Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: Indications for central and peripheral mechanisms

O.A.H. Reneerkens, K. Rutten, S. Akkerman, A. Blokland, C.L. Shaffer, F. S. Menniti, H.W.M. Steinbusch, J. Prickaerts

Research output: Contribution to journalArticleAcademicpeer-review

31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)370-379
Number of pages10
JournalNeurobiology of Learning and Memory
Volume97
Issue number4
DOIs
Publication statusPublished - May 2012

Keywords

  • Phosphodiesterase type 5
  • cGMP
  • Vardenafil
  • UK-343,664
  • Object recognition
  • Memory
  • Central and peripheral mechanisms
  • ACUTE TRYPTOPHAN DEPLETION
  • LONG-TERM POTENTIATION
  • CEREBRAL-BLOOD-FLOW
  • ONE-TRIAL TEST
  • MESSENGER-RNA
  • ERECTILE DYSFUNCTION
  • PERIRHINAL CORTEX
  • SILDENAFIL
  • CGMP
  • RAT

Cite this

@article{e152c72e9c7045ea88c02dc50dfed049,
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.",
keywords = "Phosphodiesterase type 5, cGMP, Vardenafil, UK-343,664, Object recognition, Memory, Central and peripheral mechanisms, ACUTE TRYPTOPHAN DEPLETION, LONG-TERM POTENTIATION, CEREBRAL-BLOOD-FLOW, ONE-TRIAL TEST, MESSENGER-RNA, ERECTILE DYSFUNCTION, PERIRHINAL CORTEX, SILDENAFIL, CGMP, RAT",
author = "O.A.H. Reneerkens and K. Rutten and S. Akkerman and A. Blokland and C.L. Shaffer and Menniti, {F. S.} and H.W.M. Steinbusch and J. Prickaerts",
year = "2012",
month = "5",
doi = "10.1016/j.nlm.2012.02.008",
language = "English",
volume = "97",
pages = "370--379",
journal = "Neurobiology of Learning and Memory",
issn = "1074-7427",
publisher = "Elsevier Science",
number = "4",

}

Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: Indications for central and peripheral mechanisms. / Reneerkens, O.A.H.; Rutten, K.; Akkerman, S.; Blokland, A.; Shaffer, C.L.; Menniti, F. S.; Steinbusch, H.W.M.; Prickaerts, J.

In: Neurobiology of Learning and Memory, Vol. 97, No. 4, 05.2012, p. 370-379.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: Indications for central and peripheral mechanisms

AU - Reneerkens, O.A.H.

AU - Rutten, K.

AU - Akkerman, S.

AU - Blokland, A.

AU - Shaffer, C.L.

AU - Menniti, F. S.

AU - Steinbusch, H.W.M.

AU - Prickaerts, J.

PY - 2012/5

Y1 - 2012/5

N2 - 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.

AB - 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.

KW - Phosphodiesterase type 5

KW - cGMP

KW - Vardenafil

KW - UK-343,664

KW - Object recognition

KW - Memory

KW - Central and peripheral mechanisms

KW - ACUTE TRYPTOPHAN DEPLETION

KW - LONG-TERM POTENTIATION

KW - CEREBRAL-BLOOD-FLOW

KW - ONE-TRIAL TEST

KW - MESSENGER-RNA

KW - ERECTILE DYSFUNCTION

KW - PERIRHINAL CORTEX

KW - SILDENAFIL

KW - CGMP

KW - RAT

U2 - 10.1016/j.nlm.2012.02.008

DO - 10.1016/j.nlm.2012.02.008

M3 - Article

VL - 97

SP - 370

EP - 379

JO - Neurobiology of Learning and Memory

JF - Neurobiology of Learning and Memory

SN - 1074-7427

IS - 4

ER -