Nature Medicine
6, 67 - 70 (2000)
doi:10.1038/71555
Glutamate excitotoxicity in a model of multiple sclerosisDavid Pitt2, 5, Peter Werner1, 3, 5
& Cedric S. Raine1, 2, 41
Department of Neurology, F-121N, Albert Einstein College
of Medicine, 1300 Morris Park Ave., Bronx, New York, 10461, USA
2
Department of Pathology, F-121N, Albert Einstein College
of Medicine, 1300 Morris Park Ave., Bronx, New York, 10461, USA
3
Dept. of Neurology, Beth Israel Medical Center, 10 Union Square East, New York, New York 10003, USA
4
Department of Neuroscience, F-121N, Albert Einstein
College of Medicine, 1300 Morris Park Ave., Bronx, New York, 10461, USA
5
D.P and P.W. contributed equally to this study.
Correspondence should be addressed to Peter Werner pwerner@aecom.yu.edu.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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