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      Fingolimod effects in neuroinflammation: Regulation of astroglial glutamate transporters?

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          Abstract

          Fingolimod is an oral sphingosine-1-phosphate-receptor modulator which reduces the recirculation of immune cells and may also directly target glial cells. Here we investigate effects of fingolimod on expression of astroglial glutamate transporters under pro-inflammatory conditions. In astrocyte cell culture, the addition of pro-inflammatory cytokines led to a significant downregulation of glutamate transporters glutamate transporter-1 ( slc1a2/SLC1A2) and glutamate aspartate transporter ( slc1a3/SLC1A3) expression on the mRNA or protein level. In this setting, the direct application of fingolimod-1 phosphate (F1P) on astrocytes did not change expression levels of slc1a2 and slc1a3 mRNA. The analysis of both transporters on the protein level by Western Blot and immunocytochemistry did also not reveal any effect of F1P. On a functional level, the addition of conditioned supernatants from F1P treated astrocytes to neuronal cell culture did not result in increased neurite growth. In experimental autoimmune encephalomyelitis as a model of multiple sclerosis, fingolimod treatment reduced T cell and macrophages/microglia mediated inflammation and also diminished astrocyte activation. At the same time, fingolimod restored the reduced expression of slc1a2 and slc1a3 in the inflamed spinal cord on the mRNA level and of SLC1A2 and SLC1A3 on the protein level, presumably via indirect, anti-inflammatory mechanisms. These findings provide further evidence for a predominantly peripheral effect of the compound in neuroinflammation.

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          Most cited references28

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          Glutamate uptake.

          Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.
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            FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation.

            Sphingosine 1-phosphate (S1P), a lysophospholipid, has gained relevance to multiple sclerosis through the discovery of FTY720 (fingolimod), recently approved as an oral treatment for relapsing forms of multiple sclerosis. Its mechanism of action is thought to be immunological through an active phosphorylated metabolite, FTY720-P, that resembles S1P and alters lymphocyte trafficking through receptor subtype S1P(1). However, previously reported expression and in vitro studies of S1P receptors suggested that direct CNS effects of FTY720 might theoretically occur through receptor modulation on neurons and glia. To identify CNS cells functionally contributing to FTY720 activity, genetic approaches were combined with cellular and molecular analyses. These studies relied on the functional assessment, based on clinical score, of conditional null mouse mutants lacking S1P(1) in CNS cell lineages and challenged by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. All conditional null mutants displayed WT lymphocyte trafficking that responded normally to FTY720. In marked contrast, EAE was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P(1) on GFAP-expressing astrocytes but not on neurons. In situ hybridization studies confirmed that astrocyte loss of S1P(1) was the key alteration in functionally affected mutants. Reductions in EAE clinical scores were paralleled by reductions in demyelination, axonal loss, and astrogliosis. Receptor rescue and pharmacological experiments supported the loss of S1P(1) on astrocytes through functional antagonism by FTY720-P as a primary FTY720 mechanism. These data identify nonimmunological CNS mechanisms of FTY720 efficacy and implicate S1P signaling pathways within the CNS as targets for multiple sclerosis therapies.
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              Molecular and cellular mechanisms of excitotoxic neuronal death.

              Glutamate receptor-mediated excitatory neurotransmission plays a key role in neural development, differentiation and synaptic plasticity. However, excessive stimulation of glutamate receptors induces neurotoxicity, a process that has been defined as excitotoxicity. Excitotoxicity is considered to be a major mechanism of cell death in a number of central nervous system diseases including stroke, brain trauma, epilepsy and chronic neurodegenerative disorders. Unfortunately clinical trials with glutamate receptor antagonists, that would logically prevent the effects of excessive receptor activation, have been associated with untoward side effects or little clinical benefit. Therefore, uncovering molecular pathways involved in excitotoxic neuronal death is of critical importance to future development of clinical treatment of many neurodegenerative disorders where excitotoxicity has been implicated. This review discusses the current understanding of the molecular and cellular mechanisms of excitotoxicity and their roles in the pathogenesis of diseases of the central nervous system.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                8 March 2017
                2017
                : 12
                : 3
                : e0171552
                Affiliations
                [1 ]Department of Neurology, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
                [2 ]Department of Molecular Neurology, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
                [3 ]Institute of Molecular Neurobiology, Ruhr-University, Bochum, Germany
                Heinrich-Heine-Universitat Dusseldorf, GERMANY
                Author notes

                Competing Interests: Fingolimod is a product of Novartis. There are no other patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

                • Conceptualization: D-HL AM AW SW JW RAL.

                • Formal analysis: D-HL KH LB CR JS AK RAL.

                • Funding acquisition: SW JW RAL.

                • Investigation: D-HL SS KH LB CR AK.

                • Methodology: D-HL SS SW JW RAL.

                • Project administration: D-HL RAL.

                • Resources: JS AK AM SW JW.

                • Supervision: D-HL AM SW JW RAL.

                • Validation: D-HL SS AK.

                • Visualization: D-HL RAL.

                • Writing – original draft: D-HL SS AW JS SW JW RAL.

                • Writing – review & editing: D-HL RAL.

                Article
                PONE-D-16-18937
                10.1371/journal.pone.0171552
                5342171
                28273090
                3be7e2fd-e393-411b-ae29-6a97d0bdd182
                © 2017 Lee et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 May 2016
                : 22 January 2017
                Page count
                Figures: 5, Tables: 0, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award Recipient :
                The microscope used in this study was funded by the Deutsche Forschungsgemeinschaft (DFG). Novartis Pharma Germany supported previous research on fingolimod and provided fingolimod-1 phosphate for the present study. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Glial Cells
                Macroglial Cells
                Astrocytes
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                Biochemistry
                Neurochemistry
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                Glutamate
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