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glutamate
Glutamate excitotoxicity in a
                  model of multiple sclerosis

                       David Pitt2, 5, Peter Werner1, 3, 5 & Cedric S.
                       Raine1, 2, 4
 

                       1. 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 P Werner.
                       e-mail: 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.
 

Glutamate excitotoxicity in a model of multiple sclerosis 


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