Oral fingolimod rescues the functional deficits of synapses in experimental autoimmune encephalomyelitis
Open Access
- 8 July 2011
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 165 (4), 861-869
- https://doi.org/10.1111/j.1476-5381.2011.01579.x
Abstract
BACKGROUND AND PURPOSE Alterations of glutamate-mediated synaptic transmission occur early during neuroinflammatory insults, and lead to degenerative neuronal damage in multiple sclerosis (MS) and also in experimental autoimmune encephalomyelitis (EAE), which is a murine model of MS. Fingolimod is an effective orally active agent for the treatment of MS, affecting lymphocyte invasion of the brain. However, it is still unclear if fingolimod can be neuroprotective in this disorder. EXPERIMENTAL APPROACH Using neurophysiological recordings and morphological evaluation of dendritic integrity, we evaluated the effects of oral fingolimod on the clinical score of EAE mice in order to determine whether the compound was associated with preservation of synaptic transmission. KEY RESULTS Oral fingolimod prevented and reversed the pre- and postsynaptic alterations of glutamate transmission in EAE mice. These effects were associated with a clear amelioration of the clinical deterioration seen in EAE mice, and with a significant inhibition of neuronal dendritic pathology. Fingolimod did not alter the spontaneous excitatory postsynaptic currents in control animals, suggesting that only the pathological processes behind the inflammation-induced defects in glutamate transmission were modulated by this compound. CONCLUSIONS AND IMPLICATIONS The beneficial effects of fingolimod on the clinical, synaptic and dendritic abnormalities of murine EAE might correlate with the neuroprotective actions of this agent, as observed in MS patients. LINKED ARTICLE This article is commented on by Gillingwater, pp. 858–860 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01612.xKeywords
This publication has 54 references indexed in Scilit:
- Guide to Receptors and Channels (GRAC), 5th editionBritish Journal of Pharmacology, 2011
- FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P 1 ) modulationProceedings of the National Academy of Sciences, 2010
- Mechanisms of neuronal dysfunction and degeneration in multiple sclerosisProgress in Neurobiology, 2010
- Cellular Localization of Sphingosine-1-phosphate Receptor 1 Expression in the Human Central Nervous SystemJournal of Histochemistry & Cytochemistry, 2010
- Mechanism of Action of Oral Fingolimod (FTY720) in Multiple SclerosisClinical Neuropharmacology, 2010
- Hippocampal CA1 atrophy and synaptic loss during experimental autoimmune encephalomyelitis, EAELaboratory Investigation, 2010
- Inflammation in neurodegenerative diseasesImmunology, 2010
- FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous systemBritish Journal of Pharmacology, 2009
- Sphingosine‐1‐phosphate receptors mediate neuromodulatory functions in the CNSJournal of Neurochemistry, 2009
- Multiple sclerosisThe Lancet, 2008