2. Academic Validation
  3. Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence

Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence

  • EBioMedicine. 2021 Mar;65:103276. doi: 10.1016/j.ebiom.2021.103276.
Anastasia Manousi 1,  Peter Göttle 1,  Laura Reiche 1,  Qiao-Ling Cui 2,  Luke M Healy 2,  Rainer Akkermann 1,  Joel Gruchot 1,  Jessica Schira-Heinen 1,  Jack P Antel 2,  Hans-Peter Hartung 3,  Patrick Küry 4
Affiliations

Affiliations

  • 1 Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225, Germany.
  • 2 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H4A 3K9, Canada.
  • 3 Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225, Germany; Brain and Mind Centre, University of Sydney, Camperdown NSW 2050, Australia.
  • 4 Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225, Germany. Electronic address: [email protected].
PMID: 33714029 DOI: 10.1016/j.ebiom.2021.103276
Abstract

Background: In multiple sclerosis loss of myelin and oligodendrocytes impairs saltatory signal transduction and leads to neuronal loss and functional deficits. Limited capacity of oligodendroglial precursor cells to differentiate into mature cells is the main reason for inefficient myelin repair in the central nervous system. Drug repurposing constitutes a powerful approach for identification of pharmacological compounds promoting this process.

Methods: A phenotypic compound screening using the subcellular distribution of a potent inhibitor of oligodendroglial cell differentiation, namely p57kip2, as differentiation competence marker was conducted. Hit compounds were validated in terms of their impact on developmental cell differentiation and myelination using both rat and human primary cell cultures and organotypic cerebellar slice cultures, respectively. Their effect on spontaneous remyelination was then investigated following cuprizone-mediated demyelination of the corpus callosum.

Findings: A number of novel small molecules able to promote oligodendroglial cell differentiation were identified and a subset was found to foster human oligodendrogenesis as well as myelination ex vivo. Among them the steroid danazol and the anthelminthic parbendazole were found to increase myelin repair.

Interpretation: We provide evidence that early cellular processes involved in differentiation decisions are applicable for the identification of regeneration promoting drugs and we suggest danazol and parbendazole as potent therapeutic candidates for demyelinating diseases.

Funding: This work was supported by the Jürgen Manchot Foundation, Düsseldorf; Research Commission of the Medical Faculty of Heinrich-Heine-University Düsseldorf; Christiane and Claudia Hempel Foundation; Stifterverband/Novartisstiftung; James and Elisabeth Cloppenburg, Peek and Cloppenburg Düsseldorf Stiftung and International Progressive MS Alliance (BRAVEinMS).

Keywords

CDKN1C; Cell differentiation; Drug repurposing; Nuclear protein shuttling; Remyelination; Toxin-mediated demyelination.

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