The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination.
Mult Scler
; 24(11): 1421-1432, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-28752787
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Azetidinas
/
Compostos de Benzil
/
Receptores de Lisoesfingolipídeo
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Modelos Animais de Doenças
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Remielinização
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article