title: Sildenafil ameliorates cognitive deficits and tau pathology in a senescence-accelerated mouse model.
abstract: Aging is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. In the present study we tested whether the specific phosphodiesterase 5 inhibitor sildenafil could ameliorate the age-dependent cognitive impairments shown by the senescence-accelerated mouse prone-8 (SAMP8). Sildenafil administration (7.5 mg/kg for 4 weeks) to 5-month-old SAMP8 mice attenuated spatial learning and memory impairments shown by these mice in the Morris Water Maze. Tau hyperphosphorylation (AT8 but not PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of sildenafil-treated mice, an effect probably related to a decrease in cyclin-dependent kinase 5 protein expression and activity (p25/p35 ratio). Interestingly, sildenafil also phosphorylated Akt, which was associated with an increase of glycogen synthase kinase-3β phosphorylation, providing a plausible explanation for the reductions in tau hyperphosphorylation (AT8 and PHF-1 epitopes) and attenuation of cognitive deficits shown by 9-month-old SAMP8 mice. Overall, sildenafil might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Orejana
authors.forename: Lucía
authors.initials: L
authors.lastname: Barros-Miñones
authors.forename: Joaquín
authors.initials: J
authors.lastname: Jordán
authors.forename: Elena
authors.initials: E
authors.lastname: Puerta
authors.forename: Norberto
authors.initials: N
authors.lastname: Aguirre
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D024801:Tauopathies / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)