The MS drug, fingolimod, normally acts by binding to specific receptors on the cell membrane. This binding causes the cell to internalize the receptor, eliminating its functionality. Such a mechanism has been beneficial in the treatment of MS as the internalized receptor is necessary for the trafficking of lymphocytes, immune cells that are active in MS processes. The action of fingolimod prevents lymphocytes from leaving their home tissue, ultimately preventing them from being able to damage the nervous system.
In this study, Hait et al identifies a new role for fingolimod, one in which it acts within the nucleus of the cell as a histone deacetylase (HDAC) inhibitor, a mechanism that alters gene expression. Such a mechanism has been described as “epigenetic”, meaning that it can alter the expression of genes without affecting the actual DNA code. Epigenetic phenomena have been an important focus of many studies as it provides a means in which the environment can change your genes. Interestingly, epigenetics is believed to be involved in the development of many psychiatric disorders, disorders in which the surrounding environment plays an important role.
Other HDAC inhibitors have already been shown to alter gene expression and subsequently, memory. This might happen through varied expression of genes and proteins that are important for the formation and maintenance of memories, as it has been well established that long-term memory requires the creation of new proteins. These proteins are believed to act at specific synapses between neurons, strengthening the connections between specific cells. This study shows that fingolimod can bind to HDACs and inhibit their activity. Specifically, the authors show that this happens in neurons located in the hippocampus of the brain, a neural structure important for the formation of new memories. Perhaps the most interesting part of this study shows that mice treated with the MS drug have an enhanced ability for memory extinction as measured by the decreased amount of freezing behavior of the mice during a behavioral test.
The ability to enhance or alter memory is on its way. Drugs that can accomplish such a feat would be beneficial for the treatment of devastating neurological disorders including Alzheimer’s disease and post-traumatic stress disorder (PTSD). This new study identifies a novel pathway for changing the expression of genes involved in memory and subsequently, the enhancement of memory extinction in mice as seen in behavioral testing. Perhaps most importantly, the authors have show that this is caused by an FDA-approved drug that is already being used to treat MS, bypassing the complicated barriers presented by bringing novel drugs to market. It will be interesting to follow how HDAC inhibitors like fingolimod and other epigenetic drugs will be used in the future to better understand memory formation and maintenance, processes that have been difficult to pin down so far.