title: Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer's disease.
abstract: Memory loss characterizes several neurodegenerative disorders, including Alzheimer's disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses. GEBR-32a efficiently enhances cAMP in neuronal cultures and hippocampal slices. In vivo pharmacokinetic analysis shows that GEBR-32a is rapidly distributed within the central nervous system with a very favourable brain/blood ratio. Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit. Of great relevance, our preliminary toxicological analysis indicates that GEBR-32a is not cytotoxic and genotoxic, and does not seem to possess emetic-like side effects. In conclusion, GEBR-32a could represent a very promising cognitive-enhancing drug with a great potential for the treatment of Alzheimer's disease.
authors.affiliation: Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via L. B. Alberti, 2, 16132 Genoa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ricciarelli
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
authors.affiliation: Department of Pathology &Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Villa
authors.affiliation: Department of Pharmacy, Section of Pharmacology and Toxicology, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano, 4, 16148 Genoa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rebosio
authors.affiliation: Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via L. B. Alberti, 2, 16132 Genoa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Calcagno
authors.affiliation: Department of Pharmacy, Section of Pharmacology and Toxicology, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano, 4, 16148 Genoa, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Balbi
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Britt T J
authors.initials: BT
authors.lastname: van Hagen
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.|Department of Pathology &Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
authors.forename: Elentina K
authors.initials: EK
authors.lastname: Argyrousi
authors.affiliation: Department of Pathology &Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via L. B. Alberti, 2, 16132 Genoa, Italy.
authors.forename: Maria Adelaide
authors.initials: MA
authors.lastname: Pronzato
authors.affiliation: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.affiliation: Department of Pharmacy, Section of Pharmacology and Toxicology, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano, 4, 16148 Genoa, Italy.|Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fedele
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000523:psychology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D017774:Long-Term Potentiation / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011994:Recombinant Proteins
chemical_list: D007527:Isoenzymes; D058988:Phosphodiesterase 4 Inhibitors; D011994:Recombinant Proteins; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4