The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination

Br J Pharmacol. 2015 Jan;172(1):80-92. doi: 10.1111/bph.12938. Epub 2014 Dec 15.

Abstract

Background and purpose: Modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection.

Experimental approach: In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin-induced experimental demyelination. We used histological, immunohistochemical and gene expression methods.

Key results: The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone-induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this compound alleviated ongoing axonal damage.

Conclusions and implications: We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Corpus Callosum / drug effects
  • Corpus Callosum / pathology
  • Cuprizone
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / drug therapy*
  • Demyelinating Diseases / genetics
  • Demyelinating Diseases / metabolism
  • Fingolimod Hydrochloride
  • Gene Expression Regulation / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Membrane Proteins / genetics
  • Mice, Inbred C57BL
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Phosphatidate Phosphatase / genetics
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Propylene Glycols / pharmacology
  • Propylene Glycols / therapeutic use*
  • Receptors, Lysosphingolipid / agonists*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • Sphingosine / therapeutic use

Substances

  • Amyloid beta-Protein Precursor
  • Membrane Proteins
  • Neuroprotective Agents
  • Propylene Glycols
  • Receptors, Lysosphingolipid
  • Cuprizone
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • sphingosine-1-phosphate phosphatase
  • Phosphoric Monoester Hydrolases
  • LPP3 protein, mouse
  • Phosphatidate Phosphatase
  • Fingolimod Hydrochloride
  • Sphingosine