The PDE4 inhibitor HT-0712 improves hippocampus-dependent memory in aged mice

Neuropsychopharmacology. 2014 Dec;39(13):2938-48. doi: 10.1038/npp.2014.154. Epub 2014 Jun 26.

Abstract

Aging is associated with declines in memory and cognitive function. Here, we evaluate the effects of HT-0712 on memory formation and on cAMP response element-binding protein (CREB)-regulated genes in aged mice. HT-0712 enhanced long-term memory formation in normal young mice at brain concentrations similar to those found to increase CRE-mediated gene expression in hippocampal neurons. Aged mice showed significantly poorer contextual and trace conditioning compared with young-adult mice. In aged mice, a single injection of HT-0712 significantly boosted contextual and trace long-term memory. Additional effects of HT-0712 were seen in a spatial memory task. Our parallel biochemical experiments revealed that inductions of the CREB-regulated genes, cFos, Zif268, and Bdnf, after fear conditioning were diminished in aged mice. HT-0712 facilitated expression of these CREB-regulated genes in aged hippocampus, indicating that the drug engages a CREB-regulated mechanism in vivo. These findings corroborate and extend our previous results on the mechanism of action of HT-0712 and its efficacy to enhance memory formation. Our data also indicate that HT-0712 may be effective to treat age-associated memory impairment in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aging / drug effects*
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • CREB-Binding Protein / metabolism
  • Cells, Cultured
  • Conditioning, Psychological / drug effects*
  • Early Growth Response Protein 1 / metabolism
  • Embryo, Mammalian
  • Exploratory Behavior / drug effects
  • Fear / psychology
  • Gene Expression Regulation / drug effects*
  • Hippocampus / physiology*
  • Male
  • Maze Learning / drug effects
  • Memory, Long-Term / drug effects*
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Piperidones / pharmacology
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rolipram / pharmacology

Substances

  • Brain-Derived Neurotrophic Factor
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • HT-0712
  • Phosphodiesterase 4 Inhibitors
  • Piperidones
  • Proto-Oncogene Proteins c-fos
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • Rolipram