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

卷:11

Víctor Segura¹  Marta Pérez-González³  Mar Cuadrado-Tejedor³  Ana Garcia-Osta³  Damián Muruzabal⁴  Cristina García-Muñoz⁴  Carolina García-Barroso⁴  Obdulia Rabal⁵  Juan A. Sánchez-Arias⁵  Julen Oyarzabal⁵ 

[1] Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain;

[2] Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain;

[3] Health Research Institute of Navarra (IDISNA), Pamplona, Spain;

[4] Neurobiology of Alzheimer’s Disease, Neurosciences Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain;

[5] Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain;

关键词: Alzheimer’s disease;    multitarget therapy;    histone deacetylase;    phosphodiesterase;    memory;   

DOI  :  10.3389/fnagi.2019.00149

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown