Antileishmanial Herbs from Brazil’s Atlantic Forest

Leishmaniasis is caused by parasitical protozoans of the genus Leishmania. Fourteen Leishmania spp. infect vertebrates, including humans and other mammals. Invertebrates, all called sand flies, are their natural vectors; Lutzomyia spp. in the Western Hemisphere; Phlebotomus spp., in the Eastern. Leishmaniasis is endemic in 98 countries, 1.2 million new cases occur yearly; 90% of them among poor and marginalized groups in Brazil, India, Bangladesh, Sudan, South Sudan, and Ethiopia. Clinical outcomes vary by parasite species and patient’s health. They range from single cutaneous lesions caused by several Leishmania spp. to lethal visceral harms caused by L. infantum and L. donovani. In the Western Hemisphere, one important cause of cutaneous leishmaniasis (CL) is L. amazonensis. It also causes anergic diffuse cutaneous leishmaniasis (ADCL), with parasite diffusion due to inefficient T cell response. L. braziliensis causes CL and mucosal leishmaniasis (ML), affecting cartilage and mucosa. All forms of leishmaniasis are treated with pentavalent antimonials or amphotericin B, both toxic. Local and systemic adverse events (AEs) are reported for antimonials, as well as emerging resistance. A tartar emetic trivalent antimonial, effective against ML, was too toxic for use. AEs of amphotericin can be quelled with an intravenously-administered liposomal formula. Added costs of this product severely limit use in endemic leishmaniasis areas.

The Brazilian Atlantic Forest (BAF), covering ~65,000 km2, has more woody plants/area units than any other world region. Biodiversity is next only to the Amazon region. Ethnodiversity is high. Poverty, racial and ethnic commingling, and lack of access to conventional medicine contribute to a lively common knowledge of medicinal plants. Informal and semi-structured interviews were used to collect information on plants used medicinally in Săo Vicente, Săo Paulo, Brazil, under the auspices of Săo Paulo State University (Săo Paulo, SP, Brazil). Sixteen women ranging in age from 45-81, residing in Săo Vicente, participated; selection criteria are not disclosed. The women self-identified as Afro-descended (37%), indigenous (26%), white (23%), and mixed (14%). A majority (59%) had completed high school; 25% had college degrees. Most (85%) had learned about medicinal plants in the family; 8.1%, through agricultural work; 6.6%, by reading.

Participants named 46 plants used for inflammatory conditions (17), skin conditions (12), infections (9), and other diseases (8). Specimens were collected with the recommending participants, identified at the Instituto de Botânica do Estado de Săo Paulo (Săo Paulo), and deposited at its herbarium. Five species native to the BAF were among those named for skin diseases. They were Brazilian joy weed (Alternanthera brasiliana, Amaranthaceae), Surinam-cherry (Eugenia uniflora, Myrtaceae), bellyache-bush (Jatropha gossypiifolia, Euphorbiaceae), Brazilian Peppertree (Schinus terebinthifolia, Anacardiaceae), and blue snakeweed (Stachytarpheta cayennensis, Verbenaceae). Blue snakeweed has previously been reported to inhibit promastigote and amastigote forms of L. amazonensis.

Extracts of dried and powdered leaves and/or fruits of these plants were prepared with n-hexane and subsequently with ethanol. The major components of these extracts were characterized using qualitative nuclear magnetic resonance (NMR) analysis. The extracts were investigated for potential leishmanicidal activity at different concentrations against L. amazonensis (promastigote and amastigote forms). Anti-promastigote effect, cytotoxicity, and macrophage infection and treatment were evaluated, and compared to the standard drug miltefosine, Among the ethanol extracts, that from Brazilian Peppertree leaf was the most active against promastigote forms of L. amazonensis (half-maximal effective concentration [EC50]=30.5±6.3 μg/mL); the least active was one of the Brazilian Peppertree fruit (EC50=64.6±10.2 μg/mL). Neither n-hexane nor ethanol extracts of Brazilian joy weed or bellyache-bush had leishmanicidal effects. Ethanol extracts reached half-maximal cytotoxic concentration (CC50) at levels >90 μg/mL, with Brazilian Peppertree leaf extract the most selective. Among non-polar extracts, n-hexane extracts of Brazilian Peppertree leaf and Surinam-cherry leaf achieved EC50 at ~14 μg/mL. N-hexane extracts of Brazilian Peppertree leaf and fruit were mildly cytotoxic, and, along with Surinam-cherry extracts, most selective against promastigote forms. In comparison, miltefosine reached EC50 at 3.2±0.9 μg/mL and CC50 at 38.2±3.3 μg/mL. The most active polar extract against amastigote forms was that of the Surinam-cherry leaf (EC50=22.1±5.8 μg/mL). On the other hand, the ethanol extracts from the leaves and fruits of Brazilian Peppertree were mildly active against intracellular amastigotes. Among non-polar extracts, the n-hexane extract of Surinam-cherry leaves was the most active (EC50=9.2±1.2 μg/mL) against amastigotes, followed by that from Brazilian Peppertree leaves (EC50=17.4±1.0 μg/mL).

NMR showed tirucallane type triterpenes in n-hexane extracts of Brazilian Peppertree leaf and fruit, with (Z)-schinol and (Z)-masticadieonic acid the main metabolites. Fruit extracts had mainly free unsaturated fatty acids (UFAs), while both fruit and leaf alcohol extracts were high in β-glucose. N-hexane extract of Surinam-cherry leaf was mainly composed of UFAs including the sesquiterpene atractylon. Flavonoids and glycosylated flavonoids predominated. N-hexane extract from the bellyache-bush leaf was mainly composed of UFAs. The alcohol extract had several flavonoids. Earlier reports of leishmanicidal and related effects by some of these compounds support the conclusion that ethnopharmacological data may provide drug leads against leishmaniasis.

Resource:

Santos BM, Bezerra-Souza A, Aragaki S, et al. Ethnopharmacology study of plants from Atlantic forest with leishmanicidal activity. Evid Based Complement Alternat Med. February 2019;2019:8780914. doi: 10.1155/2019/8780914.

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