Universidade Federal de Uberlândia, Instituto de Biotecnologia, Laboratório de Bioquímica e Toxinas Animais, Uberlândia, MG, Brasil.
Universidade Federal de Uberlândia, Instituto de Ciências Biomédicas, Departamento de Farmacologia, Uberlândia, MG, Brasil.
Mem Inst Oswaldo Cruz. 2022 Apr 29;117:e210157. doi: 10.1590/0074-02760210157. eCollection 2022.
Leishmania parasites cause leishmaniasis that range from self-limiting cutaneous lesions to more serious forms of the disease. The search for potential drug targets focusing on biochemical and metabolic pathways revealed the sterol biosynthesis inhibitors (SBIs) as a promising approach. In this class of inhibitors is found ketoconazole, a classical inhibitor of 14α-methysterol 14-demethylase.
The present study aimed to better understand the biological response of Leishmania (Leishmania) amazonensis promastigotes at the cellular level after ketoconazole treatment.
Herein, techniques, such as fluorimetry, flow cytometry, fluorescence microscopy, electron and scanning microscopy were used to investigate the cellular structures and to identify organelles affected by ketoconazole treatment.
The study demonstrated, for the first time, the effect of ketoconazole on mitochondrion functioning and its probable relationship to cell cycle and death on L. (L.) amazonensis promastigotes (IFLA/BR/67/PH8 strain).
Ketoconazole-induced mitochondrial damages led to hyperpolarisation of this single organelle and autophagic vacuoles formation, as a parasite survival strategy. These damages did not reflect directly on the parasite cell cycle, but drove the parasites to death, making them susceptible to ketoconazole treatment in in vitro models.
利什曼原虫寄生虫会引起利什曼病，从自限性皮肤损伤到更严重的疾病形式不等。针对生化和代谢途径的潜在药物靶点的研究发现，甾体生物合成抑制剂（SBIs）是一种很有前途的方法。在这类抑制剂中发现了酮康唑，它是 14α-甲羟甾醇 14-脱甲基酶的经典抑制剂。
本研究旨在更好地了解酮康唑处理后利什曼原虫（Leishmania）亚马逊株前鞭毛体在细胞水平上的生物学反应。
本文采用荧光法、流式细胞术、荧光显微镜、电子显微镜和扫描电子显微镜等技术，研究细胞结构，并鉴定酮康唑处理影响的细胞器。
该研究首次证明了酮康唑对线粒体功能的影响，以及其与 L.（L.）亚马逊株前鞭毛体（IFLA/BR/67/PH8 株）细胞周期和死亡的可能关系。
酮康唑诱导的线粒体损伤导致该单一细胞器的超极化和自噬空泡的形成，这是寄生虫的一种生存策略。这些损伤并没有直接反映在寄生虫的细胞周期上，但导致寄生虫死亡，使它们在体外模型中对酮康唑治疗敏感。
