Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer’s disease

• Published in: Scientific reports 2017-04, Vol.7 (1), p.46320, Article 46320
• Main Authors: Ricciarelli, Roberta, Brullo, Chiara, Prickaerts, Jos, Arancio, Ottavio, Villa, Carla, Rebosio, Claudia, Calcagno, Elisa, Balbi, Matilde, van Hagen, Britt T. J., Argyrousi, Elentina K., Zhang, Hong, Pronzato, Maria Adelaide, Bruno, Olga, Fedele, Ernesto
• Format: Article
• Language: English
• Subjects: 13; 13/95; 631/378/1595/1554; 631/378/2591/2592; 64; 64/60; 692/617/375/365/1283; 9/30; 96; 96/95; Alzheimer Disease - drug therapy; Alzheimer Disease - etiology; Alzheimer Disease - metabolism; Alzheimer Disease - psychology; Alzheimer's disease; Animals; Brain slice preparation; Cells, Cultured; Central nervous system; Cognitive ability; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Cytotoxicity; DNA Damage - drug effects; Genotoxicity; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Humanities and Social Sciences; Humans; Intracellular Space; Isoenzymes - antagonists & inhibitors; Isoforms; Long-term potentiation; Long-Term Potentiation - drug effects; Memory; Memory - drug effects; Mice; Mice, Transgenic; Molecular Structure; multidisciplinary; Neurodegenerative diseases; Pharmacokinetics; Phosphodiesterase; Phosphodiesterase 4 Inhibitors - chemical synthesis; Phosphodiesterase 4 Inhibitors - pharmacology; Recombinant Proteins; Rodents; Science; Side effects; Transgenic mice; Vomiting
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep46320

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.