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Can PDE Inhibition Improve Cognition? : Translational Insights Can PDE inhibition improve cognition? : Translational insights Citation for published version (APA): Reneerkens, O. A. H. (2013). Can PDE inhibition improve cognition? : Translational insights. Maastricht University. https://doi.org/10.26481/dis.20130418or Document status and date: Published: 01/01/2013 DOI: 10.26481/dis.20130418or Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 26 Sep. 2021 Can PDE inhibition improve cognition? Translational insights Copyright © Olga A. H. Reneerkens, Maastricht, 2013 ISBN: 978 94 91602 08 5 Can PDE inhibition improve cognition? Translational insights All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without permission in writing from the author, or, when appropriate, from the publishers of the publications. Cover illustration by Hans Klaasse Typesetting and layout by Olga A. H. Reneerkens Printed by Print Service Ede Financial support for the publication of this dissertation was kindly provided by the Van Leersumfonds (Koninklijke Nederlandse Akademie van Wetenschappen) and Internationale Stichting Alzheimer Onderzoek Additional financial support for this publication was granted by Alzheimer Nederland (Amersfoort) Can PDE inhibition improve cognition? Translational insights Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, Prof. Dr. L.L.G. Soete, volgens het besluit van het College van Decanen, in het openbaar te verdedigen op donderdag 18 april 2013 om 14.00 uur door Olga Antonia Hendrika Reneerkens Geboren op 29 juni 1982 te Maastricht Promotor: Prof. Dr. H.W.M. Steinbusch Copromotor: Dr. J. Prickaerts Beoordelingscommissie: Prof. Dr. F. Verhey (voorzitter) Dr. M. Meeter (Vrije Universiteit Amsterdam, Nederland) Prof. Dr. J.G. Ramaekers Dr. T. Steckler (Janssen Pharmaceutica, Johnson & Johnson, België) Contents CHAPTER 1 General introduction 7 CHAPTER 2 Selective phosphodiesterase inhibitors: a promising target 15 for cognition enhancement CHAPTER 3 Phosphodiesterase type 5 (PDE5) inhibition improves 57 object recognition memory: Indications for central and peripheral mechanisms CHAPTER 4 Inhibition of phoshodiesterase type 2 or type 10 reverses 79 object memory deficits induced by scopolamine or MK-801 CHAPTER 5 The PDE5 inhibitor vardenafil does not affect auditory 97 sensory gating in rats and humans CHAPTER 6 PDE2 and PDE10, but not PDE5, inhibition affect basic 115 auditory information processing in rats: a pilot study CHAPTER 7 The effects of the PDE5 inhibitor vardenafil on cognitive 127 performance in healthy adults: a behavioural-EEG study CHAPTER 8 General discussion 147 Summary 157 Samenvatting 161 Dankwoord 165 Curriculum Vitae 171 Publications 175 Abbreviations 179 CHAPTER 1 General introduction CHAPTER 1 GENERAL INTRODUCTION Cognitive impairment is one of the major complaints people suffering from neurodegenerative and psychiatric disorders such as Alzheimer’s disease or other types of dementia and schizophrenia have to face (Keller 2006; O'Carroll 2000). This impairment has a large, negative impact on the quality of the daily life of these patients and their family and friends. In the US, the prevalence of Alzheimer’s disease among people of 71 years or older is 9.7%, but the total of people suffering from dementia is as high as 13.9%, which leads us to a number of approximately 3.4 million individuals (Plassman et al. 2007). The Alzheimer’s association (2009) estimated the cost implications related to Alzheimer’s disease and other dementias at 148 billion dollars in the United States (US) alone and did not include 94 billion dollars of unpaid services of an estimated 10 million caregivers. In Europe, the total prevalence of dementia in the population aged 65 and older was 4.9 million in 2004 and the total costs were estimated at 55 billion euros (Andlin-Sobocki et al. 2005). There are several drugs which have shown to be effective in improving symptoms of mild-to-moderate Alzheimer’s disease, such as donepezil and rivastigmine, but for more severe Alzheimer’s and other types of dementia, the options are very limited or