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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
INTRODUCTION
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
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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