The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination

Mult Scler. 2018 Oct;24(11):1421-1432. doi: 10.1177/1352458517721355. Epub 2017 Jul 28.

Abstract

Background: In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely.

Objective: A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules.

Methods: In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes. Nitroreductase converts the innocuous pro-drug metronidazole to a cytotoxin. Spontaneous remyelination occurs after metronidazole-induced demyelinating responses. As tadpoles are transparent, these events can be monitored in vivo and quantified. At the end of metronidazole-induced demyelination, tadpoles were screened in water containing the compounds tested. After 72 h, remyelination was assayed by counting numbers of oligodendrocytes per optic nerve.

Results: Among a battery of molecules tested, siponimod, a dual agonist of sphingosine-1-phosphate receptor 1 and 5, was among the most efficient favoring remyelination. Crispr/cas9 gene editing showed that the promyelinating effect of siponimod involves the sphingosine-1-phosphate receptor 5.

Conclusion: This Xenopus transgenic line constitutes a simple in vivo screening platform for myelin repair therapeutics. We validated several known promyelinating compounds and demonstrated that the strong remyelinating efficacy of siponimod implicates the sphingosine-1-phosphate receptor 5.

Keywords: Crispr/Cas9; Multiple sclerosis; Xenopus laevis; demyelination; gene editing; oligodendrocyte; remyelination; transgenic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Azetidines / pharmacology*
  • Benzyl Compounds / pharmacology*
  • Disease Models, Animal*
  • Female
  • Larva
  • Male
  • Receptors, Lysosphingolipid / agonists*
  • Remyelination / drug effects*
  • Remyelination / physiology
  • Xenopus

Substances

  • Azetidines
  • Benzyl Compounds
  • Receptors, Lysosphingolipid
  • siponimod