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Development of Zebrafish Demyelination Model for Evaluation of Remyelination Compounds and RORγt Inhibitors

Development of Zebrafish Demyelination Model for Evaluation of Remyelination Compounds and RORγt Inhibitors

Xiao-Yu Zhu, Sheng-Ya Guo, Bo Xia, Chun-Qi Li, Lei Wang, Yong-Hui Wang

J Pharmacol Toxicol Methods. Jul-Aug 2019;98:106585.

PMID: 31112751

Abstract:

RAR-related orphan receptor-γt (RORγt) directs differentiation of proinflammatory T helper 17 cells and is a potential therapeutic target for chronic autoimmune and inflammatory diseases including multiple sclerosis. In this study, zebrafish at days post fertilization treated with ethidium bromide (EB) at a concentration of 75 μM for 72 h were determined as the optimum conditions for the demyelination model development. Zebrafish motility was recorded automatically using a video-track motion detector and quantitative myelin assay was measured by FluoroMyelin staining. A well-known remyelination agent thyroxine (T4) was tested to confirm whether EB-induced motility and myelin damage could be rescued. Two RORγt lead inhibitors GSK805 and SR1001 were assessed for their therapeutic effects on remyelination, axon regeneration, motor neuron promotion and anti-inflammation. T4 significantly improved EB-induced motility dysfunction and myelin damage and promoted myelin basic protein (MBP) regeneration in the demyelinated zebrafish. GSK805 and SR1001 enhanced remyelination in a dose-dependent manner and promoted MBP regeneration. Both GSK805 and SR1001 markedly recovered EB-induced axon and motor neuron damage, and exhibited significantly inhibitory effects of neutrophil infiltration and macrophage recruitment. These results indicate that EB treatment can induce zebrafish demyelination; and the zebrafish demyelination model in combination with quantitative motility and myelin assays is a predictive, reproducible and relatively high throughput screening for rapidly in vivo identification of remyelination compounds and RORγt inhibitors.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1335106030	SR1001		1335106-03-0	Price

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