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dc.creatorCuadrado-Tejedor, M. (Mar)-
dc.creatorPérez-González, M. (Marta)-
dc.creatorGarcía-Muñoz, C. (Cristina)-
dc.creatorMuruzábal, D. (Damián)-
dc.creatorGarcia-Barroso, C. (C.)-
dc.creatorRabal, O. (Obdulia)-
dc.creatorSegura, V. (Víctor)-
dc.creatorSánchez-Arias, J.A. (Juan A.)-
dc.creatorOyarzabal, J. (Julen)-
dc.creatorGarcia-Osta, A. (Ana)-
dc.date.accessioned2022-05-27T13:23:16Z-
dc.date.available2022-05-27T13:23:16Z-
dc.date.issued2019-
dc.identifier.citationCuadrado-Tejedor, M. (Mar); Pérez-González, M. (Marta); García-Muñoz, C. (Cristina); et al. "Taking advantage of the selectivity of histone deacetylases and phosphodiesterase inhibitors to design better therapeutic strategies to treat alzheimer’s disease". Frontiers in Aging Neuroscience. 11 (149), 2019,es
dc.identifier.issn1663-4365-
dc.identifier.urihttps://hdl.handle.net/10171/63570-
dc.description.abstractThe discouraging results with therapies for Alzheimer’s disease (AD) in clinical trials, highlights the urgent need to adopt new approaches. Like other complex diseases, it is becoming clear that AD therapies should focus on the simultaneous modulation of several targets implicated in the disease. Recently, using reference compounds and the first-in class CM-414, we demonstrated that the simultaneous inhibition of histone deacetylases [class I histone deacetylases (HDACs) and HDAC6] and phosphodiesterase 5 (PDE5) has a synergistic therapeutic effect in AD models. To identify the best inhibitory balance of HDAC isoforms and PDEs that provides a safe and efficient therapy to combat AD, we tested the compound CM-695 in the Tg2576 mouse model of this disease. CM-695 selectively inhibits HDAC6 over class I HDAC isoforms, which largely overcomes the toxicity associated with HDAC class 1 inhibition. Furthermore, CM-695 inhibits PDE9, which is expressed strongly in the brain and has been proposed as a therapeutic target for AD. Chronic treatment of aged Tg2576 mice with CM-695 ameliorates memory impairment and diminishes brain Aβ, although its therapeutic effect was no longer apparent 4 weeks after the treatment was interrupted. An increase in the presence of 78-KDa glucose regulated protein (GRP78) and heat shock protein 70 (Hsp70) chaperones may underlie the therapeutic effect of CM-695. In summary, chronic treatment with CM-695 appears to reverse the AD phenotype in a safe and effective manner. Taking into account that AD is a multifactorial disorder, the multimodal action of these compounds and the different events they affect may open new avenues to combat AD.es_ES
dc.description.sponsorshipThis work was supported by grants from FIS projects (11/02861 and 14/01244). We also thank the Foundation for Applied Medical Research, University of Navarra (Pamplona, Spain) as well as Fundación Fuentes Dutor for financial support and the Asociación de Amigos of University of Navarra for the grant to MP-G.es_ES
dc.language.isoenges_ES
dc.publisherFrontiers Media SAes_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.subjectAlzheimer’s diseasees_ES
dc.subjectMultitarget therapyes_ES
dc.subjectHistone deacetylasees_ES
dc.subjectPhosphodiesterasees_ES
dc.subjectMemoryes_ES
dc.titleTaking advantage of the selectivity of histone deacetylases and phosphodiesterase inhibitors to design better therapeutic strategies to treat alzheimer’s diseasees_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.description.noteThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.es_ES
dc.identifier.doi10.3389/fnagi.2019.00149-
dadun.citation.number149es_ES
dadun.citation.publicationNameFrontiers in Aging Neurosciencees_ES
dadun.citation.volume11es_ES

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