Laboratório de Bioquímica de Tripanosomatideos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brazil.
PLoS One. 2011 Feb 8;6(2):e14666. doi: 10.1371/journal.pone.0014666.
Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania, affects more than 12 million people worldwide. Quercetin has generated considerable interest as a pharmaceutical compound with a wide range of therapeutic activities. One such activity is exhibited against the bloodstream parasite Trypanosoma brucei and amastigotes of Leishmania donovani. However, the mechanism of protozoan action of quercetin has not been studied.
METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we report here the mechanism for the antileishmanial activity of quercetin against Leishmania amazonensis promastigotes. Quercetin inhibited L. amazonensis promastigote growth in a dose- and time- dependent manner beginning at 48 hours of treatment and with maximum growth inhibition observed at 96 hours. The IC(50) for quercetin at 48 hours was 31.4 µM. Quercetin increased ROS generation in a dose-dependent manner after 48 hours of treatment. The antioxidant GSH and NAC each significantly reduced quercetin-induced cell death. In addition, quercetin caused mitochondrial dysfunction due to collapse of mitochondrial membrane potential.
CONCLUSIONS/SIGNIFICANCE: The effects of several drugs that interfere directly with mitochondrial physiology in parasites such as Leishmania have been described. The unique mitochondrial features of Leishmania make this organelle an ideal drug target while minimizing toxicity. Quercetin has been described as a pro-oxidant, generating ROS which are responsible for cell death in some cancer cells. Mitochondrial membrane potential loss can be brought about by ROS added directly in vitro or induced by chemical agents. Taken together, our results demonstrate that quercetin eventually exerts its antileishmanial effect on L. amazonensis promastigotes due to the generation of ROS and disrupted parasite mitochondrial function.
利什曼病是一种由利什曼原虫属原生动物引起的寄生虫病，影响全球超过 1200 万人。槲皮素作为一种具有广泛治疗活性的药物化合物引起了相当大的兴趣。其中一种活性表现为对血液寄生虫锥虫和利什曼原虫的无鞭毛体的作用。然而，槲皮素对原生动物的作用机制尚未得到研究。
方法/主要发现：在本研究中，我们在此报告了槲皮素对利什曼原虫亚马逊滋养体的抗利什曼活性的作用机制。槲皮素以剂量和时间依赖的方式抑制 L. amazonensis 前鞭毛体的生长，从治疗 48 小时开始，并在 96 小时观察到最大生长抑制。48 小时时槲皮素的 IC 50 为 31.4µM。槲皮素在治疗 48 小时后以剂量依赖性方式增加 ROS 的产生。抗氧化剂 GSH 和 NAC 均显著降低了槲皮素诱导的细胞死亡。此外，槲皮素由于线粒体膜电位崩溃而导致线粒体功能障碍。
结论/意义：已经描述了几种直接干扰寄生虫（如利什曼原虫）线粒体生理学的药物的作用。利什曼原虫独特的线粒体特征使其成为理想的药物靶点，同时最大限度地减少毒性。槲皮素已被描述为一种促氧化剂，可在一些癌细胞中产生 ROS，导致细胞死亡。ROS 可以直接在体外添加或通过化学剂诱导导致线粒体膜电位丧失。总之，我们的结果表明，槲皮素最终通过产生 ROS 和破坏寄生虫的线粒体功能对 L. amazonensis 前鞭毛体发挥抗利什曼作用。
