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Glutamate excitotoxicity in a model of multiple sclerosis

Abstract

Glutamate excitotoxicity mediated by the AMPA/kainate type of glutamate receptors damages not only neurons but also the myelin-producing cell of the central nervous system, the oligodendrocyte1. In multiple sclerosis, myelin, oligodendrocytes and some axons are lost as a result of an inflammatory attack on the central nervous system2. Because glutamate is released in large quantities by activated immune cells3, we expected that during inflammation in MS, glutamate excitotoxicity might contribute to the lesion. We addressed this by using the AMPA/kainate antagonist NBQX to treat mice sensitized for experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of multiple sclerosis. Treatment resulted in substantial amelioration of disease, increased oligodendrocyte survival and reduced dephosphorylation of neurofilament H, an indicator of axonal damage4. Despite the clinical differences, treatment with NBQX had no effect on lesion size and did not reduce the degree of central nervous system inflammation. In addition, NBQX did not alter the proliferative activity of antigen-primed T cells in vitro, further indicating a lack of effect on the immune system. Thus, glutamate excitotoxicity seems to be an important mechanism in autoimmune demyelination, and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for multiple sclerosis.

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Figure 1: Clinical course of adoptive transfer EAE: Effect of treatment with NBQX.
Figure 2: CNPase-immunoreactive oligodendrocytes in lumbar spinal cord sections.
Figure 3: Axonal damage, assessed by immunoreactivity for abnormally dephosphorylated neurofilament H.

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Acknowledgements

We thank C. Weaver, F.C. Chiu and B. Cannella for discussions; P. Cobban-Bond for administrative assistance; and M. Pakingan, N. Rempel and E. Swanson for technical assistance. This work was supported in part by the National Multiple Sclerosis Society PP0693 (P.W. and D.P.), the Singer Foundation (P.W.), United States Public Health Service grants NS 08952, NS 11920 and NS 07098; the Sol Goldman Charitable Trust -NMSS RG 1001-I-9; and the Wollowick Family Foundation (C.S.R.). D.P. is a Deutsche Forschungsgemeinschaft postdoctoral fellow.

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Pitt, D., Werner, P. & Raine, C. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 6, 67–70 (2000). https://doi.org/10.1038/71555

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