Searching for Disease Modifiers—PKC Activation and HDAC Inhibition—A Dual Drug Approach to Alzheimer's Disease that Decreases Aβ Production while Blocking Oxidative Stress

Abstract

Alzheimer's disease (AD) is a well-studied process characterized by the presence of amyloid plaques and neurofibrillary tangles. In this study, a series of protein kinase C (PKC) activators were investigated, some of which also exhibit histone deacetylases (HDACs) inhibitory activity, under the hypothesis that such compounds might provide a new path forward in the discovery of drugs for the treatment of AD. The PKC activating properties of these drugs were expected to enhance the α-secretase pathway in the processing of amyloid precursor protein (APP), while their HDAC inhibition was anticipated to confer neuroprotective activity. We found that the benzolactams compounds 9 and 11-14 caused a concentration-dependent increase in sAPPα and decrease in β-amyloid (Aβ) production using concentrations of these drugs in the range of 0.1∼10 μM, consistent with a shift of APP metabolism towards the α-secretase-processing pathway. Moreover, 9-14 showed neuroprotective effects in the 10 to 20 μM range in the homocysteate (HCA) cortical neuron model of oxidative stress. In parallel, we found that the most neuroprotective compounds caused increased levels of histone acetylation (H4), thus indicating their likely ability to inhibit histone deacetylase activity. As the majority of the compounds studied also show nanomolar binding affinities for PKC, we conclude that it is possible to design, de novo, agents that combine both PKC activating properties along with HDAC inhibitory properties, thereby resulting in agents capable of modulating amyloid processing while showing neuroprotection. These findings may offer a new approach to therapies that exhibit disease-modifying effects, as opposed to symptomatic relief, in the treatment of AD.

Histone Deacetylase Inhibitors for Treating a Spectrum of Diseases Not Related to Cancer

“…In this regard, the antiinflammatory properties of HDACi's appear to be neuroprotective. In animal models of Alzheimer disease, the most studied neurodegenerative disease, HDAC inhibition decreased β-amyloid production and effective neuroprotection was associated with increased acetylation of histone 4 (94). In a model of closed head trauma, the antiinflammatory properties of HDACi's prevented the deterioration of neurological impairment, even when administered 24 hours after the injury (93).…”

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

“…The structurally simplest member of the family is (-)-indolactam V (ILV, 34), which can be produced in large quantities in Actinomycetes and has therefore been used as a starting point for the synthesis of new derivatives [58]. Several groups -the Irie, the Kozikowski, and the Endo groups -have carried out research into these compounds, revealed important structure-activity relationships and developed novel indolactam and benzolactam derivatives with improved selectivity profiles (see, for example, [133][134][135]). …”

A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1

“…61,62 We thus explored whether bizine might confer neuroprotection against HCA-induced oxidative stress. Indeed, 0.5 µM bizine led to significantly enhanced survival of neurons after HCA treatment in a dose-dependent fashion (Figure 7A,B).…”