PMID- 26457123
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20151012
LR  - 20190108
IS  - 1868-7075 (Print)
IS  - 1868-7083 (Electronic)
IS  - 1868-7075 (Linking)
VI  - 7
DP  - 2015
TI  - 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.
PG  - 108
LID - 10.1186/s13148-015-0142-9 [doi]
LID - 108
AB  - 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.
FAU - Cuadrado-Tejedor, M
AU  - Cuadrado-Tejedor M
AD  - Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied 
      Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.
AD  - Anatomy Department, School of Medicine, University of Navarra, Pamplona, Spain.
FAU - Garcia-Barroso, C
AU  - Garcia-Barroso C
AD  - Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied 
      Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.
FAU - Sanzhez-Arias, J
AU  - Sanzhez-Arias J
AD  - Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for 
      Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, 31008 
      Pamplona, Spain.
FAU - Mederos, S
AU  - Mederos S
AD  - Cajal Institute, CSIC, Madrid, Spain.
FAU - Rabal, O
AU  - Rabal O
AD  - Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for 
      Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, 31008 
      Pamplona, Spain.
FAU - Ugarte, A
AU  - Ugarte A
AD  - Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for 
      Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, 31008 
      Pamplona, Spain.
FAU - Franco, R
AU  - Franco R
AD  - Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied 
      Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.
AD  - Department of Biochemistry and Molecular Biology, Faculty of Biology, University 
      of Barcelona, Barcelona, Spain.
FAU - Pascual-Lucas, M
AU  - Pascual-Lucas M
AD  - Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied 
      Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.
FAU - Segura, V
AU  - Segura V
AD  - Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of 
      Navarra, Pamplona, Spain.
FAU - Perea, G
AU  - Perea G
AD  - Cajal Institute, CSIC, Madrid, Spain.
FAU - Oyarzabal, J
AU  - Oyarzabal J
AD  - Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for 
      Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, 31008 
      Pamplona, Spain.
FAU - Garcia-Osta, A
AU  - Garcia-Osta A
AD  - Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied 
      Medical Research (CIMA), University of Navarra, Pio XII, 31008 Pamplona, Spain.
LA  - eng
PT  - Journal Article
DEP - 20151008
PL  - Germany
TA  - Clin Epigenetics
JT  - Clinical epigenetics
JID - 101516977
PMC - PMC4599811
OTO - NOTNLM
OT  - Alzheimer's disease (AD)
OT  - Amyloid
OT  - Gene transcription
OT  - Histone deacetylase (HDAC)
OT  - Memory
OT  - Phosphodiesterase (PDE)
OT  - Tau
EDAT- 2015/10/13 06:00
MHDA- 2015/10/13 06:01
PMCR- 2015/10/08
CRDT- 2015/10/13 06:00
PHST- 2015/05/05 00:00 [received]
PHST- 2015/09/28 00:00 [accepted]
PHST- 2015/10/13 06:00 [entrez]
PHST- 2015/10/13 06:00 [pubmed]
PHST- 2015/10/13 06:01 [medline]
PHST- 2015/10/08 00:00 [pmc-release]
AID - 142 [pii]
AID - 10.1186/s13148-015-0142-9 [doi]
PST - epublish
SO  - Clin Epigenetics. 2015 Oct 8;7:108. doi: 10.1186/s13148-015-0142-9. eCollection 
      2015.