A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

Abstract

The targeting of two independent but synergistic enzymatic activities, histone deacetylases (HDACs, class I and HDAC6) and phosphodiesterase 5 (PDE5), has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMPresponsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission. Thus, CM-414 may serve as the starting point to discover balanced dual inhibitors with an optimal efficacy and safety profile for clinical testing on AD patients.

Histone deacetylase inhibition induces odor preference memory extension and maintains enhanced AMPA receptor expression in the rat pup model

“…The cytosolic effects of HDAC6 inhibition increase mitochondrial transport (Chen et al 2010), another feature of network circuit changes supporting memory consolidation or expression. Finally, HDAC6 inhibition in conjunction with phosphodiesterase inhibition promotes LTP and rescues spine density changes and cognitive dysfunction in mice modeling Alzheimer's disease (Cuadrado-Tejedor et al 2017). The specific effect(s) of HDAC6 and histone deacetylation inhibition contributing to memory extension in the present experiments remain to be identified.…”

“…To identify whether another HDAC inhibitor could extend memory and to determine whether HDAC inhibition enhances memory specifically to the conditioned odor (rather than a generalized enhanced memory to odors) we designed an experiment using tubacin, a specific HDAC 6 inhibitor (Cuadrado-Tejedor et al 2017;Perry et al 2017) and a different odor in addition to peppermint. Our prolonged memory model revealed that there was no preference memory in TSA + O/O group 5 d after training (Fig.…”

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…Clinical evidence of enhanced synaptic plasticity and memory improvement following PDE5 inhibitors administration (in particular, by using compounds able to cross the BBB such as sildenafil, tadalafil, and vardenafil) in AD patients were collected during the last years . Combinations of tadalafil (IC 50 PDE5A = 9.4 nM), sildenafil (IC 50 PDE5A = 8.5 nM) (Figure ) or vardenafil (IC 50 PDE5A = 0.89 nM), and vorinostat 3 were preclinically validated in a mouse model of AD, showing a synergistic effect for increased levels of histone acetylation via recruitment of CBP, similarly to what observed by the treatment with previously discovered hybrid PDE5/pan‐HDAC inhibitors in mice . The effect of the HDAC6‐selective inhibitor tubastatin A in combination with PDE5Ai has been evaluated against SH‐SY5Y neuroblastoma cell lines, with the aim to highlight the role of this specific HDAC isoform in such disease.…”

“…[340][341][342] Combinations of tadalafil (IC 50 PDE5A = 9.4 nM), sildenafil (IC 50 PDE5A = 8.5 nM) ( Figure 9) 343 or vardenafil (IC 50 PDE5A = 0.89 nM), 344 and vorinostat 3 were preclinically validated in a mouse model of AD, 345 showing a synergistic effect for increased levels of histone acetylation via recruitment of CBP, similarly to what observed by the treatment with previously discovered hybrid PDE5/pan-HDAC inhibitors in mice. 346 The effect of the HDAC6-selective inhibitor tubastatin A in combination with PDE5Ai has been evaluated against SH-SY5Y neuroblastoma cell lines, with the aim to highlight the role of this specific HDAC isoform in such disease. A marked increase of H3K9 acetylation has been registered compared to cells treated with tubastatin A alone.…”

Advances and Current Challenges Associated with the Use of Human Induced Pluripotent Stem Cells in Modeling Neurodegenerative Disease

“…In another study of monozygotic twins discordant for AD, increased gene expression of sirtuin 1, an enzyme with a role in acetylation of DNA-associated proteins, as well as histone deacetylases (HDAC) HDAC2 and HDAC9, were observed in the AD-exhibiting twin [D'Addario et al, 2017]. In fact, expression of HDAC2, a known key player in functional plasticity in learning and memory, was previously shown to be upregulated in AD brains [Gräff et al, 2012] and current research is being focused on reducing HDAC protein expression as a target for the treatment of AD [Cuadrado-Tejedor et al, 2017;Yang et al, 2017;Volmar et al, 2018]. The role of noncoding RNA has been extensively reviewed elsewhere but includes influences on neuroinflammation, generation and clearance of amyloid-β (Aβ) and τ proteins, synaptic integrity and function, activity of mitochondria and endoplasmic reticulum, and the cell cycle [Maoz et al, 2017;Millan, 2017;Idda et al, 2018].…”