. Alaíde et al.

    Plant-derived antimalarial agents: new leads and efficient phythomedicines. Part I. Alkaloids

    Anais da Academia Brasileira de Ciíncas

    (2009)
  • A. Bassoli et al.

    Modern Alkaloids: Structure, Synthesis and Biology

  • G. Benelli et al.

    Declining malaria, rising dengue and Zika virus: insights for mosquito vector control

    Parasitol. Res.

    (2016)
  • G. Benelli et al.

    Mosquito vectors and the spread of cancer: an overlooked connection?

    Parasitol. Res.

    (2016)
  • G. Benelli et al.

    Biological control of mosquito vectors: past, present and future

    Insects

    (2016)
  • G. Benelli

    Research in mosquito control: current challenges for a brighter future

    Parasitol. Res.

    (2015)
  • G. Benelli

    Plant-mediated biosynthesis of nanoparticles as an emerging tool against mosquitoes of medical and veterinary importance: a review

    Parasitol. Res.

    (2016)
  • G. Benelli

    Green synthesized nanoparticles in the fight against mosquito-borne diseases and cancer–a brief review

    Enzyme Microbial. Technol.

    (2016)
  • R. Blanchard

    Le paludisme à Madagascar

    Rev. Madagascar

    (1901)
  • E. Callaway et al.

    Anti-parasite drugs sweep Nobel prize in medicine 2015

    Nature

    (2015)
  • M. Carraz et al.

    A plant-derived morphinan as a novel lead compound active against malaria liver stages

    PLoS Med.

    (2006)
  • B.K. Cassels et al.

    A simple relationship between stereostructure and specific rotation for the bis (benzylisoquinoline)

    Heterocycles

    (1980)
  • J.M. Cohen et al.

    Malaria resurgence: a systematic review and assessment of its causes

    Malaria J .

    (2012)
  • P.M. Dewick

    Medicinal Natural Products: A Biosynthetic Approach

    (2009)
  • A.M. Dondorp et al.

    Artemisinin resistance in Plasmodium falciparum malaria

    N. Engl J. Med.

    (2009)
  • F. Drislane et al.

    Blueprints Neurology

    (2010)
  • A. Elizabeth et al.

    Spread of artemisinin resistance in Plasmodium falciparum malaria

    N. Engl. J. Med.

    (2014)
  • P.K. Endress

    Reproductive structures and phylogenetic significance of extant primitive angiosperms

    Plant Syst. Evol.

    (1986)
  • E. Fattorusso et al.

    Alkaloids and the bitter taste

    Modern Alkaloids: Structure, Isolation, Synthesis and Biology

    (2007)
  • F. Frappier et al.

    Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells

    Antimicrob. Ag. Chemother.

    (1996)
  • M. Frederich et al.

    Indole alkaloids from Strychnos species and their antiplasmodial and cytotoxic activities

    Chem. Nat. Comp.

    (2003)
  • M. Frederich et al.

    In vitro activities of Strychnos alkaloids and extracts against Plasmodium falciparum

    Antimicrob. Agents Chemother.

    (1999)
  • M. Frederich et al.

    Antiplasmodial activity of alkaloids from various Strychnos species

    J. Nat. Prod.

    (2002)
  • O.R. Gottlieb

    Micromolecular Evolution, Systematics and Ecology. An Essay into a Novel Botanical Discipline

    (1982)
  • P. Guyana et al.

    Past and new challenges for malaria control and elimination: the role of operational research for innovation in designing interventions

    Malaria J.

    (2015)
  • S.D. Hayes et al.

    Molecular mechanisms of drug resistance

    Biochem. J.

    (1990)
  • E. Hempelmann

    Hemozoin biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors

    Parasitol. Res.

    (2007)
  • H. Humbert et al.

    Carte internationale du tapis végétale, Madagascar

    (1965)
  • M. Jensen et al.

    Seventy-five years of Resochin® in the fight against malaria

    Parasitol. Res.

    (2009)
  • P. Jun et al.

    Endovascular treatment of medically refractory cerebral vasospasm following aneurysmal subarachnoid hemorrhage

    Am. J. Neuroradiol.

    (2010)
  • S.U. Karaagac

    Insecticide resistance

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    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.

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