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

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Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, Milstien S, Lichtman AH, Spiegel S

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

Nat Neurosci. 2014 Jul;17(7):971-80. doi: 10.1038/nn.3728. Epub 2014 May 25.

PubMed ID

24859201 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Fingolimod	Histone deacetylase 1	Protein	Humans	Unknown	Inhibitor	Details