An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination

Nat Commun. 2016 Apr 26;7:11312. doi: 10.1038/ncomms11312.

Abstract

Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Carbohydrate Sequence
  • Cells, Cultured
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism*
  • Chondroitin Sulfate Proteoglycans / antagonists & inhibitors
  • Chondroitin Sulfate Proteoglycans / biosynthesis*
  • Chondroitin Sulfate Proteoglycans / chemistry
  • Female
  • Glucosamine / chemistry
  • Glucosamine / pharmacology
  • Humans
  • Mice, Inbred C57BL
  • Molecular Structure
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • Oligodendroglia / drug effects
  • Oligodendroglia / metabolism*
  • Remyelination / drug effects
  • Remyelination / physiology*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Stem Cells / drug effects
  • Stem Cells / metabolism*
  • Uridine Diphosphate Sugars / chemistry
  • Uridine Diphosphate Sugars / pharmacology

Substances

  • 4-fluoro-N-acetylhexosamine uridine diphosphate
  • Chondroitin Sulfate Proteoglycans
  • Small Molecule Libraries
  • Uridine Diphosphate Sugars
  • Glucosamine