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Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis.

TitlePromoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis.
Publication TypeJournal Article
Year of Publication2017
AuthorsMedina-Rodríguez EMaría, Bribián A, Boyd A, Palomo V, Pastor J, Lagares A, Gil C, Martínez A, Williams AC, de Castro F
JournalSci Rep
Volume7
Pagination43545
Date Published2017 Mar 03
ISSN2045-2322
Abstract

Multiple Sclerosis (MS) is a neurodegenerative disease where immune-driven demyelination occurs with inefficient remyelination, but therapies are limited, especially those to enhance repair. Here, we show that the dual phosphodiesterase (PDE)7- glycogen synthase kinase (GSK)3 inhibitor, VP3.15, a heterocyclic small molecule with good pharmacokinetic properties and safety profile, improves in vivo remyelination in mouse and increases both adult mouse and adult human oligodendrocyte progenitor cell (OPC) differentiation, in addition to its immune regulatory action. The dual inhibition is synergistic, as increasing intracellular levels of cAMP by cyclic nucleotide PDE inhibition both suppresses the immune response and increases remyelination, and in addition, inhibition of GSK3 limits experimental autoimmune encephalomyelitis in mice. This combination of an advantageous effect on the immune response and an enhancement of repair, plus demonstration of its activity on adult human OPCs, leads us to propose dual PDE7-GSK3 inhibition, and specifically VP3.15, as a neuroprotective and neuroreparative disease-modifying treatment for MS.

DOI10.1038/srep43545
Alternate JournalSci Rep
PubMed ID28256546
PubMed Central IDPMC5335257
Publication institute
CRM