Striking a Nerve: MS Drug Provides Clue to PTSD Target


A new study in mice suggests that the launch of a first-in-class drug, advances in basic molecular biology, and clever researchers have combined to identify a new therapeutic target and a lead compound for post-traumatic stress and other anxiety disorders.

The first-in-class drug is fingolimod (Gilenya), an immunomodulator approved for multiple sclerosis; the molecular biology knowledge involves sphingosine-1-phosphate (S1P) and its receptors; and the clever researchers were a group at Virginia Commonwealth University in Richmond led by Sarah Spiegel, PhD.

As Spiegel and colleagues explained in a report appearing online in Nature Neuroscience, fingolimod -- and more particularly its phosphorylated active metabolite (call it fingolimod-P) -- acts as a mimic of S1P. In MS, that action leads to downregulation of the S1P type 1 receptor (S1PR1) on activated T cells, which inhibits their ability to migrate out of lymph nodes to facilitate demyelination of nerve fibers.

But S1P is multifunctional and acts on other targets besides S1PR1. One of its actions is to inhibit histone deacetylases (HDACs) in the nucleus of certain cell types, including brain neurons, giving the substance a role in epigenetic regulation. Consequently, the researchers had the idea to test whether native fingolimod or its phosphorylated metabolite would have similar effects.

At the cellular level, they found that fingolimod-P did indeed inhibit histone deacetylases in neurons, specifically in the hippocampus -- the brain's center for learning and memory.

Because previous studies had linked HDACs to hippocampal processes, Spiegel and colleagues sought to examine whether fingolimod would affect the acquisition and retention of fear memories.

They used immunodeficient "SCID" mice for the experiments, to eliminate confounding by the drug's effects on lymphocyte trafficking.

Compared with SCID mice treated with saline, animals given daily doses of fingolimod did not show deficits in their ability to learn to anticipate and avoid context-dependent electric shocks. Nor did the drug affect retention of such memories for 48 hours.

But in tests of "fear extinction" -- a process by which animals (including humans) keep fear at appropriate levels, preventing fear from becoming overtly disabling -- the drug boosted the level of fear control.

In the fear-extinction experiments, the same mice were exposed to the same contexts in which they previously received shocks, this time with no shock. This normally leads to progressive reductions in signs of fearfulness such as motionlessness.

In the short term (a few hours), there was no difference in the rate of fear extinction between the fingolimod- and placebo-treated animals. But the next day, the placebo-treated animals showed a return of fearfulness when exposed to the shock-related contexts, whereas the fingolimod-treated animals did not -- "indicating that extinction was preserved," Spiegel and colleagues wrote.

They suggested that this pattern was just about exactly what one would want in a therapy aimed at reducing long-lasting overreactions to fearful situations, which is essentially the definition of PTSD.

But fingolimod itself would not be the ideal way to go about it, the researchers noted. Not only does it have immunological effects that would be unwanted in people without MS -- the drug's label includes a warning about increased risk of infections, for example -- it also has adverse cardiac and pulmonary effects.

Instead, Spiegel and colleagues indicated that the study should be a jumping-off point for developing new agents with greater specificity for the nuclear anti-HDAC action in the hippocampus.
