Tuesday, May 27, 2014
Virginia Commonwealth UniversitySchool of Medicine researchers have uncovered a new mechanism of action of fingolimod, a drug widely used to treat multiple sclerosis: elimination of adverse or traumatic memories.
The findings shed light on how the drug works on the molecular level – something that has not been well understood until now.
Fingolimod, or FTY720, which is the first orally available drug for treatment of multiple sclerosis, works by suppressing the immune system. Fingolimod is a prodrug that is phosphorylated in the body to its active form, FTY720-phosphate.
In a study published by the Nature Neuroscience journal on May 25 as an Advanced Online Publication, researchers used a mouse model to show that fingolimod accumulates in the brain and inhibits histone deacetylases, which are enzymes important to regulate gene expression. The team observed an increased expression of a limited number of genes important for certain memory processes. Fingolimod acted similarly to the natural signaling lipid, sphingosine-1-phosphate, which it closely resembles.
“Our work suggests that some of the beneficial effects of FTY720/fingolimod that are not well understood might be mediated by this new activity that we have discovered,” said first author Sarah Spiegel, Ph.D., an internationally renowned researcher and professor and chair of the Department of Biochemistry and Molecular Biology in the VCU School of Medicine.
“It will be important in the future to determine whether this prodrug can reduce loss of cognitive functions and can erase adverse memories,” she said.
Spiegel added that other histone deacetylase inhibitors have long been used for treatment of psychiatric and neurological disorders, yet the mechanism of their effectiveness is not fully understood.
“FTY720/fingolimod may be a useful adjuvant therapy to help stop aversive memories such as in post-traumatic stress disorder and other anxiety disorders,” Spiegel said.
“The work has not been extended to show effectiveness in humans at this time. We are still working to fully understand the molecular underpinnings of the drug and its link to memory,” she said.
The work is based on previous findings by Spiegel’s group that were published in Science in 2009. They had reported that sphingosine-1-phosphate formed in the nucleus of cells is a natural inhibitor of histone deacetylases and a regulator of gene expression.
Spiegel, Mann T. and Sara D. Lowry Professor of Oncology and co-leader of the Cancer Cell Signaling research program at the VCU Massey Cancer Center, collaborated with a multidisciplinary team of researchers from across the VCU campus, including the Department of Pharmacology and Toxicology, Department of Neurology, Department of Biochemistry and Molecular Biology and the Department of Anatomy and Neurobiology. Researchers from the Chinese Academy of Sciences in Shanghai also contributed to this work.
The paper is titled: “Active, phosphorylated form of fingolimod inhibits histone deacetylases and facilitates fear extinction memory.”
This work was supported by the National Institutes of Health grant R37GMO43880.
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