Bibliographic
Previous studies have demonstrated that sildenafil, a specific PDE5 inhibitor can restore cognitive function in mouse models of AD, suggesting that PDE5 may be a novel therapeutic target for the treatment of AD. However another very potent PDE5 inhibitor, tadalafil, was proven unable to achieve similar benefits to those of sildenafil in Tg AD mice; the lack of efficacy was attributed to inability to cross the blood brain barrier (BBB). The aim of this work was to unequivocally show whether tadalafil may cross the BBB or not, and to revisit its lack of effect in AD mice models. Its efficacy is proven, tadalafil may be a better candidate than sildenafil due to its longer half-life and its proven safety profile. In this study J20 mice were administered equivalent doses of sildenafil or tadalafil. After a 10 week treatment with either of these compounds, the performance of the mice in the Morris Water Maze test improved when compared with the Tg mice mice that received vehicle. Results also showed that tadalafil crossed the BBB and that chronic treatment lead to the accumulation of the drug in the brain at concentrations high enough to inhibit PDE5. Biochemical analysis revealed that neither sildenafil nor tadalafil altered the amyloid burden, although both compounds reduced Tau phosphorylation in mouse hippocampus. This study provides some evidence of the potential benefits of a chronic tadalafil treatment in AD therapy.