Savva Kyriaki, Zachariou Margarita, Kynigopoulos Demos, Fella Eleni, Vitali Maria-Ioanna, Kosofidou Xeni, Spyrou Michail, Sargiannidou Irene, Panayiotou Elena, Dietis Nikolas, Spyrou George M
Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus.
Department of Neuropathology, The Cyprus Institute of Neurology and Genetics, 2371 Nicosia, Cyprus.
Life (Basel). 2023 Apr 27;13(5):1095. doi: 10.3390/life13051095.
Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common type of dementia. Although a considerably large amount of money has been invested in drug development for AD, no disease modifying treatment has been detected so far. In our previous work, we developed a computational method to highlight stage-specific candidate repurposed drugs against AD. In this study, we tested the effect of the top 13 candidate repurposed drugs that we proposed in our previous work in a severity stage-specific manner using an in vitro BACE1 assay and the effect of a top-ranked drug from the list of our previous work, tetrabenazine (TBZ), in the 5XFAD as an AD mouse model. From our in vitro screening, we detected 2 compounds (clomiphene citrate and Pik-90) that showed statistically significant inhibition against the activity of the BACE1 enzyme. The administration of TBZ at the selected dose and therapeutic regimen in 5XFAD in male and female mice showed no significant effect in behavioral tests using the Y-maze and the ELISA immunoassay of Aβ40. To our knowledge, this is the first time the drug tetrabenazine has been tested in the 5XFAD mouse model of AD in a sex-stratified manner. Our results highlight 2 drugs (clomiphene citrate and Pik-90) from our previous computational work for further investigation.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，也是最常见的痴呆类型。尽管在AD药物研发方面投入了大量资金，但迄今为止尚未发现可改变疾病进程的治疗方法。在我们之前的工作中，我们开发了一种计算方法，以突出针对AD的阶段特异性候选药物。在本研究中，我们使用体外β-分泌酶1（BACE1）检测法，以疾病严重程度阶段特异性的方式测试了我们在之前工作中提出的13种候选药物的效果，并在5XFAD AD小鼠模型中测试了我们之前工作列表中排名第一的药物丁苯那嗪（TBZ）的效果。通过我们的体外筛选，我们检测到2种化合物（枸橼酸氯米芬和Pik-90）对BACE1酶的活性表现出统计学上的显著抑制作用。在雄性和雌性5XFAD小鼠中，按照选定的剂量和治疗方案给予TBZ，在使用Y迷宫的行为测试和Aβ40的酶联免疫吸附测定（ELISA）中均未显示出显著效果。据我们所知，这是丁苯那嗪首次在AD的5XFAD小鼠模型中进行性别分层测试。我们的结果突出了我们之前计算工作中的2种药物（枸橼酸氯米芬和Pik-90）以供进一步研究。
