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

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

  • Sci Rep. 2017 Mar 3;7:43545. doi: 10.1038/srep43545.
Eva María Medina-Rodríguez 1,  Ana Bribián 1 2,  Amanda Boyd 3,  Valle Palomo 4,  Jesús Pastor 5,  Alfonso Lagares 6,  Carmen Gil 4,  Ana Martínez 4,  Anna Williams 3,  Fernando de Castro 1 2
Affiliations

Affiliations

  • 1 Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca la Peraleda s/n, E- 45071, Toledo, Spain.
  • 2 Instituto Cajal-CSIC, Avda. Dr. Arce 37, E-28002, Madrid, Spain.
  • 3 MRC-Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, EH164UU, Edinburgh, UK.
  • 4 Centro de Investigaciones Biológicas, CIB-CSIC, Calle Ramiro de Maeztu 9, E-28040, Madrid, Spain.
  • 5 Servicio de Neurofisiología Clínica, Hospital La Princesa, Calle Diego de León 62, E-28006,Madrid, Spain.
  • 6 Servicio de Neurocirugía, Hospital 12 de Octubre, Avda. de Córdoba s/n, E-28041,Madrid, Spain.
PMID: 28256546 DOI: 10.1038/srep43545
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.

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