Back to Search Start Over

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

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
Source :
Scientific Reports. 4/14/2017, p46320. 1p.
Publication Year :
2017

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20452322
Database :
Academic Search Index
Journal :
Scientific Reports
Publication Type :
Academic Journal
Accession number :
122632919
Full Text :
https://doi.org/10.1038/srep46320