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.
Parasit Vectors. 2017 Nov 13;10(1):567. doi: 10.1186/s13071-017-2509-6.
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.
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.
The three compounds exhibited leishmanicidal activity on both parasite forms with IC 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 (IC 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.
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.
利什曼病和恰加斯病是由原生动物寄生虫利什曼原虫和克氏锥虫分别引起的危及生命的疾病。由于缺乏有效的药物治疗和对它们的研究工作稀缺，它们被称为“被忽视的疾病”。因此，开发新型有效的药物是一项重要且紧迫的需求。天然产物是开发新药的生物活性分子的重要来源。在这项研究中，我们评估了从小叶泽兰中分离得到的三种倍半萜内酯（STLs）依兰烯、乌德醛和多马汀 B 对利什曼原虫（MNYC/BZ/62/M）和克氏锥虫（Dm28c）的活性。此外，还评估了依兰烯和乌德醛的体内杀锥虫活性以及这些 STLs 对寄生虫超微结构的影响。
在体外评估了三种 STLs 对利什曼原虫无鞭毛体和鞭毛体以及克氏锥虫前鞭毛体生长的抑制作用。通过透射电子显微镜（TEM）检查 STLs 对寄生虫超微结构的影响。还在急性克氏锥虫感染（RA 株）的小鼠模型中研究了依兰烯和乌德醛。血清中丙氨酸氨基转移酶、天冬氨酸氨基转移酶和乳酸脱氢酶的活性被用作肝毒性的生化标志物。
三种化合物对两种寄生虫形式均具有杀利什曼原虫活性，对鞭毛体的 IC 值为 0.42-0.54μg/ml，对细胞内无鞭毛体的 IC 值为 0.85-1.64μg/ml。对克氏锥虫前鞭毛体也观察到类似的结果（IC 0.35-0.60μg/ml）。TEM 评价显示，暴露于 STLs 后，利什曼原虫鞭毛体和克氏锥虫前鞭毛体均出现明显的超微结构改变，如强烈的空泡化和线粒体肿胀。在体内研究中，依兰烯和乌德醛显著降低了循环寄生虫（50-71%），且未检测到肝毒性迹象。
依兰烯、乌德醛和多马汀 B 对不同寄生虫阶段具有显著的杀利什曼原虫和杀锥虫活性。这些结果表明，这些化合物可能为开发针对这些被忽视的寄生虫病的新药提供有价值的线索。
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