Choi Jung Il, Lee Hyunjo, Kim Dong Jun, Park Eun Suk, Lee Kyung Yeon, Yang Hui-Jun
Basic-Clinical Convergence Research Institute, University of Ulsan, Ulsan 44033, Republic of Korea.
Department of Neurology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Republic of Korea.
Biomedicines. 2024 Mar 8;12(3):611. doi: 10.3390/biomedicines12030611.
The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson's disease (PD). Astemizole also interacts with an anomalous aggregation of Alzheimer's disease-related amyloid-β (Aβ) peptide and has inhibitory activity on the human prion protein PrP. We hypothesized that the proposed preclinical benefits of astemizole on PD can be associated with the attenuation of pathological α-synuclein (α-syn) aggregation. We tested the effects of astemizole on the fibrillation processes of amyloid peptides using thioflavin T aggregation monitoring, Congo red spectral analysis, cell viability study, and transmission electron microscopic imaging. We found that astemizole did not inhibit α-syn aggregation in vitro even at a high molar ratio but inhibited the assembly of Aβ aggregates. Our results suggest that the inhibitory effect of astemizole on amyloid formation is target-protein selective, and the proposed beneficial effects of this compound observed in translational PD models might not be due to its ameliorating effects on α-syn aggregation.
抗组胺药阿司咪唑在帕金森病（PD）的几种临床前疾病模型中已显示出疾病修饰作用。阿司咪唑还与阿尔茨海默病相关淀粉样β（Aβ）肽的异常聚集相互作用，并对人朊病毒蛋白PrP具有抑制活性。我们推测，阿司咪唑在临床前对PD的益处可能与病理性α-突触核蛋白（α-syn）聚集的减弱有关。我们使用硫黄素T聚集监测、刚果红光谱分析、细胞活力研究和透射电子显微镜成像来测试阿司咪唑对淀粉样肽纤维形成过程的影响。我们发现，即使在高摩尔比下，阿司咪唑在体外也不抑制α-syn聚集，但抑制Aβ聚集体的组装。我们的结果表明，阿司咪唑对淀粉样蛋白形成的抑制作用具有靶蛋白选择性，在转化性PD模型中观察到的该化合物的有益作用可能不是由于其对α-syn聚集的改善作用。
