Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer’s disease

Clinical Epigenetics

A. Garcia-Osta³  J. Oyarzabal⁴  G. Perea²  V. Segura¹  M. Pascual-Lucas³  R. Franco⁵  A. Ugarte⁴  O. Rabal⁴  S. Mederos²  J. Sanzhez-Arias⁴  C. Garcia-Barroso³  M. Cuadrado-Tejedor⁶ 

[1] Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain;Cajal Institute, CSIC, Madrid, Spain;Neurobiology of Alzheimer’s Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, Pamplona, 31008, Spain;Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, Pamplona, 31008, Spain;Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain;Anatomy Department, School of Medicine, University of Navarra, Pamplona, Spain

关键词: Gene transcription;    Tau;    Amyloid;    Memory;    Alzheimer’s disease (AD);    Phosphodiesterase (PDE);    Histone deacetylase (HDAC);   

Others  :  1230680
DOI  :  10.1186/s13148-015-0142-9

 received in 2015-05-05, accepted in 2015-09-28,  发布年份 2015

【 摘 要 】

Background

Given the implication of histone acetylation in memory processes, histone deacetylase inhibitors (HDACIs) have been postulated as potential modulators of cognitive impairment in Alzheimer’s disease (AD). However, dose-dependent side effects have been described in patients with the currently available broad-spectrum HDACIs, explaining why their therapeutic potential has not been realized for chronic diseases. Here, by simultaneously targeting two independent enzyme activities, histone deacetylase (HDAC) and phosphodiesterase-5 (PDE5), we propose a novel mode of inhibitory action that might increase the therapeutic specificity of HDACIs.

Results

The combination of vorinostat, a pan-HDACI, and tadalafil, a PDE5 inhibitor, rescued the long-term potentiation impaired in slices from APP/PS1 mice. When administered in vivo, the combination of these drugs alleviated the cognitive deficits in AD mice, as well as the amyloid and tau pathology, and it reversed the reduced dendritic spine density on hippocampal neurons. Significantly, the combination of vorinostat and tadalafil was more effective than each drug alone, both against the symptoms and in terms of disease modification, and importantly, these effects persisted after a 4-week washout period.

Conclusions

The results highlight the pharmacological potential of a combination of molecules that inhibit HDAC and PDE5 as a therapeutic approach for AD treatment.

【 授权许可】

   
2015 Cuadrado-Tejedor et al.

【 图 表 】

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