Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice

Behav Brain Res. 2013 Aug 1:250:230-7. doi: 10.1016/j.bbr.2013.05.017. Epub 2013 May 16.

Abstract

Memory deficit is a marker of Alzheimer's disease (AD) that has been highly associated with the dysfunction of cyclic GMP (cGMP) signaling and an ongoing inflammatory process. Phosphodiesterase-5 (PDE5) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement. However, it is still unknown whether inhibition of PDE5 reversed β-amyloid peptide (Aβ)-induced neuroinflammation in APP/PS1 transgenic (Tg APP/PS1) mice. The present study evaluated the cognitive behaviors, inflammatory mediators, and cGMP/PKG/pCREB signaling in 15-month-old Tg APP/PS1 mice and age-matched wild-type (WT) mice that were treated with PDE5 inhibitor sildenafil and the inhibitor of cGMP-dependent protein kinase Rp-8-Br-PET-cGMPS. In comparison with WT mice, Tg APP/PS1 mice were characterized by impaired cognitive ability, neuroinflammatory response, and down-regulated cGMP signaling. Sildenafil reversed these memory deficits and cGMP/PKG/pCREB signaling dysfunction; it also reduced both the soluble Aβ1-40 and Aβ1-42 levels in the hippocampus. These effects of sildenafil were prevented by intra-hippocampal infusion of the Rp-8-Br-PET-cGMPS. These results suggest that sildenafil could restore cognitive deficits in Tg APP/PS1 mice by the regulation of PKG/pCREB signaling, anti-inflammatory response and reduction of Aβ levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Analysis of Variance
  • Animals
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology
  • Cognition Disorders / genetics
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / therapeutic use
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Encephalitis / complications
  • Encephalitis / genetics
  • Encephalitis / prevention & control*
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Phosphodiesterase 5 Inhibitors / therapeutic use*
  • Piperazines / therapeutic use*
  • Presenilin-1 / genetics
  • Purines / therapeutic use
  • RNA, Messenger / metabolism
  • Recognition, Psychology / drug effects
  • Recognition, Psychology / physiology
  • Sildenafil Citrate
  • Sulfones / therapeutic use*
  • Thionucleotides

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Cytokines
  • PSEN1 protein, human
  • Phosphodiesterase 5 Inhibitors
  • Piperazines
  • Presenilin-1
  • Purines
  • RNA, Messenger
  • Sulfones
  • Thionucleotides
  • 8-bromoguanosino-3',5'-cyclic monophosphorothioate
  • Sildenafil Citrate
  • Cyclic GMP