Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease

The 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 disea...

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Autores: Cuadrado-Tejedor, Mar, Pérez-González, Marta, García-Muñoz, Cristina, Muruzabal, Damián, Garcia-Barroso, Carolina, Rabal, Obdulia, Segura, Victor, Sánchez-Arias, Juan Antonio, Oyarzabal, Julen, Garcia-Osta, Ana
Formato: artículo
Fecha de publicación:2019
País:España
Recursos:Universidad Camilo José Cela (UCJC)
Repositorio:Depósito Digital e-UCJC
OAI Identifier:oai:repositorio.ucjc.edu:20.500.12020/1553
Acesso em linha:https://pubmed.ncbi.nlm.nih.gov/31281249/
http://hdl.handle.net/20.500.12020/1553
https://doi.org/10.3389/fnagi.2019.00149
Access Level:acceso abierto
Palavra-chave:Biología Celular y Molecular
Ciencias Biomédicas
Alzheimer’s Disease
Multitarget Therapy
Histone Deacetylase
Phosphodiesterase
Memory
32 Ciencias Médicas
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spelling Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's DiseaseCuadrado-Tejedor, MarPérez-González, MartaGarcía-Muñoz, CristinaMuruzabal, DamiánGarcia-Barroso, CarolinaRabal, ObduliaSegura, VictorSánchez-Arias, Juan AntonioOyarzabal, JulenGarcia-Osta, AnaBiología Celular y MolecularCiencias BiomédicasAlzheimer’s DiseaseMultitarget TherapyHistone DeacetylasePhosphodiesteraseMemory32 Ciencias MédicasThe 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.Frontiers Media2019info:eu-repo/semantics/articlehttps://pubmed.ncbi.nlm.nih.gov/31281249/http://hdl.handle.net/20.500.12020/1553https://doi.org/10.3389/fnagi.2019.00149reponame:Depósito Digital e-UCJCinstname:Universidad Camilo José Cela (UCJC)Inglésinfo:eu-repo/semantics/openAccessoai:repositorio.ucjc.edu:20.500.12020/15532026-05-27T07:36:51Z
dc.title.none.fl_str_mv Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease
title Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease
spellingShingle Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease
Cuadrado-Tejedor, Mar
Biología Celular y Molecular
Ciencias Biomédicas
Alzheimer’s Disease
Multitarget Therapy
Histone Deacetylase
Phosphodiesterase
Memory
32 Ciencias Médicas
title_short Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease
title_full Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease
title_fullStr Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease
title_full_unstemmed Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease
title_sort Taking Advantage of the Selectivity of Histone Deacetylases and Phosphodiesterase Inhibitors to Design Better Therapeutic Strategies to Treat Alzheimer's Disease
dc.creator.none.fl_str_mv Cuadrado-Tejedor, Mar
Pérez-González, Marta
García-Muñoz, Cristina
Muruzabal, Damián
Garcia-Barroso, Carolina
Rabal, Obdulia
Segura, Victor
Sánchez-Arias, Juan Antonio
Oyarzabal, Julen
Garcia-Osta, Ana
author Cuadrado-Tejedor, Mar
author_facet Cuadrado-Tejedor, Mar
Pérez-González, Marta
García-Muñoz, Cristina
Muruzabal, Damián
Garcia-Barroso, Carolina
Rabal, Obdulia
Segura, Victor
Sánchez-Arias, Juan Antonio
Oyarzabal, Julen
Garcia-Osta, Ana
author_role author
author2 Pérez-González, Marta
García-Muñoz, Cristina
Muruzabal, Damián
Garcia-Barroso, Carolina
Rabal, Obdulia
Segura, Victor
Sánchez-Arias, Juan Antonio
Oyarzabal, Julen
Garcia-Osta, Ana
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Biología Celular y Molecular
Ciencias Biomédicas
Alzheimer’s Disease
Multitarget Therapy
Histone Deacetylase
Phosphodiesterase
Memory
32 Ciencias Médicas
topic Biología Celular y Molecular
Ciencias Biomédicas
Alzheimer’s Disease
Multitarget Therapy
Histone Deacetylase
Phosphodiesterase
Memory
32 Ciencias Médicas
description The 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://pubmed.ncbi.nlm.nih.gov/31281249/
http://hdl.handle.net/20.500.12020/1553
https://doi.org/10.3389/fnagi.2019.00149
url https://pubmed.ncbi.nlm.nih.gov/31281249/
http://hdl.handle.net/20.500.12020/1553
https://doi.org/10.3389/fnagi.2019.00149
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Depósito Digital e-UCJC
instname:Universidad Camilo José Cela (UCJC)
instname_str Universidad Camilo José Cela (UCJC)
reponame_str Depósito Digital e-UCJC
collection Depósito Digital e-UCJC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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