title: Zaprinast impairs spatial memory by increasing PDE5 expression in the rat hippocampus.
abstract: 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 30 min after the zaprinast injection with respect to 24h after injection by measuring both cyclic nucleotide levels and PDE activity. As expected, 30 min 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.
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin", "Sapienza" University of Rome, Italy. Electronic address: mauro.giorgi@uniroma1.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giorgi
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Pompili
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin", "Sapienza" University of Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cardarelli
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Castelli
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin", "Sapienza" University of Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Biagioni
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Italy; Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sancesario
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Gasbarri
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004924:Escape Reaction / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000473:pathology*; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D011688:Purinones / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors
chemical_list: D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D000242:Cyclic AMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C011145:zaprinast; D006152:Cyclic GMP
keywords: Cyclic nucleotide; Hippocampus; Phosphodiesterase; Spatial memory; Striatum; Zaprinast