Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults

M A Van Duinen, A Sambeth, P R A Heckman, S Smit, M Tsai, G Lahu, T Uz, A Blokland, J Prickaerts

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double-blind, randomized, placebo-controlled, 4-way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event-related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 μg roflumilast. Specifically, immediate recall performance on the VLT increased 2-3 words, accompanied by an enhanced P600 peak during word presentation at the third learning trial. No side effects typical for PDE4-Is were reported for the lowest and effective dose of 100 μg roflumilast. The current proof-of-concept study shows for the first time the potential of low-dose roflumilast administration as a memory enhancer in humans.

Original languageEnglish
Pages (from-to)31-38
Number of pages8
JournalNeuropharmacology
Volume131
DOIs
Publication statusPublished - 15 Mar 2018

Keywords

  • PHOSPHODIESTERASE-4 INHIBITOR
  • PDE4
  • Memory
  • ALZHEIMERS-DISEASE
  • IMPROVES MEMORY
  • Roflumilast
  • cAMP
  • COGNITION ENHANCEMENT
  • ROLIPRAM
  • N-OXIDE
  • HIPPOCAMPUS
  • OBSTRUCTIVE PULMONARY-DISEASE
  • TRYPTOPHAN DEPLETION
  • Verbal learning task
  • LONG-TERM POTENTIATION
  • Cyclopropanes/pharmacology
  • Humans
  • Evoked Potentials/drug effects
  • Male
  • Electroencephalography
  • Healthy Volunteers
  • Dose-Response Relationship, Drug
  • Young Adult
  • Adult
  • Female
  • Surveys and Questionnaires
  • Mental Recall/drug effects
  • Double-Blind Method
  • Protein Kinases/blood
  • Benzamides/pharmacology
  • Aminopyridines/pharmacology
  • Cross-Over Studies
  • Adolescent
  • Verbal Learning/drug effects
  • Phosphodiesterase 4 Inhibitors/pharmacology

Cite this

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title = "Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults",
abstract = "The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double-blind, randomized, placebo-controlled, 4-way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event-related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 μg roflumilast. Specifically, immediate recall performance on the VLT increased 2-3 words, accompanied by an enhanced P600 peak during word presentation at the third learning trial. No side effects typical for PDE4-Is were reported for the lowest and effective dose of 100 μg roflumilast. The current proof-of-concept study shows for the first time the potential of low-dose roflumilast administration as a memory enhancer in humans.",
keywords = "PHOSPHODIESTERASE-4 INHIBITOR, PDE4, Memory, ALZHEIMERS-DISEASE, IMPROVES MEMORY, Roflumilast, cAMP, COGNITION ENHANCEMENT, ROLIPRAM, N-OXIDE, HIPPOCAMPUS, OBSTRUCTIVE PULMONARY-DISEASE, TRYPTOPHAN DEPLETION, Verbal learning task, LONG-TERM POTENTIATION, Cyclopropanes/pharmacology, Humans, Evoked Potentials/drug effects, Male, Electroencephalography, Healthy Volunteers, Dose-Response Relationship, Drug, Young Adult, Adult, Female, Surveys and Questionnaires, Mental Recall/drug effects, Double-Blind Method, Protein Kinases/blood, Benzamides/pharmacology, Aminopyridines/pharmacology, Cross-Over Studies, Adolescent, Verbal Learning/drug effects, Phosphodiesterase 4 Inhibitors/pharmacology",
author = "{Van Duinen}, {M A} and A Sambeth and Heckman, {P R A} and S Smit and M Tsai and G Lahu and T Uz and A Blokland and J Prickaerts",
note = "Copyright {\circledC} 2017 Elsevier Ltd. All rights reserved.",
year = "2018",
month = "3",
day = "15",
doi = "10.1016/j.neuropharm.2017.12.019",
language = "English",
volume = "131",
pages = "31--38",
journal = "Neuropharmacology",
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Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults. / Van Duinen, M A; Sambeth, A; Heckman, P R A; Smit, S; Tsai, M; Lahu, G; Uz, T; Blokland, A; Prickaerts, J.

In: Neuropharmacology, Vol. 131, 15.03.2018, p. 31-38.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults

AU - Van Duinen, M A

AU - Sambeth, A

AU - Heckman, P R A

AU - Smit, S

AU - Tsai, M

AU - Lahu, G

AU - Uz, T

AU - Blokland, A

AU - Prickaerts, J

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

PY - 2018/3/15

Y1 - 2018/3/15

N2 - The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double-blind, randomized, placebo-controlled, 4-way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event-related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 μg roflumilast. Specifically, immediate recall performance on the VLT increased 2-3 words, accompanied by an enhanced P600 peak during word presentation at the third learning trial. No side effects typical for PDE4-Is were reported for the lowest and effective dose of 100 μg roflumilast. The current proof-of-concept study shows for the first time the potential of low-dose roflumilast administration as a memory enhancer in humans.

AB - The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double-blind, randomized, placebo-controlled, 4-way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event-related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 μg roflumilast. Specifically, immediate recall performance on the VLT increased 2-3 words, accompanied by an enhanced P600 peak during word presentation at the third learning trial. No side effects typical for PDE4-Is were reported for the lowest and effective dose of 100 μg roflumilast. The current proof-of-concept study shows for the first time the potential of low-dose roflumilast administration as a memory enhancer in humans.

KW - PHOSPHODIESTERASE-4 INHIBITOR

KW - PDE4

KW - Memory

KW - ALZHEIMERS-DISEASE

KW - IMPROVES MEMORY

KW - Roflumilast

KW - cAMP

KW - COGNITION ENHANCEMENT

KW - ROLIPRAM

KW - N-OXIDE

KW - HIPPOCAMPUS

KW - OBSTRUCTIVE PULMONARY-DISEASE

KW - TRYPTOPHAN DEPLETION

KW - Verbal learning task

KW - LONG-TERM POTENTIATION

KW - Cyclopropanes/pharmacology

KW - Humans

KW - Evoked Potentials/drug effects

KW - Male

KW - Electroencephalography

KW - Healthy Volunteers

KW - Dose-Response Relationship, Drug

KW - Young Adult

KW - Adult

KW - Female

KW - Surveys and Questionnaires

KW - Mental Recall/drug effects

KW - Double-Blind Method

KW - Protein Kinases/blood

KW - Benzamides/pharmacology

KW - Aminopyridines/pharmacology

KW - Cross-Over Studies

KW - Adolescent

KW - Verbal Learning/drug effects

KW - Phosphodiesterase 4 Inhibitors/pharmacology

U2 - 10.1016/j.neuropharm.2017.12.019

DO - 10.1016/j.neuropharm.2017.12.019

M3 - Article

C2 - 29241652

VL - 131

SP - 31

EP - 38

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -