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Glatiramer Acetate Protects Against Inflammatory Synaptopathy in Experimental Autoimmune Encephalomyelitis

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Abstract

Glutamate-mediated excitotoxicity is supposed to induce neurodegeneration in multiple sclerosis (MS). Glatiramer acetate (GA) is an immunomodulatory agent used in MS treatment with potential neuroprotective action. Aim of the present study was to investigate whether GA has effects on glutamate transmission alterations occurring in experimental autoimmune encephalomyelitis (EAE), to disclose a possible mechanism of GA-induced neuroprotection in this mouse model of MS. Single neuron electrophysiological recordings and immunofluorescence analysis of microglia activation were performed in the striatum of EAE mice, treated or not with GA, at different stages of the disease. GA treatment was able to reverse the tumor necrosis factor-α (TNF-α)-induced alterations of striatal glutamate-mediated excitatory postsynaptic currents (EPSCs) of EAE mice. Incubation of striatal slices of control animals with lymphocytes taken from EAE mice treated with GA failed to replicate such an anti-glutamatergic effect, while activated microglial cells stimulated with GA in vitro mimicked the effect of GA treatment of EAE mice. Consistently, EAE mice treated with GA had less microglial activation and less TNF-α expression than untreated EAE animals. Furthermore, direct application of GA to EAE slices replicated the in vivo protective activity of GA. Our results show that GA is neuroprotective against glutamate toxicity independently of its peripheral immunodulatory action, and through direct modulation of microglial activation and TNF-α release in the grey matter of EAE and possibly of MS brains.

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Acknowledgments

The authors thank Vladimiro Batocchi, Massimo Tolu and Maria Teresa Ciotti for excellent technical assistance. This investigation was supported by a grant from TEVA to DC, by the Italian National Ministero della Salute and by Fondazione TERCAS to DC; by a grant from the European Community (AXREGEN: Axonal regeneration, plasticity & stem cells - Grant agreement 21 4003) founding PhD fellowship of NH.

Conflict of Interest

Silvia Rossi received honoraria for writing from Bayer Schering and funding for traveling from Novartis, Teva, and Merck Serono. She is involved as sub-investigator in clinical trials for Novartis, Merck Serono, Teva, Bayer Schering, Sanofi-aventis, and Biogen Idec.

Valentina De Chiara received funding for traveling by Teva. She is involved as study coordinator in clinical trials for Novartis, Merck Serono, Teva, Bayer Schering, Sanofi-aventis, and Biogen Idec.

Giorgio Bernardi is the principal investigator in clinical trials for Merck Serono and Teva.

Diego Centonze acted as an Advisory Board member of Merck-Serono, Teva, Novartis, Biogen, Bayer Schering, and received funding for traveling and honoraria for speaking or consultation fees from Merck Serono, Teva, Novartis, Bayer Schering, Sanofi-aventis, and Biogen Idec. He is also the principal investigator in clinical trials for Novartis, Merck Serono, Teva, Bayer Schering, Sanofi-aventis, and Biogen Idec.

The other authors have no conflict of interests to declare.

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Authors and Affiliations

  1. Fondazione Santa Lucia/Centro Europeo per la Ricerca sul Cervello (CERC), Via del Fosso di Fiorano 64, 00143, Rome, Italy

    Antonietta Gentile, Silvia Rossi, Valeria Studer, Caterina Motta, Valentina De Chiara, Alessandra Musella, Helena Sepman, Diego Fresegna, Gabriele Musumeci, Giorgio Grasselli, Nabila Haji, Georgia Mandolesi & Diego Centonze

  2. Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133, Rome, Italy

    Antonietta Gentile, Silvia Rossi, Valeria Studer, Caterina Motta, Valentina De Chiara, Alessandra Musella, Diego Fresegna & Diego Centonze

  3. National Institute of Neuroscience, University of Turin, Turin, Italy

    Nabila Haji

  4. Department of Neurobiology, University of Chicago, Chicago, IL, 60637, USA

    Giorgio Grasselli

  5. Teva Pharmaceuticals, Netanya, Israel

    Sagit Weiss & Liat Hayardeny

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  1. Antonietta Gentile
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  2. Silvia Rossi
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  3. Valeria Studer
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  4. Caterina Motta
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  14. Georgia Mandolesi
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  15. Diego Centonze
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Correspondence to Diego Centonze.

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Gentile, A., Rossi, S., Studer, V. et al. Glatiramer Acetate Protects Against Inflammatory Synaptopathy in Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol 8, 651–663 (2013). https://doi.org/10.1007/s11481-013-9436-x

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  • DOI: https://doi.org/10.1007/s11481-013-9436-x

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