title: Tadalafil crosses the blood-brain barrier and reverses cognitive dysfunction in a mouse model of AD.
abstract: 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'.
authors: Cell and Molecular Neuropharmacology, Neurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Av. Pio XII 55, 31008 Pamplona, Spain.
authors: Carolina
authors: C
authors: García-Barroso
authors: Ana
authors: A
authors: Ricobaraza
authors: María
authors: M
authors: Pascual-Lucas
authors: Nora
authors: N
authors: Unceta
authors: Alberto J
authors: AJ
authors: Rico
authors: Maria Aranzazu
authors: MA
authors: Goicolea
authors: Joan
authors: J
authors: Sallés
authors: José Luis
authors: JL
authors: Lanciego
authors: Julen
authors: J
authors: Oyarzabal
authors: Rafael
authors: R
authors: Franco
authors: Mar
authors: M
authors: Cuadrado-Tejedor
authors: Ana
authors: A
authors: García-Osta
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002243:Carbolines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D058986:Phosphodiesterase 5 Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D011687:Purines / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013045:Species Specificity; D013450:Sulfones / Q000627:therapeutic use; D000068581:Tadalafil; D014018:Tissue Distribution
chemical_list: D002243:Carbolines; D018697:Nootropic Agents; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5