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Cited by 209Sphingolipid Metabolism and SignalingMemory and Neural MechanismsHistone Deacetylase Inhibitors Research

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

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Hait, Nitai C, Wise, Laura E, Allegood, Jeremy C, O'Brien, Megan, Avni, Dorit, Reeves, Thomas M, Knapp, Pamela E, Lu, Junyan +5 more·2014·Nature Neuroscience
DOI 10.1038/nn.3728PMC PMC4256678
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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.

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Cited by

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Authors
Hait, N. C., Wise, L. E., Allegood, J. C., O'Brien, M., Avni, D., Reeves, T. M., Knapp, P. E., Lu, J., Luo, C., Miles, M. F., Milstien, S., Lichtman, A. H., & Spiegel, S.
Affiliations
  • Virginia Commonwealth University (US)
  • Chinese Academy of Sciences (CN)
Corresponding author
Spiegel, Sarah
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2014-05-25
Volume
17
Issue
7
Pages
971-980
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.3728
PMC
PMC4256678
OpenAlex
W1998033088
Cited by
209
References
7
Citations by year
2026: 6 · 2025: 9 · 2024: 15 · 2023: 12 · 2022: 15 · 2021: 13 · 2020: 27 · 2019: 18 · 2018: 17 · 2017: 26 · 2016: 24 · 2015: 18 · 2014: 9
FWCI
9.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Natural Science Foundation of China
  • National Institutes of Health
  • National Institute on Alcohol Abuse and Alcoholism (R01AA020634)
  • National Institute on Aging (R21AG042745)
  • National Institute on Drug Abuse (P01DA009789)
  • National Cancer Institute (R01CA061774, P30CA016059)
  • National Institute of General Medical Sciences (R01GM043880, R37GM043880)
  • National Institute of Neurological Disorders and Stroke (R01NS057758)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Keywords
fingolimod, sphingosine-1-phosphate, sphingosine kinase 2, histone deacetylase inhibition, histone acetylation, fear extinction memory, spatial memory, hippocampus, multiple sclerosis, drug repurposing, memory impairment
MeSH terms
Fingolimod Hydrochloride, Sphingosine Kinase, Animals, Brain, Exploratory Behavior, Extinction, Psychological, Fear, Hippocampus, Immunosuppressive Agents, Isoenzymes, Learning Disabilities, Lysophospholipids, Memory, Mice, Inbred C57BL, Models, Molecular, Phosphorylation, Propylene Glycols, Sphingosine, Blotting, Western, Gene Expression, Mice, SCID, Phosphotransferases (Alcohol Group Acceptor), Maze Learning, Spectrometry, Mass, Electrospray Ionization, Mice, Histone Deacetylase 1, Histone Deacetylase Inhibitors

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