title: The PDE4 inhibitor HT-0712 improves hippocampus-dependent memory in aged mice.
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.
authors: Dart Neuroscience, LLC, San Diego, CA, USA.
authors: Marco
authors: M
authors: Peters
authors: Dart Neuroscience, LLC, San Diego, CA, USA.
authors: Matthew
authors: M
authors: Bletsch
authors: Dart Neuroscience, LLC, San Diego, CA, USA.
authors: Jennifer
authors: J
authors: Stanley
authors: Dart Neuroscience, LLC, San Diego, CA, USA.
authors: Damian
authors: D
authors: Wheeler
authors: Dart Neuroscience, LLC, San Diego, CA, USA.
authors: Roderick
authors: R
authors: Scott
authors: Dart Neuroscience, LLC, San Diego, CA, USA.
authors: Tim
authors: T
authors: Tully
mesh_terms: D000367:Age Factors; D000375:Aging / Q000187:drug effects*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000187:drug effects*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000523:psychology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D057567:Memory, Long-Term / Q000187:drug effects*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010881:Piperidones / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C000599150:HT-0712; D058988:Phosphodiesterase 4 Inhibitors; D010881:Piperidones; D016760:Proto-Oncogene Proteins c-fos; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D020889:Rolipram