Leishmaniasis represents a spectrum of diseases caused by infection with protozoan pathogens of the genus Leishmania. It is a major neglected tropical disease associated with high rates of disability and death, with extended endemic areas in the Americas. Despite current therapeutic approaches, current treatments for leishmaniasis are unsatisfactory due to high associated toxicity, cost, complex administration and the emergence of resistant strains. Because of this, efforts have greatly increased over the last decade to identify novel compounds with anti-leishmanial properties. Thus, one strategy in the search for new compounds is the screening of molecules purified from plant sources. The current work reviewed the available information about the Argentinean natural sources reported as effective against Leishmania spp.; including: its relevant chemical compounds, efficiency and applied methodology. Reported studies need to be considered as precursors works to extend the search between the profuse native plants from Argentina.

Keywords: Leishmaniasis, Natural compounds, Argentina, Complementary medicine

Recently, Bekhit et al. [9] reviewed many natural derivatives, including: flavonoids, chalcones, naphthoquinones, iridoids, saponins, quinolones, diterpenoids and lignans; with reported in vivo and in vitro activity; and scarce or null toxicity. No reports about secondary resistance to the mentioned compounds are available. However, as occurs between cancer chemotherapeutics agents, the existence of several acceptable treatment options increases the achievable alternatives in secondary resistant disease cases.

Among the Argentinean natural sources, there are several native plants which evidenced activity against different Leishmania species. However, to promote the use of natural derivatives, the scientific approaches to determine leishmanicidal properties needs to considerate some particularities.

Plants conditions and origin

In relation to the plant sources, it is known that bioactive compounds are the secondary metabolites defined by the plant physiology status [10]. Then, adaptive features to soils, temperature, light-dark cycles, water salinity and availability are very important determinants of secondary metabolites presence and concentration. For this reason, in the current review, we considered only studies which involved Argentinean native plants grown in the country. In fact, regardless of some properties reported in plants considered as native from Argentina; because they were obtained and harvested in other remote countries, these findings are out of consideration in the present work.

EXPERIMENTAL APPROACHES TO DETERMINE LEISHMANICIDAL ACTIVITY

Other opportune item to consider is related to the experimental methodology used to assign the leishmanicidal activity. Leishmania spp. is a digenetic organisms alternating between a flagellated promastigote, in the gut of the sand fly vector; and an intracellular amastigote, in the mammalian host. While, the in vitro systems may be potentially used for compounds which have direct lethal action on parasite; other compounds which actions are related to host defense system, cannot be study by this methodology. Therefore, sometimes, in vitro assays may not be transferable to in vivo situations [11].

In addition, inside of in vitro models, it is important to take into account the stages of development of the parasite used experimentally. The promastigotes grown in axenic cultures have been used to screen potential anti-leishmanial agents and the advantages of this system explain its wide popularity. The simplest model to be utilized is the one in which the promastigotes multiply in cell free media [12]. The technique is simple and easily applicable; however, the metabolism and ecology of promastigote differ widely from those of amastigote (target form). In consequence, the screening data obtained from in vitro test with promastigote have very little value in animals [13]. Ideally, to be efficient and exhaustive, a drug screening procedure requires conditions that mimic the environment encountered by the target cell. For Leishmania, intracellular form of the parasite (amastigotes) might represent the typical conditions. In fact, a direct comparison of the drug susceptibility towards standard anti-leishmanial drugs, between amastigotes and axenic amastigotes, demonstrates a good correlation to many, if not all the drug tested [14].

About the in vivo models related to leishmaniasis, when cutaneous forms are studied, the methods to infect animals are intradermal or subcutaneous inoculations [15,16]; while in the visceral forms: intravenous, intraperitoneal and intracardiac inoculations are commonly used [17,18]. The assays outputs can change between lesions measurements, pathological analysis and serological determinations. Usually, blood samples and dissected organs are used to perform DNA, proteins, cytokines or inflammatory cells determinations. 

A less common method is the use of bioluminescent parasites to quantify Leishmania spp. infection in the ear; which is a more sophisticated and accurate approach compared with the more traditional measurements of lesion diameter, volume, and thickness [19].

Actually, the vast majority of leishmaniasis in vivo models use a needle challenge of parasites alone and in large quantities. Moreover, Leishmania spp. is transmitted to animals and humans by a sand fly vector. The current use of murine models has been questioned in that it does not represent the clinical disease progression or immune response seen in humans [20].

Argentinean plants effective against Leishmania spp.

In Table 1 are summarized the reported Argentinean plants bioactive against Leishmania spp. To be exhaustive, the parasites species and stages, plant sources used and main chemical groups described in the bibliography, are ordered and enumerated.

At least, 8 different species were reported as leishmanicidal agents, included into 5 taxonomic families. All the mentioned plants were reported as used by its ethnopharmacological properties, and none of them were originally related to the leishmaniasis disease.

From a chemical point of view, there are 2 different species without an analytical characterization of metabolites. Both, the methanolic extracts of Mikania periplocifolia and Parietaria debilis evidenced leishmanicidal activity against L. mexicana amastigotes, but not chemical structures were described as related to the induced cytotoxicity. By other side, phenols, and particularly flavonoids, are the most common plant metabolites related to the anti-parasitic activity. The 3-Heptadecyl-5-methoxy-phenol and 1,3-Dimethoxy-5-pentadecyl-benzene derived from Oxalis erythrorhiza; 2,8-dihydroxy-7H-furo[2,3-f]chromen-7-one derived from Tibouchina paratropica; hispidulin from Ambrosia tenuifolia; santin from Eupatorium buniifolium; 5-desmethylsinensetin and eupatorin obtained from Stevia satureiifolia represent the major group of identified compounds related to the Argentinean anti-leishmanial natural derived compounds. One particular consideration is necessary to embelin, a natural derivative identified from Oxalis erythrorhiza. The compound is widely reported as component of herbs used in the traditional medicine of India. Between its described properties, it is relevant to mention the effects on chronic diseases such as tumors, autoimmune inflammatory diseases, parasitic infections, microbial infections, diabetes, obesity and cardio-cerebral vascular diseases [27]. Finally, lindbergin E, F, G and H isolated from Elaphoglossum lindbergii are the unique acylphloroglucinos which reported cytotoxicity in Leishmania species. 

CONCLUSION

The reviewed works provide a several number of promissory compounds; however, to confirm its reported activities, the uses of in vivo models result mandatory. Notwithstanding, in most of the cases, the chemical characterization of bioactive molecules could facilitate further researches and promote synthetic molecules production and semi-synthetic modifications destined to enhance the original properties described and its bioavailabitlity. Finally, well conduced researches between Argentinean natural sources are promissory to detect plant derivatives with therapeutic properties against leishmaniasis. 

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