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Clobetasol and Halcinonide Act as Smoothened Agonists to Promote Myelin Gene Expression and RxRγ Receptor Activation

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  • Giampiero Porcu
  • Eliseo Serone
  • Velia De Nardis
  • Daniele Di Giandomenico
  • Giuseppe Lucisano
  • Marco Scardapane
  • Anna Poma
  • Antonella Ragnini-Wilson

Abstract

One of the causes of permanent disability in chronic multiple sclerosis patients is the inability of oligodendrocyte progenitor cells (OPCs) to terminate their maturation program at lesions. To identify key regulators of myelin gene expression acting at the last stages of OPC maturation we developed a drug repositioning strategy based on the mouse immortalized oligodendrocyte (OL) cell line Oli-neu brought to the premyelination stage by stably expressing a key factor regulating the last stages of OL maturation. The Prestwick Chemical Library® of 1,200 FDA-approved compound(s) was repositioned at three dosages based on the induction of Myelin Basic Protein (MBP) expression. Drug hits were further validated using dosage-dependent reproducibility tests and biochemical assays. The glucocorticoid class of compounds was the most highly represented and we found that they can be divided in three groups according to their efficacy on MBP up-regulation. Since target identification is crucial before bringing compounds to the clinic, we searched for common targets of the primary screen hits based on their known chemical-target interactomes, and the pathways predicted by top ranking compounds were validated using specific inhibitors. Two of the top ranking compounds, Halcinonide and Clobetasol, act as Smoothened (Smo) agonists to up-regulate myelin gene expression in the Oli-neuM cell line. Further, RxRγ activation is required for MBP expression upon Halcinonide and Clobetasol treatment. These data indicate Clobetasol and Halcinonide as potential promyelinating drugs and also provide a mechanistic understanding of their mode of action in the pathway leading to myelination in OPCs. Furthermore, our classification of glucocorticoids with respect to MBP expression provides important novel insights into their effects in the CNS and a rational criteria for their choice in combinatorial therapies in de-myelinating diseases.

Suggested Citation

  • Giampiero Porcu & Eliseo Serone & Velia De Nardis & Daniele Di Giandomenico & Giuseppe Lucisano & Marco Scardapane & Anna Poma & Antonella Ragnini-Wilson, 2015. "Clobetasol and Halcinonide Act as Smoothened Agonists to Promote Myelin Gene Expression and RxRγ Receptor Activation," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-22, December.
  • Handle: RePEc:plo:pone00:0144550
    DOI: 10.1371/journal.pone.0144550
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    1. Fadi J. Najm & Mayur Madhavan & Anita Zaremba & Elizabeth Shick & Robert T. Karl & Daniel C. Factor & Tyler E. Miller & Zachary S. Nevin & Christopher Kantor & Alex Sargent & Kevin L. Quick & Daniela , 2015. "Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo," Nature, Nature, vol. 522(7555), pages 216-220, June.
    2. Vishal A. Deshmukh & Virginie Tardif & Costas A. Lyssiotis & Chelsea C. Green & Bilal Kerman & Hyung Joon Kim & Krishnan Padmanabhan & Jonathan G. Swoboda & Insha Ahmad & Toru Kondo & Fred H. Gage & A, 2013. "A regenerative approach to the treatment of multiple sclerosis," Nature, Nature, vol. 502(7471), pages 327-332, October.
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