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.

Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement

“…MR6-26-2 was found to be the best compound to redeem cell viability of several fALS mutants tested here with negligible toxicity to the wild-type SOD1. Synergistic association of drugs targeting different mechanisms have been reported as a strategy to improve therapeutic effects on ALS 41 . Combined therapies of ebselen-based compounds/ALS drugs showed no synergistic improvement in in vitro neuroprotective activity compared to single-compound treatments.…”

The epigenetic regulatory effect of histone acetylation and deacetylation on skeletal muscle metabolism-a review

“…It also inhibits the activity of interleukin-8 (IL-8) and tumor necrosis factor TNF-α, further improving muscle function (To et al, 2017;Bin et al, 2019;Li et al, 2021). In addition, the mechanism of action of resveratrol in improving skeletal muscle atrophy and aging is similar to that of theophylline (Sun et al, 2017;Li et al, 2022;Parrella et al, 2022) (Figure 4).…”

Therapeutic effects of resveratrol on epigenetic mechanisms in age‐related diseases: A comprehensive review

“…The loss of subunits of this complex such as RBBP4 and RBBP7 and its impaired integrity are the signs Pegoraro and colleagues observed in aged cells. The aging process causes an increase in the susceptibility to long-term DNA damage, resulting in this effect (Pegoraro et al, 2009).…”

“…Furthermore, epigenetic is one of the most important fields by which RSV exerts its antiaging effects (Pyo et al, 2020b). Affecting noncoding RNAs (e.g., miRNAs and long noncoding RNAs), regulating histone and chromatin changes, and changing DNA methylation status are the main mechanisms by which RSV play its role as an epigenetic modulator and consequent antiaging effects (Hayakawa et al, 2022; Lee et al, 2012; Parrella et al, 2022; Shu et al, 2020; Zadi Heydarabad et al, 2018).…”