Kola acuminata proanthocyanidins:: a class of anti-trypanosomal compounds effective against Trypanosoma brucei
Kola acuminata proanthocyanidins:: a class of anti-trypanosomal compounds effective against Trypanosoma brucei
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DOI：
10.1016/j.ijpara.2004.10.019
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发表时间：
2005-01-01
影响因子：
4
通讯作者：
Urade, Y
中科院分区：
文献类型：
--
作者：
Kubata, BK;Nagamune, K;Urade, Y
在撒哈拉以南非洲的许多地区，非洲锥虫正以惊人的速度复发。然而，由于有用药物的数量有限，现有药物的副作用和缺点，以及寄生虫产生耐药性，因此没有成功的化疗方法。在这里，我们描述了一个新的铅抗锥虫化合物分离的Kola acuminata（Makasu）。我们纯化的原花青素的色谱程序，并确认其同质性和结构的核磁共振和基质辅助激光解吸电离飞行时间质谱，分别。在体外，该化合物以剂量和时间依赖性方式有效地诱导生长停滞和血流形式的锥虫裂解。在小鼠模型中，它表现出锥虫抑制作用，将感染的治疗动物的寿命延长至感染后8天，而感染的未治疗动物的寿命为4天。原花青素对哺乳动物细胞的细胞毒性低，而处理BF显示出大量扩大的鞭毛口袋和溶酶体样结构所造成的激烈形成的多泡体和囊泡在这些细胞器。观察到的超微结构改变引起质膜破裂和细胞内容物的释放，表明坏死过程，而不是程序性细胞死亡。有趣的是，原花青素对BF起作用，但对原环形式的锥虫不起作用。这种新的抗锥虫化合物应进一步研究，以确定其作为抗锥虫药物的有效性和适用性，并可用作定义BF锥虫中新的特异性药物靶点的工具。(C)2004年澳大利亚寄生虫学会由爱思唯尔有限公司出版。保留所有权利。
Human African trypanosomiasis is undergoing an alarming rate of recrudescence in many parts of sub-Saharan Africa. Yet, there is no successful chemotherapy for the disease due to a limited number of useful drugs, side effects and drawbacks of the existing medication, as well as the development of drug resistance by the parasite. Here we describe a new lead anti-trypanosomal compound isolated from Kola acuminata (Makasu). We purified a proanthocyanidin by chromatographic procedures and confirmed its homogeneity and structure by Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption ionisation Time-of-Flight mass spectrometry, respectively. In vitro, this compound potently induced growth arrest and lysis of bloodstream form trypanosomes in a dose- and time-dependent manner. In a mouse model, it exhibited a trypanostatic effect that extended the life of infected, treated animals up to 8 days post-infection against the 4 days for infected, untreated animals. The proanthocyanidin showed a low cytotoxicity against mammalian cells, whereas treated-BF showed massive enlargement of their flagellar pocket and lysosome-like structures caused by an intense formation of multivesicular bodies and vesicles within these organelles. The observed ultrastructural alterations caused rupture of plasma membranes and the release of cell contents, indicative of a necrotic process rather than a programmed cell death. Interestingly, the proanthocyanidin acted against BF but not procyclic form trypanosomes. This new anti-trypanosomal compound should be further studied to determine its efficacy and suitability as an anti-trypanosomal drug and may be used as a tool to define novel specific drug targets in BF trypanosomes. (C) 2004 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.