Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination

作者：Preisner Anna; Albrecht Stefanie; Cui Qiao Ling; Hucke Stephanie; Ghelman Julia; Hartmann Christine; Taketo Makoto Mark; Antel Jack; Klotz Luisa; Kuhlmann Tanja^*

来源：Acta Neuropathologica, 2015, 130(2): 247-261.

DOI：10.1007/s00401-015-1426-z

• Multiple sclerosis
• Oligodendrocytes
• Remyelination
• Indometacin
• beta-Catenin
• GSK3 beta

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/beta-catenin pathway. Here, we demonstrate that indometacin, a non-steroidal anti-inflammatory drug (NSAID) that has been also shown to modulate the Wnt/beta-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 GSK3 beta inhibitors, luciferase reporter assays and oligodendrocytes expressing a mutant, dominant stable beta-catenin indicate that the mechanism of action of indometacin depends on GSK3 beta activity and beta-catenin phosphorylation. Indometacin might represent a promising treatment option to enhance endogenous remyelination in MS patients.

• 出版日期2015-8