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Updated: May 31, 2026
Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin
Published on: March 26, 2015
Fingolimod modulates microglial activation to augment markers of remyelination
Samuel J Jackson1, Gavin Giovannoni, David Baker
1Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. s.j.jackson@qmul.ac.uk
Introduction:
Microglial activation in multiple sclerosis has been postulated to contribute to long-term neurodegeneration during disease. Fingolimod has been shown to impact on the relapsing remitting phase of disease by modulating autoreactive T-cell egress from lymph organs. In addition, it is brain penetrant and has been shown to exert multiple effects on nervous system cells.
Methods:
In this study, the impact of fingolimod and other sphingosine-1-phosphate receptor active molecules following lysophosphotidyl choline-induced demyelination was examined in the rat telencephalon reaggregate, spheroid cell culture system. The lack of immune system components allowed elucidation of the direct effects of fingolimod on CNS cell types in an organotypic situation.
Results:
Following demyelination, fingolimod significantly augmented expression of myelin basic protein in the remyelination phase. This increase was not associated with changes in neurofilament levels, indicating de novo myelin protein expression not associated with axonal branching. Myelin wrapping was confirmed morphologically using confocal and electron microscopy. Increased remyelination was associated with down-regulation of microglial ferritin, tumor necrosis factor alpha and interleukin 1 during demyelination when fingolimod was present. In addition, nitric oxide metabolites and apoptotic effectors caspase 3 and caspase 7 were reduced during demyelination in the presence of fingolimod. The sphingosine-1-phosphate receptor 1 and 5 agonist BAF312 also increased myelin basic protein levels, whereas the sphingosine-1-phosphate receptor 1 agonist AUY954 failed to replicate this effect on remyelination.
Conclusions:
The results presented indicate that modulation of S1P receptors can ameliorate pathological effectors associated with microglial activation leading to a subsequent increase in protein and morphological markers of remyelination. In addition, sphingosine-1-phosphate receptor 5 is implicated in promoting remyelination in vitro. This knowledge may be of benefit for treatment of chronic microglial inflammation in multiple sclerosis.
Insights
Fingolimod promotes remyelination in a multiple sclerosis model by modulating microglial activation and sphingosine-1-phosphate receptors. This study highlights S1P receptor 5's role in enhancing myelin repair, offering potential therapeutic insights for chronic neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglial activation contributes to neurodegeneration in multiple sclerosis (MS).
- Fingolimod modulates T-cell egress and affects central nervous system (CNS) cells.
- Understanding direct effects on CNS cells is crucial for MS treatment.
Purpose of the Study:
- To investigate the impact of fingolimod and other sphingosine-1-phosphate (S1P) receptor modulators on demyelination and remyelination.
- To elucidate the direct effects of these molecules on CNS cells in an organotypic culture system.
- To explore the role of S1P receptors in ameliorating pathological processes in MS.
Main Methods:
- Used a rat telencephalon spheroid cell culture system with lysophosphatidylcholine-induced demyelination.
- Examined the effects of fingolimod and specific S1P receptor agonists (BAF312, AUY954).
- Assessed myelin basic protein, neurofilaments, microglial markers, nitric oxide, and apoptosis via microscopy and biochemical analysis.
Main Results:
- Fingolimod significantly increased myelin basic protein expression, indicating enhanced remyelination.
- Morphological analysis confirmed increased myelin wrapping.
- Fingolimod reduced microglial activation markers (ferritin, TNF-α, IL-1), nitric oxide, and apoptosis.
- S1P receptor 1 and 5 agonist BAF312 also promoted remyelination, while S1P receptor 1 agonist AUY954 did not.
Conclusions:
- Modulation of S1P receptors can reduce pathological effects of microglial activation.
- Increased protein and morphological markers of remyelination were observed.
- Sphingosine-1-phosphate receptor 5 is implicated in promoting in vitro remyelination.
- Findings may inform treatments for chronic microglial inflammation in multiple sclerosis.
