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阿尔茨海默病和帕金森病的细胞模型:处于生物学与药物发现的交叉点

Cell models for Alzheimer's and Parkinson's disease: At the interface of biology and drug discovery.

作者信息

Cetin Sandra, Knez Damijan, Gobec Stanislav, Kos Janko, Pišlar Anja

机构信息

University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, Ljubljana 1000, Slovenia.

University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, Ljubljana 1000, Slovenia.

出版信息

Biomed Pharmacother. 2022 May;149:112924. doi: 10.1016/j.biopha.2022.112924. Epub 2022 Apr 8.

DOI:10.1016/j.biopha.2022.112924
PMID:36068783
Abstract

Neurodegenerative diseases are severely debilitating conditions characterized primarily by progressive neuronal loss and impairment of the nervous system. Alzheimer's and Parkinson's diseases are the most common neurodegenerative disorders, and their impact is increasing as average life expectancy increases worldwide. Although the underlying mechanisms of both progressive diseases have been extensively studied, we still lack a comprehensive understanding of the molecular basis of both diseases. Current therapeutic options do not slow the progression of the diseases and only provide symptom relief. Cell models that resemble the characteristics of the disease in question are important in drug discovery projects because they provide information about the therapeutic benefits of drugs under development. Here, we review current in vitro cell models used to study the molecular basis of Alzheimer's and Parkinson's disease focusing on their potential for discovering of disease-modifying therapeutics to combat neurodegenerative diseases. We discuss phenotypic screening as an important approach for identifying novel therapeutic molecules. Advances in the development of cell-based assays for drug discovery are discussed, ranging from simple monoculture cell models to high-throughput three-dimensional cell models. Finally, we critically present the limitations of cell models and the caveats encountered in drug discovery to find effective treatment for neurodegenerative diseases.

摘要

神经退行性疾病是严重使人衰弱的病症,主要特征为进行性神经元丧失和神经系统损害。阿尔茨海默病和帕金森病是最常见的神经退行性疾病,随着全球平均预期寿命的增加,它们的影响也在扩大。尽管这两种进行性疾病的潜在机制已得到广泛研究,但我们仍缺乏对这两种疾病分子基础的全面理解。目前的治疗选择并不能减缓疾病的进展,仅能缓解症状。与相关疾病特征相似的细胞模型在药物研发项目中很重要,因为它们能提供有关正在研发药物治疗益处的信息。在此,我们综述了目前用于研究阿尔茨海默病和帕金森病分子基础的体外细胞模型,重点关注其发现改变疾病进程疗法以对抗神经退行性疾病的潜力。我们讨论了表型筛选作为识别新型治疗分子的重要方法。还讨论了用于药物研发的基于细胞检测方法的进展,从简单的单培养细胞模型到高通量三维细胞模型。最后,我们批判性地阐述了细胞模型的局限性以及在药物研发中为找到神经退行性疾病有效治疗方法所遇到的注意事项。

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