Abstract
BackgroundLeishmaniasis and Chagas disease are life-threatening illnesses caused by the protozoan parasites Leishmania spp. and Trypanosoma cruzi, respectively. They are known as “neglected diseases” due to the lack of effective drug treatments and the scarcity of research work devoted to them. Therefore, the development of novel and effective drugs is an important and urgent need. Natural products are an important source of bioactive molecules for the development of new drugs. In this study, we evaluated the activity of enhydrin, uvedalin and polymatin B, three sesquiterpene lactones (STLs) isolated from Smallanthus sonchifolius, on Leishmania mexicana (MNYC/BZ/62/M) and Trypanosoma cruzi (Dm28c). In addition, the in vivo trypanocidal activity of enhydrin and uvedalin and the effects of these STLs on parasites’ ultrastructure were evaluated.MethodsThe inhibitory effect of the three STLs on the growth of L. mexicana amastigotes and promastigotes as well as T. cruzi epimastigotes was evaluated in vitro. The changes produced by the STLs on the ultrastructure of parasites were examined by transmission electron microscopy (TEM). Enhydrin and uvedalin were also studied in a murine model of acute T. cruzi infection (RA strain). Serum activities of the hepatic enzymes alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase were used as biochemical markers of hepatotoxicity.ResultsThe three compounds exhibited leishmanicidal activity on both parasite forms with IC50 values of 0.42–0.54 μg/ml for promastigotes and 0.85–1.64 μg/ml for intracellular amastigotes. Similar results were observed on T. cruzi epimastigotes (IC50 0.35–0.60 μg/ml). The TEM evaluation showed marked ultrastructural alterations, such as an intense vacuolization and mitochondrial swelling in both L. mexicana promastigotes and T. cruzi epimastigotes exposed to the STLs. In the in vivo study, enhydrin and uvedalin displayed a significant decrease in circulating parasites (50–71%) and no signs of hepatotoxicity were detected.ConclusionsEnhydrin, uvedalin and polymatin B possess significant leishmanicidal and trypanocidal activity on different parasite stages. These results show that these compounds may provide valuable leads for the development of new drugs against these neglected parasitic diseases.
Highlights
Leishmaniasis and Chagas disease are life-threatening illnesses caused by the protozoan parasites Leishmania spp. and Trypanosoma cruzi, respectively
We have demonstrated the leishmanicidal and trypanocidal activities of enhydrin, uvedalin and polymatin B, three sesquiterpene lactones (STLs) isolated from S. sonchifolius that belong to the germacranolide group
Considering that amastigotes are the clinically relevant stage of the parasite and that they are present in mammalian hosts, including humans, we have evaluated the activity of enhydrin and uvedalin on this intracellular stage
Summary
Leishmaniasis and Chagas disease are life-threatening illnesses caused by the protozoan parasites Leishmania spp. and Trypanosoma cruzi, respectively. They are known as “neglected diseases” due to the lack of effective drug treatments and the scarcity of research work devoted to them. Leishmaniasis is a poverty-associated, diverse and complex disease presenting several different forms, of which cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL) are the most common This disease is caused by different species of the kinetoplastid protozoan genus Leishmania, which is transmitted to humans by phlebotomine sand flies. The World Health Organization recommends the use of pentavalent antimonials as first-line drugs [3] These compounds are toxic and have poor effectiveness in the treatment of chronic manifestations of CL. Alternative treatments include the use of liposomal amphotericin-B (ANF); this drug cannot be widely employed due to its high cost and delivery requirements [4]
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