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
| Autor: | Maria Pascual-Lucas, Ana Ugarte, Carolina García-Barroso, Sara Mederos, Ana Garcia-Osta, Gertrudis Perea, Rafael Franco, Victor Segura, Julen Oyarzabal, J. Sanzhez-Arias, Mar Cuadrado-Tejedor, Obdulia Rabal |
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| Přispěvatelé: | Universitat de Barcelona, Ministerio de Economía y Competitividad (España), European Commission, Instituto de Salud Carlos III |
| Předmět: |
Amyloid
Alzheimer’s disease (AD) Pharmacology Biology Bioinformatics Memory Genetics medicine Molecular Biology Vorinostat Genetics (clinical) Histone deacetylase 5 Phosphodiesterase (PDE) Research Long-term potentiation Alzheimer's disease Epigenètica Histone deacetylase (HDAC) Histone Malaltia d'Alzheimer Gene transcription Acetylation cGMP-specific phosphodiesterase type 5 Synaptic plasticity biology.protein Epigenetics Histone deacetylase Tau Alzheimer’s disease Developmental Biology medicine.drug |
| Zdroj: | Recercat. Dipósit de la Recerca de Catalunya instname Clinical Epigenetics Digital.CSIC. Repositorio Institucional del CSIC Dipòsit Digital de la UB Universidad de Barcelona |
| Popis: | [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. This study was supported by FIMA (Spain), the FIS project (11/02861 and 14/01244) to AGO, MINECO (Ramón y Cajal Program, RYC-2012-12014, and BFU2013-47265R) to G.P and a Torres Quevedo grant (from MINECO PTQ-12-05641) to AU. |
| Databáze: | OpenAIRE |
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