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
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Received:
25 Apr 2019;
Published Online:
27 Sep 2019.
*
Correspondence:
Mx. Tim Vanmierlo, University of Hasselt, Hasselt, Belgium, tim.vanmierlo@uhasselt.be