title: Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis.
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.
authors.affiliation: Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca la Peraleda s/n, E- 45071, Toledo, Spain.
authors.forename: Eva María
authors.initials: EM
authors.lastname: Medina-Rodríguez
authors.affiliation: Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca la Peraleda s/n, E- 45071, Toledo, Spain.|Instituto Cajal-CSIC, Avda. Dr. Arce 37, E-28002, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Bribián
authors.affiliation: MRC-Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, EH164UU, Edinburgh, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Boyd
authors.affiliation: Centro de Investigaciones Biológicas, CIB-CSIC, Calle Ramiro de Maeztu 9, E-28040, Madrid, Spain.
authors.forename: Valle
authors.initials: V
authors.lastname: Palomo
authors.affiliation: Servicio de Neurofisiología Clínica, Hospital La Princesa, Calle Diego de León 62, E-28006,Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Pastor
authors.affiliation: Servicio de Neurocirugía, Hospital 12 de Octubre, Avda. de Córdoba s/n, E-28041,Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lagares
authors.affiliation: Centro de Investigaciones Biológicas, CIB-CSIC, Calle Ramiro de Maeztu 9, E-28040, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.affiliation: Centro de Investigaciones Biológicas, CIB-CSIC, Calle Ramiro de Maeztu 9, E-28040, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
authors.affiliation: MRC-Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, EH164UU, Edinburgh, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Williams
authors.affiliation: Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos, Finca la Peraleda s/n, E- 45071, Toledo, Spain.|Instituto Cajal-CSIC, Avda. Dr. Arce 37, E-28002, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: de Castro
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000074586:Remyelination / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7