PDF(Pubmed)
Abstract：
Naegleria fowleri, known as the brain-eating amoeba, is the pathogen that causes the primary amoebic meningoencephalitis (PAM), a severe neurodegenerative disease with a fatality rate exceeding 95%. Moreover, PAM cases commonly involved previous activities in warm freshwater bodies that allow amoebae-containing water through the nasal passages. Hence, awareness among healthcare professionals and the general public are the key to contribute to a higher and faster number of diagnoses worldwide. Current treatment options for PAM, such as amphotericin B and miltefosine, are limited by potential cytotoxic effects. In this context, the repurposing of existing compounds has emerged as a promising strategy. In this study, the evaluation of the COVID Box which contains 160 compounds demonstrated significant in vitro amoebicidal activity against two type strains of N. fowleri. From these compounds, terconazole, clemastine, ABT-239 and PD-144418 showed a higher selectivity against the parasite compared to the remaining products. In addition, programmed cell death assays were conducted with these four compounds, unveiling compatible metabolic events in treated amoebae. These compounds exhibited chromatin condensation and alterations in cell membrane permeability, indicating their potential to induce programmed cell death. Assessment of mitochondrial membrane potential disruption and a significant reduction in ATP production emphasized the impact of these compounds on the mitochondria, with the identification of increased ROS production underscoring their potential as effective treatment options. This study emphasizes the potential of the mentioned COVID Box compounds against N. fowleri, providing a path for enhanced PAM therapies.
摘要：
NaegleriaFowleri,被称为食脑变形虫，是导致原发性阿米巴脑膜脑炎（PAM）的病原体，一种严重的神经退行性疾病，死亡率超过95%。此外，PAM病例通常涉及温暖的淡水体内的先前活动，这些活动允许含有变形虫的水通过鼻腔。因此，医疗保健专业人员和公众的认识是促进全球更多和更快诊断数量的关键。目前PAM的治疗选择，如两性霉素B和米替福辛，受到潜在细胞毒性作用的限制。在这种情况下，现有化合物的再利用已经成为一种有希望的策略。在这项研究中,对包含160种化合物的COVIDBox的评估表明，对两种类型的牛牛的体外杀变形虫具有显着的体外杀变形虫活性。从这些化合物中，特康唑,氯马斯汀,与其余产物相比,ABT-239和PD-144418对寄生虫显示出更高的选择性。此外,用这四种化合物进行程序性细胞死亡测定，揭示治疗变形虫中相容的代谢事件。这些化合物表现出染色质凝聚和细胞膜通透性的改变，表明它们诱导程序性细胞死亡的潜力。线粒体膜电位破坏和ATP产生的显着减少的评估强调了这些化合物对线粒体的影响，随着ROS产生增加的识别，强调了它们作为有效治疗选择的潜力。这项研究强调了上述COVIDBox化合物对抗牛牛的潜力，为增强PAM治疗提供了一条途径。
