title: Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.
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.
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [2] Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [3].
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
authors.affiliation: 1] Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [2].
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wise
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [2] Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: O'Brien
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [2] Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Dorit
authors.initials: D
authors.lastname: Avni
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Reeves
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [2] Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [2] Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D000068876:Fingolimod Hydrochloride; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000502:physiology; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000502:physiology; D007859:Learning Disabilities / Q000235:genetics / Q000523:psychology; D008246:Lysophospholipids / Q000494:pharmacology; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008958:Models, Molecular; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D000068876:Fingolimod Hydrochloride; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate