Phosphodiesterase 4D inhibition boosts remyelination in multiple sclerosis

Abstract

Event Abstract Back to Event Phosphodiesterase 4D inhibition boosts remyelination in multiple sclerosis Melissa Schepers1, 2, Dean Paes1, 2, Assia Tiane1, 2, Evelien Houben1, Olga Bruno3, Chiara Brullo3, Niels Hellings1, Jos Prickaerts2 and Tim Vanmierlo1, 2* 1 University of Hasselt, Belgium 2 School for Mental Health and Neuroscience, Maastricht University, Netherlands 3 Sezione di Chimica del Farmaco, Dipartimento di Farmacia, University of Genova, Italy Progressive multiple sclerosis (pMS) is a chronic demyelinating disorder of the central nervous system (CNS). pMS is featured by failing remyelination processes due to the inability of oligodendrocyte precursor cells (OPC) to differentiate into myelin-forming oligodendrocytes. Phosphodiesterase 4 (PDE4) is a family of enzymes that hydrolyze and inactivate cyclic adenosine monophosphate (cAMP), a second messenger crucially involved in OPC differentiation. We recently found that the aspecific PDE4 inhibitor roflumilast induces in vitro and in vivo remyelination. Yet, the use of aspecific PDE4 inhibitors coincides with emetic side-effects at the repair-inducing dose. Therefore, we hypothesize that selective inhibition of PDE4D promotes remyelination at non-emetic doses. The PDE4D inhibitor Gebr32a (5µM) accelerated in vitro OPC differentiation and showed accelerated ex vivo remyelination in lysolecithin-demyelinated mouse brain slices. Next, 10-week-old male C57bl6 mice were subjected to demyelination in the cuprizone model (6 weeks, 0.3% cuprizone w/w). Upon withdrawal of the cuprizone, mice were treated with either with Gebr32a (7days: 0.1mg/kg or 0.3mg/kg) or vehicle. Compared to vehicle, Gebr32a 0.3mg/kg treatment displayed an enhanced remyelination by yielding an increased expression of myelin basic protein (MBP) in the corpus callosum and dendate gyrus while improving memory performance in the object location task (OLT) . The improved remyelination and spatial memory performance following Gebr32a treatment at a non-emetic dose, prompt us to conclude that PDE4D inhibition boosts the endogenous repair mechanisms in cuprizone fed mice and thereby improves cognitive performances. Keywords: Phosphodiesterase (PDE), Multiple scleorsis (MS), Cognition, oligodendrocyte precursor cell (OPC), CNS repair Conference: 13th National Congress of the Belgian Society for Neuroscience , Brussels, Belgium, 24 May - 24 May, 2019. Presentation Type: Poster presentation Topic: Cellular/Molecular Neuroscience Citation: Schepers M, Paes D, Tiane A, Houben E, Bruno O, Brullo C, Hellings N, Prickaerts J and Vanmierlo T (2019). Phosphodiesterase 4D inhibition boosts remyelination in multiple sclerosis. Front. Neurosci. Conference Abstract: 13th National Congress of the Belgian Society for Neuroscience . doi: 10.3389/conf.fnins.2019.96.00034 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 25 Apr 2019; Published Online: 27 Sep 2019. * Correspondence: Mx. Tim Vanmierlo, University of Hasselt, Hasselt, Belgium, tim.vanmierlo@uhasselt.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Melissa Schepers Dean Paes Assia Tiane Evelien Houben Olga Bruno Chiara Brullo Niels Hellings Jos Prickaerts Tim Vanmierlo Google Melissa Schepers Dean Paes Assia Tiane Evelien Houben Olga Bruno Chiara Brullo Niels Hellings Jos Prickaerts Tim Vanmierlo Google Scholar Melissa Schepers Dean Paes Assia Tiane Evelien Houben Olga Bruno Chiara Brullo Niels Hellings Jos Prickaerts Tim Vanmierlo PubMed Melissa Schepers Dean Paes Assia Tiane Evelien Houben Olga Bruno Chiara Brullo Niels Hellings Jos Prickaerts Tim Vanmierlo Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.