Histone Deacetylase Inhibition Activity and Molecular Docking of (E )‐Resveratrol: Its Therapeutic Potential in Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy is an autosomal recessive motor neuron disease that is caused by mutation of the survival motor neuron gene (SMN1) but all patients retain a nearly identical copy, SMN2. The disease severity correlates inversely with increased SMN2 copy. Currently, the most promising therapeutic strategy for spinal muscular atrophy is induction of SMN2 gene expression by histone deacetylase inhibitors. Polyphenols are known for protection against oxidative stress and degenerative diseases. Among our candidate prodrug library, we found that (E )-resveratrol, which is one of the polyphenolic compounds, inhibited histone deacetylase activity in a concentration-dependent manner and half-maximum inhibition was observed at 650 microM. Molecular docking studies showed that (E )-resveratrol had more favorable free energy of binding (-9.09 kcal/mol) and inhibition constant values (0.219 microM) than known inhibitors. To evaluate the effect of (E )-resveratrol on SMN2 expression, spinal muscular atrophy type I fibroblast cell lines was treated with (E )-resveratrol. The level of full-length SMN2 mRNA and protein showed 1.2- to 1.3-fold increase after treatment with 100 microM (E )-resveratrol in only one cell line. These results indicate that response to (E )-resveratrol treatment is variable among cell lines. This data demonstrate a novel activity of (E )-resveratrol and that it could be a promising candidate for the treatment of spinal muscular atrophy.

Investigations of Curcumin and Resveratrol on Neurite Outgrowth: Perspectives on Spinal Muscular Atrophy

“…Both compounds have a neurite-promoting effect, which was shown in several reports [29–31]. The effects of curcumin and resveratrol on a cell culture model for SMA were also reported, and it was shown that both increased full-length SMN2 gene expression in a SMA patient fibroblast cell line [32–34]. Considering these findings, in the present study, we aimed to restore the neurite outgrowth defect observed in SMA, using curcumin and resveratrol.…”

Alteration of splice site selection in the LMNA gene and inhibition of progerin production via AMPK activation

“…Additionally, histone deacetylases (HDACs) have also been shown to modulate alternative splicing by influencing splice site selection [114]. Provocatively, in addition to AMPK itself exhibiting histone deacetylase inhibiting activity, a number of naturally occurring (e.g., resveratrol and curcumin) and synthetic (e.g., belinostat, trichostatin A, and vorinostat) HDAC inhibitors that alter or modulate alternative splicing have been shown to be AMPK activators [115][116][117][118][119][120]. Of particular interest is the observation by Columbaro et al that the combined use of trichostatin A and mevinolin (lovastatin), a member of the statin class of cholesterol-lowering medications that inhibits HMG-CoA reductase and farnesyltransferase, leads to a significant reduction of progerin levels in cultured HGPS fibroblasts, leading to a rescue of nuclear-shape abnormalities, heterochromatin organization, and a recovery of ribonucleoprotein staining patterns [121].…”

Cytoprotection by Natural and Synthetic Polyphenols in the Heart: Novel Mechanisms and Perspectives

“…Polyphenols could also exhibit HDACinhibiting activities. For example, resveratrol could inhibit HDAC activity in a concentration-dependent manner, but the potency is low (IC 50 > 600 M) [111]. In another recent study, Son and colleagues reported that the isoflavone derivative pomiferin, isolated from the fruit of Maclura pomifera, exhibited potent inhibitory effects on purified HDAC with an IC 50 value of ~ 1 M [112].…”