Cell and Molecular Neuropharmacology, Neurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Av. Pio XII 55, 31008 Pamplona, Spain.
Neuropharmacology. 2013 Jan;64:114-23. doi: 10.1016/j.neuropharm.2012.06.052. Epub 2012 Jul 7.
Previous studies have demonstrated that cognitive function can be restored in mouse models of Alzheimer's disease (AD) following administration of sildenafil, a specific PDE5 inhibitor (Puzzo et al., 2009; Cuadrado-Tejedor et al.). Another very potent PDE5 inhibitor with a longer half-life and safe in chronic treatments, tadalafil, may represent a better alternative candidate for AD therapy. However, tadalafil was proven unable to achieve similar benefits than those of sildenafil in AD animal models (Puzzo et al., 2009). The lack of efficacy was attributed to inability to cross the blood-brain barrier (BBB). In this paper we first measured the blood and brain levels of tadalafil to prove that the compound crosses BBB and that chronic treatment leads to accumulation in the brain of the J20 transgenic mouse model of AD. We demonstrated the presence of PDE5 mRNA in the brain of the mice and also in the human brain. After a 10 week treatment with either of these PDE5 inhibitors, the performance of the J20 mice in the Morris water maze test improved when compared with the transgenic mice that received vehicle. Biochemical analysis revealed that neither sildenafil nor tadalafil altered the amyloid burden, although both compounds reduced Tau phosphorylation in the mouse hippocampus. This study provides evidence of the potential benefits of a chronic tadalafil treatment in AD therapy. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
先前的研究表明，在阿尔茨海默病（AD）的小鼠模型中，给予特定的 PDE5 抑制剂西地那非（sildenafil）后，认知功能可以恢复（Puzzo 等人，2009 年；Cuadrado-Tejedor 等人）。另一种半衰期更长且在慢性治疗中安全的非常有效的 PDE5 抑制剂他达拉非（tadalafil），可能是 AD 治疗的更好选择。然而，他达拉非已被证明在 AD 动物模型中无法获得与西地那非相似的益处（Puzzo 等人，2009 年）。缺乏疗效归因于无法穿过血脑屏障（BBB）。在本文中，我们首先测量了他达拉非的血液和大脑水平，以证明该化合物穿过 BBB，并且慢性治疗会导致 AD 的 J20 转基因小鼠模型的大脑中积累。我们证明了 PDE5 mRNA 存在于小鼠的大脑中，也存在于人脑。在用这些 PDE5 抑制剂中的任一种进行 10 周治疗后，与接受载体的转基因小鼠相比，J20 小鼠在 Morris 水迷宫测试中的表现得到了改善。生化分析显示，西地那非和他达拉非均未改变淀粉样蛋白负荷，尽管这两种化合物都减少了小鼠海马体中的 Tau 磷酸化。这项研究为 AD 治疗中慢性他达拉非治疗的潜在益处提供了证据。本文是题为“认知增强剂”的特刊的一部分。
