PMID- 21627640 OWN - NLM STAT- MEDLINE DCOM- 20120316 LR - 20211020 IS - 1476-5381 (Electronic) IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 164 IP - 8 DP - 2011 Dec TI - Sildenafil restores cognitive function without affecting beta-amyloid burden in a mouse model of Alzheimer's disease. PG - 2029-41 LID - 10.1111/j.1476-5381.2011.01517.x [doi] AB - BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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 3beta (GSK3beta) 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. CONCLUSIONS AND IMPLICATIONS: 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. CI - (c) 2011 The Authors. British Journal of Pharmacology (c) 2011 The British Pharmacological Society. FAU - Cuadrado-Tejedor, M AU - Cuadrado-Tejedor M AD - Division of Neurosciences, CIMA, University of Navarra, Avenida Pio XII 55, Pamplona, Spain. FAU - Hervias, I AU - Hervias I FAU - Ricobaraza, A AU - Ricobaraza A FAU - Puerta, E AU - Puerta E FAU - Perez-Roldan, J M AU - Perez-Roldan JM FAU - Garcia-Barroso, C AU - Garcia-Barroso C FAU - Franco, R AU - Franco R FAU - Aguirre, N AU - Aguirre N FAU - Garcia-Osta, A AU - Garcia-Osta A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Amyloid beta-Peptides) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cytoskeletal Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Phosphodiesterase Inhibitors) RN - 0 (Piperazines) RN - 0 (Purines) RN - 0 (Sulfones) RN - 0 (activity regulated cytoskeletal-associated protein) RN - 0 (tau Proteins) RN - BW9B0ZE037 (Sildenafil Citrate) SB - IM MH - Alzheimer Disease/metabolism/*psychology MH - Amyloid beta-Peptides/*metabolism MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cognition/*drug effects MH - Cytoskeletal Proteins/metabolism MH - Fear MH - Immunohistochemistry MH - Maze Learning MH - Mice MH - Mice, Transgenic MH - Nerve Tissue Proteins/metabolism MH - Phosphodiesterase Inhibitors/*pharmacology MH - Piperazines/*pharmacology MH - Purines/pharmacology MH - Sildenafil Citrate MH - Sulfones/*pharmacology MH - tau Proteins/metabolism PMC - PMC3246665 EDAT- 2011/06/02 06:00 MHDA- 2012/03/17 06:00 PMCR- 2012/12/01 CRDT- 2011/06/02 06:00 PHST- 2011/06/02 06:00 [entrez] PHST- 2011/06/02 06:00 [pubmed] PHST- 2012/03/17 06:00 [medline] PHST- 2012/12/01 00:00 [pmc-release] AID - 10.1111/j.1476-5381.2011.01517.x [doi] PST - ppublish SO - Br J Pharmacol. 2011 Dec;164(8):2029-41. doi: 10.1111/j.1476-5381.2011.01517.x.