title: GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses.
abstract: OBJECTIVE
  Strategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3-cyclopentyloxy-4-methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR-7b, on memory performance, nausea, hippocampal cAMP and amyloid-β (Aβ) levels.
  
  
  METHODS
  To measure memory performance, we performed object recognition tests on rats and mice treated with GEBR-7b or rolipram. The emetic potential of the drug, again compared with rolipram, was evaluated in rats using the taste reactivity test and in mice using the xylazine/ketamine anaesthesia test. Extracellular hippocampal cAMP was evaluated by intracerebral microdialysis in freely moving rats. Levels of soluble Aβ peptides were measured in hippocampal tissues and cultured N2a cells by elisa.
  
  
  RESULTS
  GEBR-7b increased hippocampal cAMP, did not influence Aβ levels and improved spatial, as well as object memory performance in the object recognition tests. The effect of GEBR-7b on memory was 3 to 10 times more potent than that of rolipram, and its effective doses had no effect on surrogate measures of emesis in rodents.
  
  
  CONCLUSIONS
  Our results demonstrate that GEBR-7b enhances memory functions at doses that do not cause emesis-like behaviour in rodents, thus offering a promising pharmacological perspective for the treatment of memory impairment.
authors.affiliation: Departments of Pharmaceutical Sciences/Experimental Medicine, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Bruno
authors.forename: E
authors.initials: E
authors.lastname: Fedele
authors.forename: J
authors.initials: J
authors.lastname: Prickaerts
authors.forename: L A
authors.initials: LA
authors.lastname: Parker
authors.forename: E
authors.initials: E
authors.lastname: Canepa
authors.forename: C
authors.initials: C
authors.lastname: Brullo
authors.forename: A
authors.initials: A
authors.lastname: Cavallero
authors.forename: E
authors.initials: E
authors.lastname: Gardella
authors.forename: A
authors.initials: A
authors.lastname: Balbi
authors.forename: C
authors.initials: C
authors.lastname: Domenicotti
authors.forename: E
authors.initials: E
authors.lastname: Bollen
authors.forename: H J M
authors.initials: HJ
authors.lastname: Gijselaers
authors.forename: T
authors.initials: T
authors.lastname: Vanmierlo
authors.forename: K
authors.initials: K
authors.lastname: Erb
authors.forename: C L
authors.initials: CL
authors.lastname: Limebeer
authors.forename: F
authors.initials: F
authors.lastname: Argellati
authors.forename: U M
authors.initials: UM
authors.lastname: Marinari
authors.forename: M A
authors.initials: MA
authors.lastname: Pronzato
authors.forename: R
authors.initials: R
authors.lastname: Ricciarelli
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007097:Imines / Q000494:pharmacology*; D007649:Ketamine / Q000008:administration & dosage; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014991:Xylazine / Q000008:administration & dosage
chemical_list: C570687:GEBR-7b; D007097:Imines; D009025:Morpholines; D010726:Phosphodiesterase Inhibitors; D014991:Xylazine; D007649:Ketamine; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4