Granisetron Alleviates Alzheimer's Disease Pathology in TgSwDI Mice Through Calmodulin-Dependent Protein Kinase II/cAMP-Response Element Binding Protein Pathway
Granisetron Alleviates Alzheimer's Disease Pathology in TgSwDI Mice Through Calmodulin-Dependent Protein Kinase II/cAMP-Response Element Binding Protein Pathway
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DOI：
10.3233/jad-190849
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Kaddoumi, Amal
中科院分区：
文献类型：
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作者：
Al Rihani, Sweilem B.;Lan, Renny S.;Kaddoumi, Amal
阿尔茨海默病（AD）的特征在于血脑屏障（BBB）受损和脑中细胞内钙稳态破坏。因此，纠正血脑屏障的完整性和恢复钙稳态可能是治疗AD的有效策略。最近，我们开发了一种高通量筛选试验来筛选增强基于细胞的BBB模型完整性的化合物，其鉴定了多个命中物，其中包括格拉司琼，一种食品和药物管理局批准的药物。在这里，我们评估了格拉司琼对AD的治疗潜力。在C57 Bl/6 J年轻和老年野生型小鼠以及AD转基因小鼠模型（即TgSwDI）中测试了格拉司琼对BBB完整性和淀粉样蛋白β（A β）相关病理学的影响。我们的研究结果表明，格拉司琼增强BBB的完整性，在老年和TgSwDI小鼠。这种效应与TgSwDI小鼠大脑中A β负荷和神经炎症的总体减少有关。此外，蛋白质组学分析支持，格拉司琼显著减少体外A β诱导的钙内流，并通过恢复钙调蛋白依赖性蛋白激酶II/cAMP-反应元件结合蛋白途径纠正TgSwDI小鼠脑内钙稳态异常，这与认知改善相关。这些结果支持格拉司琼作为一种潜在的药物来控制，减缓和/或治疗AD。
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-beta (A beta)-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 A beta load and neuroinflammation in TgSwDI mice brains. In addition, and supported by proteomics analysis, granisetron significantly reduced A beta 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.