Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.

Therapeutic Approaches

Abstract

Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.

Authors

Najm, Fadi J; Madhavan, Mayur; Zaremba, Anita; Shick, Elizabeth; Karl, Robert T; Factor, Daniel C; Miller, Tyler E; Nevin, Zachary S; Kantor, Christopher; Sargent, Alex; Quick, Kevin L; Schlatzer, Daniela M; Tang, Hong; Papoian, Ruben; Brimacombe, Kyle; Shen, Min; Boxer, Matthew B; Jadhav, Ajit; Robinson, Andrew P; Podojil, Joseph R; Miller, Stephen D; Miller, Robert H; Tesar, Paul J;

Keywords

  • Animals
  • Cell Differentiation/ drug effects
  • Cerebellum/ drug effects
  • Cerebellum/ metabolism
  • Cerebellum/ pathology
  • Clobetasol/ pharmacology
  • Demyelinating Diseases/ drug therapy
  • Demyelinating Diseases/ metabolism
  • Demyelinating Diseases/ pathology
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental/ drug therapy
  • Encephalomyelitis, Autoimmune, Experimental/ metabolism
  • Encephalomyelitis, Autoimmune, Experimental/ pathology
  • Female
  • Germ Layers/ drug effects
  • Germ Layers/ metabolism
  • Germ Layers/ pathology
  • Humans
  • Lysophosphatidylcholines
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Miconazole/ pharmacology
  • Mitogen-Activated Protein Kinases/ metabolism
  • Multiple Sclerosis/ drug therapy
  • Multiple Sclerosis/ metabolism
  • Multiple Sclerosis/ pathology
  • Myelin Sheath/ drug effects
  • Myelin Sheath/ metabolism
  • Oligodendroglia/ cytology
  • Oligodendroglia/ drug effects
  • Oligodendroglia/ metabolism
  • Phenotype
  • Pluripotent Stem Cells/ cytology
  • Pluripotent Stem Cells/ drug effects
  • Pluripotent Stem Cells/ metabolism
  • Receptors, Glucocorticoid/ metabolism
  • Regeneration/ drug effects
  • Tissue Culture Techniques

External Links