Fingolomid and Memory Function.

Fingolomid (sold as Gilenya) is a immunomodulator taken orally once daily. It is used to prevent relapses in relapsing multiple sclerosis. Since fingolomid works by its effect on the sphingosine 1-phosphate receptor, which in lymphocytes regulates their exit from lymph nodes, it thus decreases immune cell trafficking in the brain, and thus decreases the tendency to white matter brain inflammation in MS.

However, sphingosine is also involved in many brain cell processes, including those used in processing memory. In the rodent research below, it is suggested that fingolomid might be used as a memory modulator in human conditions such as PTSD. Such effects have not, as far as I know, been seen in persons with MS, or are we not yet looking for those effects?



Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory

Nitai C Hait, Laura E Wise, Jeremy C Allegood, Megan O'Brien, Dorit Avni, Thomas M Reeves, Pamela E Knapp, Junyan Lu, Cheng Luo, Michael F Miles, Sheldon Milstien, Aron H Lichtman & Sarah Spiegel

Nature Neuroscience (2014) doi:10.1038/nn.3728

Received 07 March 2014 Accepted 25 April 2014 Published online 25 May 2014


FTY720 (fingolimod), an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. We show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in the brain, including the hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning, and rescues memory deficits independently of its immunosuppressive actions. Sphk2−/− mice have lower levels of hippocampal sphingosine-1-phosphate, an endogenous HDAC inhibitor, and reduced histone acetylation, and display deficits in spatial memory and impaired contextual fear extinction. Thus, sphingosine-1-phosphate and SphK2 play specific roles in memory functions and FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories.

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