PUBLICATION
Development of zebrafish demyelination model for evaluation of remyelination compounds and RORγt inhibitors
- Authors
- Zhu, X.Y., Guo, S.Y., Xia, B., Li, C.Q., Wang, L., Wang, Y.H.
- ID
- ZDB-PUB-190522-11
- Date
- 2019
- Source
- Journal of Pharmacological and Toxicological Methods 98: 106585 (Journal)
- Registered Authors
- Keywords
- Anti-inflammation, Demyelination, RORĪ³t inhibitors, Regeneration, Remyelination, Zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Axons/drug effects
- Demyelinating Diseases/drug therapy*
- Disease Models, Animal
- Ethidium/pharmacology
- Myelin Basic Protein
- Myelin Sheath/drug effects
- Nerve Regeneration/drug effects
- Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors*
- Remyelination/drug effects*
- Zebrafish/physiology*
- PubMed
- 31112751 Full text @ J. Pharmacol. Toxicol. Methods
Citation
Zhu, X.Y., Guo, S.Y., Xia, B., Li, C.Q., Wang, L., Wang, Y.H. (2019) Development of zebrafish demyelination model for evaluation of remyelination compounds and RORγt inhibitors. Journal of Pharmacological and Toxicological Methods. 98:106585.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping