Synergistic association of resveratrol and histone deacetylase inhibitors as treatment in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, progressive paralysis and finally death. Despite the research efforts, currently there is no cure for ALS. In recent years, multiple epigenetic mechanisms have been associated with neurodegenerative diseases. A pathological role for histone hypoacetylation and the abnormal NF-κB/RelA activation involving deacetylation of lysines, with the exclusion of lysine 310, has been established in ALS. Recent findings indicate that the pathological acetylation state of NF-κB/RelA and histone 3 (H3) occurring in the SOD1(G93A) murine model of ALS can be corrected by the synergistic combination of low doses of the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator resveratrol and the histone deacetylase (HDAC) inhibitors MS-275 (entinostat) or valproate. The combination of the epigenetic drugs, by rescuing RelA and the H3 acetylation state, promotes a beneficial and sexually dimorphic effect on disease onset, survival and motor neurons degeneration. In this mini review, we discuss the potential of the epigenetic combination of resveratrol with HDAC inhibitors in the ALS treatment.

Keywords: NF-κB/RelA; amyotrophic lateral sclerosis (ALS); epigenetic drugs; histone acetylation; histone deacetylase (HDAC) inhibitors; resveratrol; sexual dimorphism.

FIGURE 1

The proposed mechanism underlying the effect of the combination between resveratrol and HDAC inhibitors (HDACi) [MS-275 or valproate (VPA)] in ALS. (A) In the spinal cord of the SOD1(G93A) ALS mouse model, NF-κB/RelA is present in its aberrantly acetylated form, consisting of a hypoacetylated state with the exception of the residue K310 (ALS). In this pathological condition, the acetylation of histone H3 is decreased. (B) The treatment of SOD1(G93A) mice with the combination resveratrol/HDAC inhibitors reverts the aberrant RelA acetylation (ALS + treatment). HDAC inhibitors, by blocking HDAC activity, induce HAT-mediated acetylation of both RelA and H3 histone. Resveratrol activates the class III NAD+ -dependent HDAC SIRT1, promoting the deacetylation of RelA at residue K310. Moreover, resveratrol stimulates AMPK pathway, leading to an increase of NAD+ and AcCoA levels, enhancing the activation of SIRT1 and HATs, respectively. The modulation of RelA and H3 acetylation in the nucleus promotes the transcription of the anti-apoptotic Bcl-xL and the neurotrophic BDNF factors. Altogether, the treatment leads to a protection of MNs, a delay of symptoms’ onset, and longer survival.