Division of Neurosciences, CIMA, University of Navarra, Avenida Pio XII 55, Pamplona, Spain.
Br J Pharmacol. 2011 Dec;164(8):2029-41. doi: 10.1111/j.1476-5381.2011.01517.x.
Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory-related behaviour were investigated.
Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age-matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil.
Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin-dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain-derived neurotrophic factor (BDNF) and the activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden.
Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease.
磷酸二酯酶 5（PDE5）抑制剂通过升高 cGMP 来影响信号通路，cGMP 是一种参与神经可塑性过程的第二信使。在本研究中，研究了 PDE5 抑制剂西地那非对阿尔茨海默病病理特征和与记忆相关行为的影响。
将西地那非给予阿尔茨海默病 Tg2576 转基因小鼠模型和年龄匹配的阴性同窝小鼠（对照组）。使用 Morris 水迷宫测试和恐惧条件反射任务分析记忆功能。对用生理盐水或西地那非处理的动物的脑匀浆进行生化分析。
用西地那非治疗老年 Tg2576 动物可完全逆转其认知障碍。这种变化伴随着海马中 tau 过度磷酸化的减少以及糖原合酶激酶 3β（GSK3β）和周期蛋白依赖性激酶 5（CDK5）（p25/p35 比值）活性的降低。此外，西地那非还增加了脑源性神经营养因子（BDNF）和活性调节细胞骨架相关蛋白（Arc）在海马中的水平，而对脑淀粉样蛋白负担没有任何可检测到的改变。
西地那非改善了 Tg2576 小鼠的认知功能，其效果与淀粉样蛋白负担的变化无关。这些数据进一步加强了西地那非作为阿尔茨海默病治疗药物的潜力。
