title: PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis.
abstract: OBJECTIVE
  cAMP plays an important role in the transduction of signalling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP-specific PDEs such as PDE7 may affect the pathological processes of neuroinflammatory diseases like multiple sclerosis (MS). In the present study, we evaluated the therapeutic potential of the selective PDE7 inhibitor, TC3.6, in a model of primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS.
  
  
  METHODS
  Theiler's murine encephalomyelitis virus-induced demyelinated disease (TMEV-IDD) is one of the models used to validate the therapeutic efficacy of new drugs in MS. As recent studies have analysed the effect of PDE7 inhibitors in the EAE model of MS, here the TMEV-IDD model was used to test their efficacy in a progressive variant of MS. Mice were subjected to two protocols of TC3.6 administration: on the pre-symptomatic phase and once the disease was established.
  
  
  RESULTS
  Treatment with TC3.6 ameliorated the disease course and improved motor deficits of infected mice. This was associated with down-regulation of microglial activation and reduced cellular infiltrates. Decreased expression of pro-inflammatory mediators such as COX-2 and the cytokines, IL-1β, TNF-α, IFN-γ and IL-6 in the spinal cord of TMEV-infected mice was also observed after TC3.6 administration.
  
  
  CONCLUSIONS
  These findings support the importance of PDE7 inhibitors, and specifically TC3.6, as a novel class of agents with therapeutic potential for PPMS. Preclinical studies are needed to determine whether their effects translate into durable clinical benefits.
authors.affiliation: Departamento de Neurobiología Funcional y de Sistemas, Instituto Cajal-CSIC, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Mestre
authors.affiliation: Departamento de Química Médica I, Instituto de Química Médica-CSIC, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Redondo
authors.affiliation: Departamento de Neurobiología Funcional y de Sistemas, Instituto Cajal-CSIC, Madrid, Spain.
authors.forename: F J
authors.initials: FJ
authors.lastname: Carrillo-Salinas
authors.affiliation: Departamento de Modelos Experimentales de Enfermedades Humanas, Instituto de Investigaciones Biomédicas, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Morales-García
authors.affiliation: Departamento de Modelos Experimentales de Enfermedades Humanas, Instituto de Investigaciones Biomédicas, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Alonso-Gil
authors.affiliation: Departamento de Modelos Experimentales de Enfermedades Humanas, Instituto de Investigaciones Biomédicas, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pérez-Castillo
authors.affiliation: Departamento Biología Físico-Química, Centro de Investigaciones Biológicas-CSIC, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Gil
authors.affiliation: Departamento Biología Físico-Química, Centro de Investigaciones Biológicas-CSIC, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Departamento de Neurobiología Funcional y de Sistemas, Instituto Cajal-CSIC, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Guaza
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016716:PC12 Cells; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats
chemical_list: D010726:Phosphodiesterase Inhibitors; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7