Non-steroidal Anti-Inflammatory Drug Indometacin Enhances Endogenous Remyelination

Acta Neuropathol. 2015 Aug;130(2):247-61. doi: 10.1007/s00401-015-1426-z. Epub 2015 May 6.

Abstract

Multiple sclerosis is the most frequent demyelinating disease in the CNS that is characterized by inflammatory demyelinating lesions and axonal loss, the morphological correlate of permanent clinical disability. Remyelination does occur, but is limited especially in chronic disease stages. Despite effective immunomodulatory therapies that reduce the number of relapses the progressive disease phase cannot be prevented. Therefore, promotion of neuroprotective and repair mechanisms, such as remyelination, represents an attractive additional treatment strategy. A number of pathways have been identified that may contribute to impaired remyelination in MS lesions, among them the Wnt/β-catenin pathway. Here, we demonstrate that indometacin, a non-steroidal anti-inflammatory drug (NSAID) that has been also shown to modulate the Wnt/β-catenin pathway in colorectal cancer cells promotes differentiation of primary human and murine oligodendrocytes, myelination of cerebellar slice cultures and remyelination in cuprizone-induced demyelination. Our in vitro experiments using GSK3β inhibitors, luciferase reporter assays and oligodendrocytes expressing a mutant, dominant stable β-catenin indicate that the mechanism of action of indometacin depends on GSK3β activity and β-catenin phosphorylation. Indometacin might represent a promising treatment option to enhance endogenous remyelination in MS patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cells, Cultured
  • Cerebellum / drug effects
  • Cerebellum / pathology
  • Cerebellum / physiology
  • Cuprizone
  • Demyelinating Diseases / drug therapy
  • Demyelinating Diseases / pathology
  • Demyelinating Diseases / physiopathology
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Indomethacin / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myelin Sheath / drug effects*
  • Myelin Sheath / physiology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / pathology
  • Neural Stem Cells / physiology
  • Neuroprotective Agents / pharmacology*
  • Oligodendroglia / drug effects*
  • Oligodendroglia / pathology
  • Oligodendroglia / physiology
  • Tissue Culture Techniques
  • Wnt Signaling Pathway / drug effects

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Neuroprotective Agents
  • Cuprizone
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • Indomethacin