Glutamate excitotoxicity in a model of multiple sclerosis

Glutamate excitotoxicity mediated by the AMPA/kainate type of glutamate rec eptors damages not only neurons but also the myelin-producing cell of the c entral nervous system, the oligodendrocyte(1). In multiple sclerosis, myeli n, oligodendrocytes and some axons are lost as a result of an inflammatory attack on the central nervous system(2). Because glutamate is released in l arge quantities by activated immune cells(3), we expected that during infla mmation in MS, glutamate excitotoxicity might contribute to the lesion. We addressed this by using the AMPA/kainate antagonist NBQX to treat mice sens itized for experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of multiple scler osis. Treatment resulted in substantial amelioration of disease, increased oligodendrocyte survival and reduced dephosphorylation of neurofilament H, an indicator of axonal damage(4). Despite the clinical differences, treatme nt 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 pr oliferative activity of antigen-primed T cells in vitro, further indicating a lack of effect on the immune system. Thus, glutamate excitotoxicity seem s to be an important mechanism in autoimmune demyelination, and its prevent ion with AMPA/kainate antagonists may prove to be an effective therapy for multiple sclerosis.