title: Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer's disease.
abstract: BACKGROUND
  Given the implication of histone acetylation in memory processes, histone deacetylase inhibitors (HDACIs) have been postulated as potential modulators of cognitive impairment in Alzheimer's disease (AD). However, dose-dependent side effects have been described in patients with the currently available broad-spectrum HDACIs, explaining why their therapeutic potential has not been realized for chronic diseases. Here, by simultaneously targeting two independent enzyme activities, histone deacetylase (HDAC) and phosphodiesterase-5 (PDE5), we propose a novel mode of inhibitory action that might increase the therapeutic specificity of HDACIs.
  
  
  RESULTS
  The combination of vorinostat, a pan-HDACI, and tadalafil, a PDE5 inhibitor, rescued the long-term potentiation impaired in slices from APP/PS1 mice. When administered in vivo, the combination of these drugs alleviated the cognitive deficits in AD mice, as well as the amyloid and tau pathology, and it reversed the reduced dendritic spine density on hippocampal neurons. Significantly, the combination of vorinostat and tadalafil was more effective than each drug alone, both against the symptoms and in terms of disease modification, and importantly, these effects persisted after a 4-week washout period.
  
  
  CONCLUSIONS
  The results highlight the pharmacological potential of a combination of molecules that inhibit HDAC and PDE5 as a therapeutic approach for AD treatment.
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.|Anatomy Department, School of Medicine, University of Navarra, Pamplona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Cuadrado-Tejedor
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Garcia-Barroso
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, 31008 Pamplona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Sanzhez-Arias
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Mederos
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, 31008 Pamplona, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Rabal
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, 31008 Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ugarte
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.|Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Franco
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pascual-Lucas
authors.affiliation: Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Segura
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Perea
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, 31008 Pamplona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Oyarzabal
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Garcia-Osta
keywords: Alzheimer’s disease (AD); Amyloid; Gene transcription; Histone deacetylase (HDAC); Memory; Phosphodiesterase (PDE); Tau