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.

M Cuadrado-Tejedor,A Garcia-Osta,A Ugarte,J Sanzhez-Arias,C Garcia-Barroso,M Pascual-Lucas,R Franco,O Rabal,G Perea,J Oyarzabal,S Mederos,V Segura

doi:10.1186/s13148-015-0142-9

Abstract

BackgroundGiven 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.ResultsThe 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.ConclusionsThe results highlight the pharmacological potential of a combination of molecules that inhibit HDAC and PDE5 as a therapeutic approach for AD treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0142-9) contains supplementary material, which is available to authorized users.

Highlights

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)
The concomitant inhibition of HDAC and PDE5 has a synergistic effect on histone acetylation Using primary neuronal cultures, we tested whether the combination of vorinostat and tadalafil had a synergistic effect on the induction of histone 3 acetylation at lys9 (AcH3K9), an epigenetic mark implicated in memory enhancement in mice [13, 14]
When we exposed the cultured neurons to different concentrations of vorinostat and tadalafil for 2 h (10, 100 and 500 nM), we detected a strong induction of AcH3K9 by vorinostat at concentrations of 100 and 500 nM, whereas no effect was found with tadalafil (Fig. 1a)

Summary

Introduction

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). 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. 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. There is considerable evidence that epigenetic regulation is a dynamic and critical mechanism modulating neuronal function. One epigenetic mechanism that regulates gene transcription is histone acetylation, a modification that is known to enhance or constrain cognitive functions. Since the side effects reported for HDACIs in humans are dose dependent [3], the use of lower doses of pan-HDAC inhibitors to reduce their toxicity could represent another solution, combining them with other ADrelated drugs to obtain a compound or synergistic effect

Results

Discussion

Conclusion