Vendrametto Michele Cristina, Santos Adriana Oliveira dos, Nakamura Celso Vataru, Dias Filho Benedito Prado, Cortez Diógenes Aparício Garcia, Ueda-Nakamura Tânia
Programa de Pós-graduação em Ciências Farmacêuticas, Departamento de Análises Clínicas, Universidade Estadual de Maringá, Av. Colombo 5790, Paraná, Brazil.
Parasitol Int. 2010 Jun;59(2):154-8. doi: 10.1016/j.parint.2009.12.009. Epub 2010 Jan 11.
Infection with Leishmania spp. causes a disease with multifaceted clinical manifestations in humans. The treatment for leishmaniasis is dependent on a limited range of drugs. Here we investigated the antileishmanial activity of eupomatenoid-5, a neolignan isolated from leaves of Piper regnellii var. pallescens. We showed that eupomatenoid-5 had a dose-dependent activity during 72h of treatment, exhibiting IC(50) of 9.0microg/mL and 13.0microg/mL for promastigote and axenic amastigote forms, respectively, and IC(50) of 5.0microg/mL for intracellular amastigote forms of Leishmania amazonensis. When L. amazonensis was treated with eupomatenoid-5, it underwent considerable ultrastructural alterations, as shown by transmission electron microscopy. Among the alterations was the appearance of intense exocytic activity in the region of the flagellar pocket, myelin-like figures, and vacuoles in the cytoplasm of parasites treated with 9.0microg/mL. Cells treated with 25.0microg/mL showed a very large structure, apparently an extension of the endoplasmic reticulum. Also, mitochondrial swelling was detected at this concentration, indicating damage and significant change in this organelle. A cytotoxicity assay showed that the action of the isolated compound is more specific for protozoa and it is not toxic to macrophages. Our studies indicated that eupomatenoid-5 might be a potential new drug for the treatment of leishmaniasis, because this compound displays interesting antileishmanial activity in vitro against promastigote, axenic amastigote, and intracellular amastigote forms of L. amazonensis.
利什曼原虫属感染会导致人类出现具有多方面临床表现的疾病。利什曼病的治疗依赖于有限种类的药物。在此，我们研究了从苍白雷氏胡椒叶中分离出的新木脂素——优波马替诺-5的抗利什曼原虫活性。我们发现，在72小时的治疗过程中，优波马替诺-5具有剂量依赖性活性，对前鞭毛体和无菌无鞭毛体形式的半数抑制浓度（IC50）分别为9.0微克/毫升和13.0微克/毫升，对亚马逊利什曼原虫细胞内无鞭毛体形式的IC50为5.0微克/毫升。当用优波马替诺-5处理亚马逊利什曼原虫时，透射电子显微镜显示其发生了相当大的超微结构改变。这些改变包括在用9.0微克/毫升处理的寄生虫细胞质中，鞭毛囊区域出现强烈的胞吐活动、髓鞘样结构和液泡。用25.0微克/毫升处理的细胞显示出一个非常大的结构，显然是内质网的延伸。此外，在该浓度下检测到线粒体肿胀，表明该细胞器受到损伤并发生了显著变化。细胞毒性试验表明，分离出的化合物对原生动物的作用更具特异性，对巨噬细胞无毒。我们的研究表明，优波马替诺-5可能是一种治疗利什曼病的潜在新药，因为该化合物在体外对亚马逊利什曼原虫的前鞭毛体、无菌无鞭毛体和细胞内无鞭毛体形式均表现出有趣的抗利什曼原虫活性。
