Glutamate excitotoxicity mediated by the AMPA/kainate-type of glutamate receptors is known not only to damage neurons but also the myelin-producing cell of the central nervous system (CNS), the oligodendrocyte. In Multiple Sclerosis (MS), myelin, oligodendrocytes and axons are lost or damaged as a result of an inflammatory attack on the CNS. Activated immune cells produce glutamate in large quantities by deamidating glutamine via glutaminase. Thus, we hypothesized that during inflammation in MS, glutamate excitotoxicity may contribute to the lesion. This was addressed by treating mice sensitized to develop acute experimental autoimmune encephalomyelitis (EAE) with an AMPA/kainate antagonist, NBQX. Treatment resulted in substantial amelioration of disease, increased oligodendrocyte survival and reduced axonal damage, as indicated by the levels of dephosphorylated neurofilament-H. Despite the clinical differences, NB QX-treatment had no effect on lesion size and did not reduce the degree of CNS inflammation. In addition, NBQX did not alter the proliferative activity of antigen-primed T cells in vitro, further indicating a lack of effect at the level of the immune system. In separate studies, infiltrating immune cells present in perivascular cuffs, commonly the site of entry for invading immune cells, were found to express glutaminase in abundance, supporting the production of glutamate in inflammatory lesions. Thus, glutamate excitotoxicity appears to be an important mechanism in autoimmune demyelination and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for MS.