PMID- 22771768
OWN - NLM
STAT- MEDLINE
DCOM- 20130211
LR  - 20191210
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 64
DP  - 2013 Jan
TI  - Chronic phosphodiesterase type 2 inhibition improves memory in the APPswe/PS1dE9 
      mouse model of Alzheimer's disease.
PG  - 124-36
LID - S0028-3908(12)00306-1 [pii]
LID - 10.1016/j.neuropharm.2012.06.048 [doi]
AB  - Alzheimer's disease (AD) is characterized by progressive cognitive deficits and 
      synaptic dysfunction. Over the last decade phosphodiesterase inhibitors (PDEIs) 
      have received increasing attention as putative cognition enhancers and have been 
      suggested as a novel treatment strategy for AD. Given their ability to prevent 
      hydrolysis of cAMP and/or cGMP, they can stimulate the cAMP/protein kinase A 
      (PKA)/cAMP element-binding protein (CREB) and cGMP/PKG/CREB pathway to enhance 
      synaptic transmission by increasing CREB phosphorylation (pCREB) and 
      brain-derived neurotrophic factor (BDNF) transcription. Based on previous 
      research, we hypothesized that chronic PDE2I treatment would improve AD-related 
      cognitive deficits, by decreasing amyloid-beta (Abeta) plaque load, enhancing pCREB and 
      BDNF levels and increasing synaptic density in the hippocampus of 8-month-old 
      APPswe/PS1dE9 mice. Results indicated that chronic PDE2I treatment could indeed 
      improve memory performance in APPswe/PS1dE9 mice, without affecting anxiety, 
      depressive-like behavior or hypothalamus-pituitary-adrenal axis regulation. 
      However, no treatment effects were observed on Abeta plaque load, pCREB or BDNF 
      concentrations, or presynaptic density in the hippocampus, suggesting that other 
      signaling pathways and/or effector molecules might be responsible for its 
      cognition-enhancing effects. Presynaptic density in the stratum lucidum of the 
      CA3 subregion was significantly higher in APPswe/PS1dE9 mice compared to WT 
      controls, possibly reflecting a compensatory mechanism. In conclusion, PDEs in 
      general, and PDE2 specifically, could be considered as promising therapeutic 
      targets for cognition enhancement in AD, although the underlying mechanism of 
      action remains to be elucidated. This article is part of a Special Issue entitled 
      'Cognitive Enhancers'.
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Sierksma, Annerieke S R
AU  - Sierksma AS
AD  - Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and 
      Life Science, School for Mental Health and Neuroscience (MHeNS), Maastricht 
      University, Maastricht, The Netherlands.
FAU - Rutten, Kris
AU  - Rutten K
FAU - Sydlik, Sebastian
AU  - Sydlik S
FAU - Rostamian, Somayeh
AU  - Rostamian S
FAU - Steinbusch, Harry W M
AU  - Steinbusch HW
FAU - van den Hove, Daniel L A
AU  - van den Hove DL
FAU - Prickaerts, Jos
AU  - Prickaerts J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120704
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 
      (2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 
      (3H)-one)
RN  - 0 (Imidazoles)
RN  - 0 (Nootropic Agents)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Triazines)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 2)
SB  - IM
MH  - Alzheimer Disease/*drug therapy/metabolism/pathology/physiopathology
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Cognition Disorders/etiology/prevention & control
MH  - Cyclic Nucleotide Phosphodiesterases, Type 2/*antagonists & inhibitors
MH  - *Disease Models, Animal
MH  - Hippocampus/drug effects/metabolism/pathology
MH  - Humans
MH  - Imidazoles/therapeutic use
MH  - Male
MH  - Memory Disorders/etiology/*prevention & control
MH  - Memory, Short-Term/*drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neurons/drug effects/metabolism/pathology
MH  - Nootropic Agents/*therapeutic use
MH  - Phosphodiesterase Inhibitors/*therapeutic use
MH  - Random Allocation
MH  - Recognition, Psychology/drug effects
MH  - Spatial Behavior/drug effects
MH  - Triazines/therapeutic use
EDAT- 2012/07/10 06:00
MHDA- 2013/02/12 06:00
CRDT- 2012/07/10 06:00
PHST- 2012/03/30 00:00 [received]
PHST- 2012/06/22 00:00 [revised]
PHST- 2012/06/24 00:00 [accepted]
PHST- 2012/07/10 06:00 [entrez]
PHST- 2012/07/10 06:00 [pubmed]
PHST- 2013/02/12 06:00 [medline]
AID - S0028-3908(12)00306-1 [pii]
AID - 10.1016/j.neuropharm.2012.06.048 [doi]
PST - ppublish
SO  - Neuropharmacology. 2013 Jan;64:124-36. doi: 10.1016/j.neuropharm.2012.06.048. 
      Epub 2012 Jul 4.