Zaprinast impairs spatial memory by increasing PDE5 expression in the rat hippocampus

• Published in: Behavioural brain research 2015-02, Vol.278, p.129-136
• Main Authors: Giorgi, Mauro, Pompili, Assunta, Cardarelli, Silvia, Castelli, Valentina, Biagioni, Stefano, Sancesario, Giuseppe, Gasbarri, Antonella
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Cyclic AMP - metabolism; Cyclic GMP - metabolism; Cyclic nucleotide; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Dose-Response Relationship, Drug; Escape Reaction - drug effects; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; In Vitro Techniques; Male; Maze Learning - drug effects; Memory Disorders - chemically induced; Memory Disorders - pathology; Motor Activity - drug effects; Phosphodiesterase; Phosphodiesterase Inhibitors - toxicity; Purinones - toxicity; Rats; Rats, Wistar; Reaction Time - drug effects; Spatial memory; Striatum; Time Factors; Zaprinast
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2014.09.038

•Zaprinast inhibits both striatal and hippocampal PDE activity to a different extent.•After zaprinast treatment, the increase of cyclic nucleotides induces PDE5 expression.•PDE5 induction in the hippocampus causes a significant memory impairment. In this work, we report the effect of post-training intraperitoneal administration of zaprinast on rat memory retention in the Morris water maze task that revealed a significant memory impairment at the intermediate dose of 10mg/kg. Zaprinast is capable of inhibiting both striatal and hippocampal PDE activity but to a different extent which is probably due to the different PDE isoforms expressed in these areas. To assess the possible involvement of cyclic nucleotides in rat memory impairment, we compared the effects obtained 30min after the zaprinast injection with respect to 24h after injection by measuring both cyclic nucleotide levels and PDE activity. As expected, 30min after the zaprinast administration, we observed an increase of cyclic nucleotides, which returned to a basal level within 24h, with the exception of the hippocampal cGMP which was significantly decreased at the dose of 10mg/kg of zaprinast. This increase in the hippocampal region is the result of a cGMP-specific PDE5 induction, confirmed by sildenafil inhibition, in agreement with literature data that demonstrate transcriptional regulation of PDE5 by cAMP/cGMP intracellular levels. Our results highlight the possible rebound effect of PDE inhibitors.