Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/149500
Title: 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.
Author: Cuadrado-Tejedor, M.
Garcia-Barroso, C.
Sanzhez-Arias, J.
Mederos, S.
Rabal, O.
Ugarte, A.
Franco Fernández, Rafael
Pascual-Lucas, M.
Segura, Victor
Perea, G.
Oyarzabal, Julen
Garcia-Osta, A.
Keywords: Malaltia d'Alzheimer
Epigenètica
Alzheimer's disease
Epigenetics
Issue Date: 8-Oct-2015
Publisher: BioMed Central
Abstract: 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.
Note: Reproducció del document publicat a: https://doi.org/10.1186/s13148-015-0142-9
It is part of: Clinical Epigenetics, 2015, vol. 7, num. 108
URI: http://hdl.handle.net/2445/149500
Related resource: https://doi.org/10.1186/s13148-015-0142-9
ISSN: 1868-7075
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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