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Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination

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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.

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Acknowledgments

This study was supported by grants from the German Research Foundation (SFB-TR128-B7; Ku1477/6-1), the Interdisciplinary Clinical Research Center, Münster (IZKF; KuT3/006/11) and the Hertie Foundation (P1130073) to TK.

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    Authors and Affiliations

    1. Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany

      Anna Preisner, Stefanie Albrecht, Julia Ghelman & Tanja Kuhlmann

    2. Montreal Neurological Institute, McGill University, Montreal, QC, Canada

      Qiao-Ling Cui & Jack Antel

    3. Department of Neurology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

      Stephanie Hucke & Luisa Klotz

    4. Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

      Christine Hartmann

    5. Department of Pharmacology, Kyoto University Graduate School of Medicine Yoshida- Konoé-cho, Sakyo-Ku, Kyoto, 606-8501, Japan

      Makoto Mark Taketo

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    1. Anna Preisner
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    Correspondence to Tanja Kuhlmann.

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    A. Preisner and S. Albrecht contributed equally.

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    Preisner, A., Albrecht, S., Cui, QL. et al. Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination. Acta Neuropathol 130, 247–261 (2015). https://doi.org/10.1007/s00401-015-1426-z

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