A new study in mice of the multiple sclerosis drug fingolimod (Gilenya) suggests the drug may be a new therapeutic target for a treatment of post-traumatic stress and other anxiety disorders.
A new study in mice of the multiple sclerosis (MS) immunomodulator drug fingolimod (Gilenya) suggests the drug may be a new therapeutic target for a treatment of post-traumatic stress and other anxiety disorders.
In an online report in Nature Neuroscience, Sarah Spiegel, PhD, and colleagues at Virginia Commonwealth University in Richmond, VA, the researchers examined whether fingolimod would affect the acquisition and retention of fear memories, using immunodeficient SCID mice for the studies to eliminate confounding by the drug’s effect on lymphocyte trafficking.
In mice tested for “fear extinction,” the drug was able to boost the level of fear control. In the short term there was no difference in the rate of fear extinction between drug and placebo groups. However, the next day, the placebo-treated animals showed a return of fearfulness when exposed to the shock-related contexts and the fingolimod-treated mice did not, suggesting that extinction was preserved, the authors concluded.
“It will be important in the future to determine whether this prodrug can reduce loss of cognitive functions and can erase adverse memories,” Spiegel said in a statement.
The researchers noted that fingolimod itself was not the best drug to use because of side effects and adverse events associated with the drug, but they said the study should be a launch point for developing new agents with greater specificity for activity in the hippocampus.
Spiegel added that the beneficial effects of fingolimod are not well understood, though the findings in this study shed light on how the drug works on the molecular level. According to the study results, the drug’s phosphorylated active metabolite (fingolimod-P) acts as a mimic of sphingosine-1-phosphate (S1P). In MS, fingolimod and its metabolite act as mimic of S1P, leading to the downregulation of the S1P type 1 receptor on activated T cells, which inhibits their ability to migrate out of lymph nodes to facilitate demyelination of nerve fibers.
The researchers found that S1P is multifunctional and acts on other targets. It inhibits histone deacetylases (HDACs) in certain cell nuclei, including brain neurons, thus giving S1P a role in epigenetic regulation. The team tested whether fingolimod or its metabolite would have similar effects, and found that fingolimod-P was able to inhibit HDACs in neurons in the hippocampus, the center for learning and memory in the brain.