Tags

Type your tag names separated by a space and hit enter

Fingolimod modulates microglial activation to augment markers of remyelination.
J Neuroinflammation. 2011 Jul 05; 8:76.JN

Abstract

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.

Authors+Show Affiliations

Centre 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.ukNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21729281

Citation

Jackson, Samuel J., et al. "Fingolimod Modulates Microglial Activation to Augment Markers of Remyelination." Journal of Neuroinflammation, vol. 8, 2011, p. 76.
Jackson SJ, Giovannoni G, Baker D. Fingolimod modulates microglial activation to augment markers of remyelination. J Neuroinflammation. 2011;8:76.
Jackson, S. J., Giovannoni, G., & Baker, D. (2011). Fingolimod modulates microglial activation to augment markers of remyelination. Journal of Neuroinflammation, 8, 76. https://doi.org/10.1186/1742-2094-8-76
Jackson SJ, Giovannoni G, Baker D. Fingolimod Modulates Microglial Activation to Augment Markers of Remyelination. J Neuroinflammation. 2011 Jul 5;8:76. PubMed PMID: 21729281.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fingolimod modulates microglial activation to augment markers of remyelination. AU - Jackson,Samuel J, AU - Giovannoni,Gavin, AU - Baker,David, Y1 - 2011/07/05/ PY - 2011/01/27/received PY - 2011/07/05/accepted PY - 2011/7/7/entrez PY - 2011/7/7/pubmed PY - 2012/2/24/medline SP - 76 EP - 76 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 8 N2 - 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/21729281/Fingolimod_modulates_microglial_activation_to_augment_markers_of_remyelination_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-8-76 DB - PRIME DP - Unbound Medicine ER -