title: Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: indications for central and peripheral mechanisms.
abstract: A promising target for memory improvement is phosphodiesterase type 5 (PDE5), which selectively hydrolyzes cyclic guanosine monophosphate (cGMP). In rodents, PDE5 inhibitors (PDE5-Is) have been shown to improve memory performance in many behavioral paradigms. However, it is questioned whether the positive effects in animal studies result from PDE5 inhibition in the central nervous system or the periphery. Therefore, we studied the effects of PDE5 inhibition on memory and determined whether compound penetration of the blood-brain barrier (BBB) is required for this activity. Two selective PDE5-Is, vardenafil and UK-343,664, were tested in the object recognition task (ORT) in both a MK-801- and scopolamine-induced memory deficit model, and a time-delay model without pharmacological intervention. Compounds were dosed 30 min before the learning trial of the task. To determine if the PDE5-Is crossed the BBB, their concentrations were determined in plasma and brain tissue collected 30 min after oral administration. Vardenafil improved object recognition memory in all three variants of the ORT. UK-343,664 was ineffective at either preventing MK-801-induced memory disruption or time-dependent memory decay. However, UK-343,664 attenuated the memory impairment of scopolamine. Vardenafil crossed the BBB whereas UK-343,664 did not. Further, co-administration of UK-343,664 and scopolamine did not alter the brain partitioning of either molecule. This suggests that the positive effect of UK-343,664 on scopolamine-induced memory decay might arise from peripheral PDE5 inhibition. The results herein suggest that there may be multiple mechanisms that mediate the efficacy of PDE5 inhibition to improve memory performance in tasks such as the ORT and that these involve PDE5 located both within and outside of the brain. To further elucidate the underlying mechanisms, the cellular and subcellular localization of PDE5 needs to be determined.
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, The Netherlands.
authors.forename: Olga A H
authors.initials: OA
authors.lastname: Reneerkens
authors.forename: Kris
authors.initials: K
authors.lastname: Rutten
authors.forename: Sven
authors.initials: S
authors.lastname: Akkerman
authors.forename: Arjan
authors.initials: A
authors.lastname: Blokland
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Shaffer
authors.forename: Frank S
authors.initials: FS
authors.lastname: Menniti
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000187:drug effects / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics / Q000494:pharmacology; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D012601:Scopolamine / Q000493:pharmacokinetics / Q000494:pharmacology; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology; D014227:Triazines / Q000493:pharmacokinetics / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
chemical_list: D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011744:Pyrimidinones; D013450:Sulfones; D014227:Triazines; C450961:UK 343,664; D000069058:Vardenafil Dihydrochloride; D016291:Dizocilpine Maleate; D012601:Scopolamine; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5