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Updated: Feb 16, 2026
Preparation of Rat Oligodendrocyte Progenitor Cultures and Quantification of Oligodendrogenesis Using Dual-infrared Fluorescence Scanning
Published on: February 17, 2016
Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination
Yongfeng Chen1, Wei Zhen2, Tony Guo2
1Neuro-immunology Discovery Performance Unit, GSK, Shanghai, China.
Background:
Agents promoting oligodendrocyte precursor cell differentiation have the potential to restore halted and/or delayed remyelination in patients with multiple sclerosis. However, few therapeutic targets have been identified. The objective of this study was to identify novel targets for promotion of remyelination and characterize their activity in vitro and in vivo.
Methods:
A high-content screening assay with differentiation of primary rat oligodendrocyte precursor cells was used to screen GSK-proprietary annotated libraries for remyelination-promoting compounds. Compounds were further validated in vitro and in vivo models; clinical relevance of target was confirmed in human post-mortem brain sections from patients with MS.
Results:
Of ~1000 compounds screened, 36 promoted oligodendrocyte precursor cell differentiation in a concentration-dependent manner; seven were histamine receptor-3 (H3R) antagonists. Inverse agonists of H3R but not neutral antagonists promoted oligodendrocyte precursor cell (OPC) differentiation. H3R was expressed throughout OPC differentiation; H3R expression was transiently upregulated on Days 3-5 and subsequently downregulated. H3R gene knockdown in OPCs increased the expression of differentiation markers and the number of mature oligodendrocytes. Overexpression of full-length H3R reduced differentiation marker expression and the number of mature cells. H3R inverse agonist GSK247246 reduced intracellular cyclic AMP (cAMP) and downstream cAMP response element-binding protein (CREB) phosphorylation in a dose-dependent manner. Histone deacetylase (HDAC-1) and Hes-5 were identified as key downstream targets of H3R during OPC differentiation. In the mouse cuprizone/rapamycin model of demyelination, systemic administration of brain-penetrable GSK247246 enhanced remyelination and subsequently protected axons. Finally, we detected high H3R expression in oligodendroglial cells from demyelination lesions in human samples of patients with MS, and validated a genetic association between an exonic single nucleotide polymorphism in HRH3 and susceptibility to multiple sclerosis.
Conclusions:
From phenotypic screening to human genetics, we provide evidence for H3R as a novel therapeutic target to promote remyelination in patients with multiple sclerosis.
Insights
Histamine receptor-3 (H3R) antagonists show potential for promoting remyelination in multiple sclerosis. Targeting H3R with inverse agonists enhances oligodendrocyte differentiation and offers a novel therapeutic strategy for this neurodegenerative disease.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Promoting oligodendrocyte precursor cell (OPC) differentiation is crucial for remyelination in multiple sclerosis (MS).
- Identifying novel therapeutic targets for remyelination remains a significant challenge in MS research.
Purpose of the Study:
- To identify novel targets that promote OPC differentiation and remyelination.
- To characterize the activity of identified targets in vitro and in vivo models of demyelination.
Main Methods:
- High-content screening of GSK-proprietary libraries identified compounds promoting OPC differentiation.
- In vitro and in vivo models were used to validate compound efficacy.
- Human post-mortem brain sections and genetic analysis confirmed clinical relevance.
Main Results:
- Seven out of ~1000 screened compounds were histamine receptor-3 (H3R) antagonists, with inverse agonists promoting OPC differentiation.
- H3R inverse agonist GSK247246 enhanced remyelination and protected axons in a mouse model.
- Genetic association studies revealed a link between H3R and MS susceptibility.
Conclusions:
- Histamine receptor-3 (H3R) is identified as a novel therapeutic target for promoting remyelination.
- H3R inverse agonists demonstrate potential for treating multiple sclerosis by enhancing remyelination.
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09:36High-Content Screening Differentiation and Maturation Analysis of Fetal and Adult Neural Stem Cell-Derived Oligodendrocyte Precursor Cell Cultures
Published on: March 10, 2021
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