Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India.
Drug Metab Pers Ther. 2020 Aug 10;35(3):dmpt-2019-0031. doi: 10.1515/dmpt-2019-0031.
Objectives Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease in which one of the most prominent pathological features is accumulation of amyloid (Aβ) plaques. This occurs due to the process of aggregation from monomeric to polymeric forms of Aβ peptide and thus represents one of the attractive targets to treat AD. Methods After initial evaluation of a set of molecules containing N-acetylpyrazoline moiety flanked by aromatic rings on both sides as Aβ aggregation inhibitors, the most potent molecules were further investigated for mechanistic insights. These were carried out by employing techniques such as circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM), in vitro PAMPA-BBB (Blood-Brain Barrier) assay and cytotoxicity evaluation. Results Two molecules among the exploratory set displayed Aβ aggregation inhibition comparable to standard curcumin. Among the follow-up molecules, several molecules displayed more inhibition than curcumin. These molecules displayed good inhibitory activity even at lower concentrations. CD and TEM confirmed the mechanism of Aβ aggregation. These molecules were found to alleviate Aβ induced cytotoxicity. BBB penetration studies highlighted the potential of these molecules to reach central nervous system (CNS). Conclusions Thus, several promising Aβ-aggregation inhibitors were obtained as a result of this study.
阿尔茨海默病（AD）是一种慢性进行性神经退行性疾病，其最显著的病理特征之一是淀粉样蛋白（Aβ）斑块的积累。这是由于 Aβ肽从单体到聚合物形式的聚集过程引起的，因此代表了治疗 AD 的有吸引力的目标之一。
在对一组包含 N-乙酰吡唑啉部分并在两侧都有芳环的分子进行初步评估后，作为 Aβ聚集抑制剂，对最有效的分子进行了进一步的机制研究。这些研究采用了圆二色性（CD）光谱、透射电子显微镜（TEM）、体外 PAMPA-BBB（血脑屏障）测定和细胞毒性评估等技术进行。
在探索性分子中，有两个分子显示出与标准姜黄素相当的 Aβ聚集抑制作用。在后续分子中，有几个分子显示出比姜黄素更强的抑制作用。这些分子即使在较低浓度下也显示出良好的抑制活性。CD 和 TEM 证实了 Aβ聚集的机制。这些分子被发现可以减轻 Aβ诱导的细胞毒性。BBB 穿透研究强调了这些分子到达中枢神经系统（CNS）的潜力。
因此，本研究获得了几种有前途的 Aβ-聚集抑制剂。
