Different Effects of Valproic Acid on Photoreceptor Loss in Rd1 and Rd10 Retinal Degeneration Mice.

Different Effects of Valproic Acid on Photoreceptor Loss in Rd1 and Rd10 Retinal Degeneration Mice. in Molecular Vision.  http://www.molvis.org/molvis/v20/1527/

Using retinal degeneration mouse strains, this paper’s data demonstrate that the underlying etiology of the photoreceptor degeneration is important to determining the effects of Valproic Acid (VPA) on the rate of photoreceptor loss. Our results are very important, because off-label VPA clinical trials with Human RP patients are underway in the USA and South Korea. Thus, VPA might help some families, but not others, depending on the exact genetic mutation, and thus disease etiology, involved in their RP. Our study with mice would indicate that any clinical trials should make comparisons of VPA to placebo within RP patients who have the same disease etiology (same genetic mutation). Patients should also be monitored very closely to evaluate changes in the rate of visual field loss and visual acuity loss while taking VPA in such trials.

VPA (Valproic Acid) is an FDA-approved anticonvulsant used by about over 300,000 Americans with epilepsy for almost three decades. VPA does have side effects which prevent many patients from using this particular drug. In 2001, years after its FDA-approval, chemists discovered that VPA is also a potent inhibitor of histone deacetylases, and can potentially increase histone acetylation to open the chromatin’s architecture at gene promoter regions. Histone proteins organize our DNA, which is wrapped around histone core proteins, like thread around a spool. These spools are called nucleosomes, and each nucleosome has just over 2 wraps of DNA around their core. Millions of these nucleosome structures can form coils upon coils and be packed together either very tightly into a tiny space, or become loosely packed and the DNA more unwrapped and drawn out. When a gene is being used by our cells, it is on or being “expressed” and its chromatin architecture is loose, open and unwrapped so RNA-Polymerase-II can make mRNA from the gene.

When genes are turned on, histones are acetylated which causes the nucleosomes to unpack so the gene’s DNA can be used as a template to make mRNA. Because VPA can inhibit the activity of enzymes that remove acetyl groups, VPA has the potential to epigenetically promote expression of many genes. Indeed, VPA is used as a second round therapy in specific leukemias to reactivate tumor suppressor genes that have become silenced by DNA-methylation, hopefully causing leukemic cells to self destruct by apoptosis. Experiments with VPA have also been reported to alleviate symptoms in several mouse models of different neurodegenerative diseases, and researchers have speculated that VPA increases the expression of “neuroprotective” genes such as BDNF and GDNF.

However, the expression of these neurotrophic genes is rarely actually analyzed in the central nervous system of VPA-treated animal models, in vivo. The effects on BDNF expression are interpolated from other studies with neuronal cell cultures, in vitro. Despite a general lack of knowledge on the effect of VPA on the expression of genes in most tissues of the body, there is great clinical interest to carry out off-label clinical trials in human patients with various neurodegenerative conditions including RP (Retinitis Pigmentos).

As a laboratory studying the regulation of photoreceptor genes, we had already helped to show that histone acetylation is regulated in photoreceptor genes. Because VPA has the potential to alter the epigenetic regulation of thousands of genes, it is hard to predict if VPA-treatment would benefit or even harm a degenerating retina. This study shows that in mice with two different retinal degenerations (rd1, and rd10), VPA slows photoreceptor loss in one model, but accelerates it in the other! Furthermore, systemic dosing with VPA can alter the expression of neurotrophic genes and even NRL in the neural retina.

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s