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
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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.
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A subsequent empirical study by another group found that pairing a PDE inhibitor with a deacetylase inhibitor was effective in rescuing a deficit of LTP in a mouse model of Alzheimer disease.
“A subsequent empirical study by another group did find that pairing a PDE inhibitor with a deacetylase inhibitor was effective in rescuing a deficit of LTP in a mouse model of Alzheimer disease105.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [105]
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- Authors
- Cuadrado-Tejedor, M., Garcia-Barroso, C., Sanzhez-Arias, J., Mederos, S., Rabal, O., Ugarte, A., Franco, R., Pascual-Lucas, M., Segura, V., Perea, G., Oyarzabal, J., & Garcia-Osta, A.
- Affiliations
- Centro de Investigación Médica Aplicada (ES)
- Instituto Cajal (ES)
- Venue
- Clinical Epigenetics
- Published
- 2015-10-08
- Volume
- 7
- Issue
- 1
- Pages
- 108-108
- ISSN
- 1868-7075 (ISSN-L)
- 1868-7083
- PMC
- PMC4599811
- OpenAlex
- W1824477449
- Cited by
- 69
- References
- 38
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 10 · 2023: 4 · 2022: 6 · 2021: 6 · 2020: 12 · 2019: 9 · 2018: 5 · 2017: 4 · 2016: 5
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Clinical Epigenetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
- Depósito Digital e-UCJC (submittedVersion, cc-by-nc-nd)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
- Funders
- Ministery of Spain (11/02861 and 14/01244, RYC-2012-12014; and BFU2013-47265R)
- Ministerio de Educación, Cultura y Deporte (ES) (Torres Quevedo)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, histone deacetylase inhibitors, phosphodiesterase-5 inhibitors, vorinostat, tadalafil, drug combination therapy, synaptic plasticity, long-term potentiation, APP/PS1 mice, cognitive impairment, amyloid pathology, tau pathology, dendritic spine density, hippocampus, histone acetylation, disease modification
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