non-existent so far (Burns 2003). The lifetime prevalence of schizophrenia is about 4 per 1,000 (McGrath et al. 2008; Saha et al. 2005) and the total societal costs in the United Kingdom (UK) in 2004/2005 were estimated 6.7 billion pounds (Mangalore and Knapp 2007) and 62.7 billion dollars in the US in 2002 (McEvoy 2007). In Europe the costs were estimated at 35 billion euros in 2004, however, it was noted by the authors that indirect costs were not included in this estimation, but were expected to make up a substantial amount of the total costs (Andlin-Sobocki et al. 2005). Despite the increased attention for cognitive deficits in schizophrenia and the wide range of pharmalogical targets, the results are generally disappointing (Goff et al. 2011). Because of the high social as well as economical costs of cognitive impairments, it is of utmost importance to continue the search for cognitive enhancers. Recently, phosphodiesterases (PDEs) gained increased attention as a target for cognition enhancement (for review see e.g. Blokland et al. 2006; Menniti et al. 2006). PDEs are enzymes that degrade the second messenger molecules cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In total, there are eleven classes of PDEs identified based on several criteria including molecular properties, substrate specifity, and regulation (Bender and Beavo 2006). PDEs are expressed throughout the body and in the central nervous system (CNS) (Lakics et al. 2010). One fundamental distinction between the PDE classes is made on the basis of the difference in affinity for the two distinct cyclic nucleotides. A differentiation is possible between cAMP-specific enzymes (PDE4, 7, and 8), cGMP-specific enzymes (PDE5, 6, and 9), and the so-called dual- substrate PDEs, which have affinity for both cyclic nucleotides (PDE1, 2, 3, 10, and 11) (Bender and Beavo 2006). The second messengers cAMP and cGMP play an important role in intracellular signaling and in processes such as neuroplasticity including long-term potentiation (LTP) (Chien et al. 2003; Frey et al. 1993; Son et al. 1998) that form the neurophysiological origin of learning and memory (Bliss and Collingridge 1993). It has indeed been demonstrated that central administration of analogues of these second messengers can improve memory function in animals (Bernabeu et al. 1996; Matsumoto et al. 2006; Prickaerts et al. 2002). 9 GENERAL INTRODUCTION Furthermore, it has been found that specific PDE inhibitors (PDE-Is) facilitate for example LTP (e.g. Boess et al. 2004) and increase neuronal excitability (e.g. Threlfell et al. 2009). Consequently, the inhibition of PDEs could be a tool to modulate second messenger signaling and subsequently influence pathways involved in learning and memory. AIM AND OUTLINE OF THIS THESIS In this thesis we investigated whether PDE inhibition can improve cognition. This was done by using a translational approach in which we studied the effects of PDE inhibition on memory function and sensory gating in rats as well as on cognition and sensory gating in humans. First, we provide an overview of the literature on the effects of PDE-Is on cognition across species (Chapter 2). In this chapter we also discuss the possible underlying mechanisms of these effects, such as blood flow, emotional arousal and LTP. Next, we start the description of our behavioural studies with Chapter 3 in which we examined the effects of PDE5 inhibition on memory function in rats. We used two different phosphodiesterase type 5 inhibitors (PDE5-Is): vardenafil, which is assumed to cross the blood-brain barrier (BBB), and UK-343,664 as a negative control as it is assumed not to cross the BBB. We examined the efficacy of these compounds in three variants of the object recognition task (ORT): a 1 h delay interval in which memory was disrupted by either the muscarinic antagonist scopolamine or the N-methyl-D-aspartate (NMDA) receptor agonist MK-801, and a 24 h delay interval where memory degrades over time. In addition, we investigated whether vardenafil and UK-343,664 were indeed able to penetrate the BBB or not, respectively.
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