title: Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination.
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.
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Preisner
authors.forename: Stefanie
authors.initials: S
authors.lastname: Albrecht
authors.forename: Qiao-Ling
authors.initials: QL
authors.lastname: Cui
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hucke
authors.forename: Julia
authors.initials: J
authors.lastname: Ghelman
authors.forename: Christine
authors.initials: C
authors.lastname: Hartmann
authors.forename: Makoto Mark
authors.initials: MM
authors.lastname: Taketo
authors.forename: Jack
authors.initials: J
authors.lastname: Antel
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000187:drug effects* / Q000502:physiology; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D046509:Tissue Culture Techniques; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents; D003471:Cuprizone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D007213:Indomethacin