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Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis.

Authors :
Schepers, Melissa
Paes, Dean
Tiane, Assia
Rombaut, Ben
Piccart, Elisabeth
van Veggel, Lieve
Gervois, Pascal
Wolfs, Esther
Lambrichts, Ivo
Brullo, Chiara
Bruno, Olga
Fedele, Ernesto
Ricciarelli, Roberta
Ffrench-Constant, Charles
Bechler, Marie E.
van Schaik, Pauline
Baron, Wia
Lefevere, Evy
Wasner, Kobi
Grünewald, Anne
Verfaillie, Catherine
Baeten, Paulien
Broux, Bieke
Wieringa, Paul
Hellings, Niels
Prickaerts, Jos
Vanmierlo, Tim
Schepers, Melissa
Paes, Dean
Tiane, Assia
Rombaut, Ben
Piccart, Elisabeth
van Veggel, Lieve
Gervois, Pascal
Wolfs, Esther
Lambrichts, Ivo
Brullo, Chiara
Bruno, Olga
Fedele, Ernesto
Ricciarelli, Roberta
Ffrench-Constant, Charles
Bechler, Marie E.
van Schaik, Pauline
Baron, Wia
Lefevere, Evy
Wasner, Kobi
Grünewald, Anne
Verfaillie, Catherine
Baeten, Paulien
Broux, Bieke
Wieringa, Paul
Hellings, Niels
Prickaerts, Jos
Vanmierlo, Tim
Publication Year :
2023

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using th

Details

Database :
OAIster
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1374545798
Document Type :
Electronic Resource