PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis

44p.-7 fig.-1 tab.

Detalles Bibliográficos
Autores: Mestre, Leyre, Redondo, Miriam, Carrillo-Salinas, F. J., Morales-García, José A., Alonso-Gil, Sandra, Pérez Castillo, Ana, Gil, Carmen, Martínez Gil, Ana, Guaza, Carmen
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2015
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/122586
Acceso en línea:http://hdl.handle.net/10261/122586
Access Level:acceso abierto
Palabra clave:Phosphodiesterase-7 Inhibitors
Multiple sclerosis
TMEV model
Neuroinflammation
Neuroprotection
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spelling PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosisMestre, LeyreRedondo, MiriamCarrillo-Salinas, F. J.Morales-García, José A.Alonso-Gil, SandraPérez Castillo, AnaGil, CarmenMartínez Gil, AnaGuaza, CarmenPhosphodiesterase-7 InhibitorsMultiple sclerosisTMEV modelNeuroinflammationNeuroprotection44p.-7 fig.-1 tab.[Background and Purpose]: cyclic Adenosine monophosphate (cAMP) plays an important role in the transduction of signaling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP specific phosphodiesterases (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, named TC3.6 in a model of primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS. [Experimental Approach]: TMEV-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 analyzed the effect of PDE7 inhibitors in the EAE model of MS, here the TMEV-IDD model is used to test the efficacy in a progressive variant of MS. Mice were subjected to two protocols of TC3.6 administration: on the presymptomatic phase and once the disease was established. [Key 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 proinflammatory mediators such as COX-2 and the cytokines, IL-1β, TNFα, IFNγ and IL-6 in the spinal cord of TMEV-infected mice was also observed after TC3.6 administration. [Conclusion]: These findings support the interest of PDE7 inhibitors, and specifically TC3.6, as a novel class of agents with therapeutic potential for PPMS raising the possibility to develop regulatory preclinical studies to reach the clinic.The authors gratefully acknowledge the financial support of Ministry of Science and Innovation (MICINN, projects no. SAF2010-16365 and SAF2012-33600), Instituto de Salud Carlos III (project no. RD07/0060/0015, and RD07/0060/0010 RETICS Program) and Fundación Española para la Ciencia y la Tecnología (FECYT), project no. FCT-09-INC-0367.Peer reviewedJohn Wiley & SonsMinisterio de Ciencia e Innovación (España)Instituto de Salud Carlos IIIFundación Española para la Ciencia y la TecnologíaConsejo Superior de Investigaciones Científicas (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2015info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/122586reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/ 10.1111/bph.13192Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1225862026-05-22T06:33:51Z
dc.title.none.fl_str_mv PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis
title PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis
spellingShingle PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis
Mestre, Leyre
Phosphodiesterase-7 Inhibitors
Multiple sclerosis
TMEV model
Neuroinflammation
Neuroprotection
title_short PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis
title_full PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis
title_fullStr PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis
title_full_unstemmed PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis
title_sort PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis
dc.creator.none.fl_str_mv Mestre, Leyre
Redondo, Miriam
Carrillo-Salinas, F. J.
Morales-García, José A.
Alonso-Gil, Sandra
Pérez Castillo, Ana
Gil, Carmen
Martínez Gil, Ana
Guaza, Carmen
author Mestre, Leyre
author_facet Mestre, Leyre
Redondo, Miriam
Carrillo-Salinas, F. J.
Morales-García, José A.
Alonso-Gil, Sandra
Pérez Castillo, Ana
Gil, Carmen
Martínez Gil, Ana
Guaza, Carmen
author_role author
author2 Redondo, Miriam
Carrillo-Salinas, F. J.
Morales-García, José A.
Alonso-Gil, Sandra
Pérez Castillo, Ana
Gil, Carmen
Martínez Gil, Ana
Guaza, Carmen
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Instituto de Salud Carlos III
Fundación Española para la Ciencia y la Tecnología
Consejo Superior de Investigaciones Científicas (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Phosphodiesterase-7 Inhibitors
Multiple sclerosis
TMEV model
Neuroinflammation
Neuroprotection
topic Phosphodiesterase-7 Inhibitors
Multiple sclerosis
TMEV model
Neuroinflammation
Neuroprotection
description 44p.-7 fig.-1 tab.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/122586
url http://hdl.handle.net/10261/122586
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/ 10.1111/bph.13192
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv John Wiley & Sons
publisher.none.fl_str_mv John Wiley & Sons
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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