Al Rihani Sweilem B, Lan Renny S, Kaddoumi Amal
Department of Drug Discovery and Development, Harrison School of Pharmacy, Pharmacy Research Building, Auburn University, Auburn, AL, USA.
Department of Biochemistry and Molecular Biology, Biomedical Research Building, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
J Alzheimers Dis. 2019;72(4):1097-1117. doi: 10.3233/JAD-190849.
Alzheimer's disease (AD) is characterized by a compromised blood-brain barrier (BBB) and disrupted intracellular calcium homeostasis in the brain. Therefore, rectifying the BBB integrity and restoring calcium homeostasis could provide an effective strategy to treat AD. Recently, we developed a high throughput-screening assay to screen for compounds that enhance a cell-based BBB model integrity, which identified multiple hits among which is granisetron, a Food and Drug Administration approved drug. Here, we evaluated the therapeutic potential of granisetron against AD. Granisetron was tested in C57Bl/6J young and aged wild-type mice, and in a transgenic mouse model of AD namely TgSwDI for its effect on BBB intactness and amyloid-β (Aβ)-related pathology. Our study findings showed that granisetron enhanced BBB integrity in both aged and TgSwDI mice. This effect was associated with an overall reduction in Aβ load and neuroinflammation in TgSwDI mice brains. In addition, and supported by proteomics analysis, granisetron significantly reduced Aβ induced calcium influx in vitro, and rectified calcium dyshomeostasis in TgSwDI mice brains by restoring calmodulin-dependent protein kinase II/cAMP-response element binding protein pathway, which was associated with cognitive improvement. These results support granisetron repurposing as a potential drug to hold, slow, and/or treat AD.
阿尔茨海默病（AD）的特征是血脑屏障（BBB）受损以及大脑细胞内钙稳态被破坏。因此，纠正血脑屏障的完整性并恢复钙稳态可能为治疗AD提供一种有效策略。最近，我们开发了一种高通量筛选试验，以筛选能够增强基于细胞的血脑屏障模型完整性的化合物，从中鉴定出多个有效化合物，其中包括已获美国食品药品监督管理局批准的药物格拉司琼。在此，我们评估了格拉司琼治疗AD的潜力。在C57Bl/6J年轻和老年野生型小鼠以及AD转基因小鼠模型TgSwDI中测试了格拉司琼对血脑屏障完整性和淀粉样β蛋白（Aβ）相关病理的影响。我们的研究结果表明，格拉司琼增强了老年小鼠和TgSwDI小鼠的血脑屏障完整性。这种作用与TgSwDI小鼠大脑中Aβ负荷和神经炎症的总体减少有关。此外，在蛋白质组学分析的支持下，格拉司琼在体外显著减少了Aβ诱导的钙内流，并通过恢复钙调蛋白依赖性蛋白激酶II/环磷酸腺苷反应元件结合蛋白途径纠正了TgSwDI小鼠大脑中的钙稳态失调，这与认知改善有关。这些结果支持将格拉司琼重新用作一种可能预防、延缓和/或治疗AD的药物。
