Resveratrol and spinal muscular atrophy

A group of researchers at the University of Ankara (Turkey) has published these days, on the current issue of scientific journal Chemical Biology & Drug Design, an interesting article that investigates the therapeutic potential of resveratrol in the SMA. The publication, entitled "Histone deacetylase inhibition activity and molecular docking of (e)-resveratrol: its therapeutic potential in spinal muscular atrophy", focuses the attention on the properties of inhibition of histone deacetylase, properties common to many compounds have been used for test purposes on SMA (valproic acid, phenylbutyrate, tricostatin A).

The search for novel and effective SMA therapeutic agents has led to the identification of various naturally occurring compounds. Polyphenols, which possess more than one phenol unit per molecule, are plant-originated compounds. They are famous for their antioxidant properties and health benefits. Of these polyphenolic compounds, (e)-resveratrol is a naturally occurring compound and is part of the human diet (it is found in the skin of red grapes and is a constituent of red wine). (E)-resveratrol has been shown to have many biological properties, such as cardiovascular-protective, cancer-chemopreventive and anti-inflammatory properties including antioxidant activity.
The researchers found that (e)-resveratrol shows high binding capacity and HDAC inhibitor activity. It increases the level of full-length SMN2 mRNA and protein in SMA type I fibroblast cell line. On the basis of these observations, future studies will aim rational design of novel selective and potent HDAC inhibitors for the treatment of SMA. Modifications of (e)-resveratrol may increase the possibility of developing more potent candidates that are promising in the treatment of SMA.

Here the 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.

Read full text of the study

To better understand the content of research is necessary to study some technical concepts relating to the histones and their functions. Here a simple and brief explanation (Wikipedia):

Histones are the chief protein components of chromatin. They act as spools around which DNA winds and they play a role in gene regulation. There are a total of five classes of histones (H1, H2A, H2B, H3, H4) organized into two super classes as follows:
- core histones H2A, H2B, H3 and H4
- linker histone H1
Two of each of the core histones assemble to form one octameric nucleosome core particle by wrapping 146 base pairs of DNA around the protein spool in 1.65 left-handed super-helical turn. The linker histone H1 binds the nucleosome and the entry and exit sites of the DNA, thus locking the DNA into place and allowing the formation of higher order structure. The most basic such formation is the 10 nm fiber or beads on a string conformation. This involves the wrapping of DNA around nucleosomes with approximately 50 base pairs of DNA spaced between each nucleosome (also referred to as linker DNA). The assembled histones and DNA is called chromatin. Higher order structures include the 30 nm fiber (forming an irregular zigzag) and 100 nm fiber, these being the structures found in normal cells. Histone tails are normally positively charged due to amine groups present on their lysine and arginine amino acids. These positive charges help the histone tails to interact with and bind to the negatively charged phosphate groups on the DNA backbone.
Acetylation, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into amides and decreases the ability of the histones to bind to DNA. This process allows chromatin expansion, allowing for genetic transcription to take place. Deacetylation remove acetyl groups, increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. This process condenses DNA structure, preventing transcription. Hyperacetylated chromatin is transcriptionally active, and hypoacetylated chromatin is silent.
To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones. This is accomplished with the assistance of histone acetylases (HAT) which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active chromatin, and conversely the actions of histone deacetylases (HDAC) which remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. HDAC inhibitors (HDI) block HDAC action and can result in hyperacetylation of histones, therefore affecting gene expression. Histone deacetylase inhibitors have a long history of use in psychiatry, neurology, cancer therapy, etc. Some examples: valproic acid (VPA), vorinostat (SAHA), trichostatin A (TSA), phenylbutyrate.