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

  • Sci Rep. 2017 Apr 12;7:46320. doi: 10.1038/srep46320.
Roberta Ricciarelli  1 ,  Chiara Brullo  2 ,  Jos Prickaerts  3 ,  Ottavio Arancio  4 ,  Carla Villa  2 ,  Claudia Rebosio  5 ,  Elisa Calcagno  1 ,  Matilde Balbi  5 ,  Britt T J van Hagen  3 ,  Elentina K Argyrousi  3  4 ,  Hong Zhang  4 ,  Maria Adelaide Pronzato  1 ,  Olga Bruno  2 ,  Ernesto Fedele  5  6
Affiliations
  • 1. 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.
  • 2. Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
  • 3. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
  • 4. Department of Pathology &Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
  • 5. Department of Pharmacy, Section of Pharmacology and Toxicology, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano, 4, 16148 Genoa, Italy.
  • 6. Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy.
PMID: 28402318 DOI: 10.1038/srep46320
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.

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