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Germacranolide-type sesquiterpene lactones from Smallanthus sonchifolius with promising activity against Leishmania mexicana and Trypanosoma cruzi.
Parasit Vectors. 2017 Nov 13; 10(1):567.PV

Abstract

BACKGROUND

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. 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.

METHODS

The 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.

RESULTS

The 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.

CONCLUSIONS

Enhydrin, 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.

Authors+Show Affiliations

Facultad de Farmacia y Bioquímica, Cátedra de Farmacognosia, IQUIMEFA (UBA-CONICET), Universidad de Buenos Aires, Junín 956 2° F (1113), Buenos Aires, Argentina.Instituto de Histología y Embriología "Dr. Mario H. Burgos", Facultad de Ciencias Médicas, Universidad Nacional de Cuyo-CONICET, (56 5500), Mendoza, CC, Argentina.CONICET, Instituto de Microbiología y Parasitología Médica (IMPaM), Universidad de Buenos Aires, Paraguay 2155 13° F (1211), Buenos Aires, Argentina. Departamento de Microbiología, Facultad de Farmacia y Bioquímica, Inmunología y Biotecnología, Cátedra de Inmunología, Universidad de Buenos Aires, Junín 956 4° F (1113), Buenos Aires, Argentina.CONICET, Instituto de Microbiología y Parasitología Médica (IMPaM), Universidad de Buenos Aires, Paraguay 2155 13° F (1211), Buenos Aires, Argentina.Facultad de Farmacia y Bioquímica, Cátedra de Farmacognosia, IQUIMEFA (UBA-CONICET), Universidad de Buenos Aires, Junín 956 2° F (1113), Buenos Aires, Argentina.Instituto de Histología y Embriología "Dr. Mario H. Burgos", Facultad de Ciencias Médicas, Universidad Nacional de Cuyo-CONICET, (56 5500), Mendoza, CC, Argentina.CONICET, Instituto de Microbiología y Parasitología Médica (IMPaM), Universidad de Buenos Aires, Paraguay 2155 13° F (1211), Buenos Aires, Argentina. Departamento de Microbiología, Facultad de Farmacia y Bioquímica, Inmunología y Biotecnología, Cátedra de Inmunología, Universidad de Buenos Aires, Junín 956 4° F (1113), Buenos Aires, Argentina.Facultad de Farmacia y Bioquímica, Cátedra de Farmacognosia, IQUIMEFA (UBA-CONICET), Universidad de Buenos Aires, Junín 956 2° F (1113), Buenos Aires, Argentina. lmusch@ffyb.uba.ar.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29132413

Citation

Ulloa, Jerónimo L., et al. "Germacranolide-type Sesquiterpene Lactones From Smallanthus Sonchifolius With Promising Activity Against Leishmania Mexicana and Trypanosoma Cruzi." Parasites & Vectors, vol. 10, no. 1, 2017, p. 567.
Ulloa JL, Spina R, Casasco A, et al. Germacranolide-type sesquiterpene lactones from Smallanthus sonchifolius with promising activity against Leishmania mexicana and Trypanosoma cruzi. Parasit Vectors. 2017;10(1):567.
Ulloa, J. L., Spina, R., Casasco, A., Petray, P. B., Martino, V., Sosa, M. A., Frank, F. M., & Muschietti, L. V. (2017). Germacranolide-type sesquiterpene lactones from Smallanthus sonchifolius with promising activity against Leishmania mexicana and Trypanosoma cruzi. Parasites & Vectors, 10(1), 567. https://doi.org/10.1186/s13071-017-2509-6
Ulloa JL, et al. Germacranolide-type Sesquiterpene Lactones From Smallanthus Sonchifolius With Promising Activity Against Leishmania Mexicana and Trypanosoma Cruzi. Parasit Vectors. 2017 Nov 13;10(1):567. PubMed PMID: 29132413.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Germacranolide-type sesquiterpene lactones from Smallanthus sonchifolius with promising activity against Leishmania mexicana and Trypanosoma cruzi. AU - Ulloa,Jerónimo L, AU - Spina,Renata, AU - Casasco,Agustina, AU - Petray,Patricia B, AU - Martino,Virginia, AU - Sosa,Miguel A, AU - Frank,Fernanda M, AU - Muschietti,Liliana V, Y1 - 2017/11/13/ PY - 2017/02/07/received PY - 2017/10/30/accepted PY - 2017/11/15/entrez PY - 2017/11/15/pubmed PY - 2018/7/13/medline KW - In vitro assays KW - In vivo assays KW - Leishmanicidal activity KW - Sesquiterpene lactones KW - Smallanthus sonchifolius KW - Trypanocidal activity SP - 567 EP - 567 JF - Parasites & vectors JO - Parasit Vectors VL - 10 IS - 1 N2 - BACKGROUND: 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. 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. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: Enhydrin, 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. SN - 1756-3305 UR - https://www.unboundmedicine.com/medline/citation/29132413/Germacranolide_type_sesquiterpene_lactones_from_Smallanthus_sonchifolius_with_promising_activity_against_Leishmania_mexicana_and_Trypanosoma_cruzi_ L2 - https://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-017-2509-6 DB - PRIME DP - Unbound Medicine ER -