CHARACTERISTICS OF ACUTE AND CHRONIC KAINATE EXCITOTOXIC DAMAGE TO THE OPTIC-NERVE

Macroglial cells express ionotropic glutamate receptors. In the adult optic nerve, reverse transcription-PCR showed that the native receptor s are formed by subunits belonging to the lpha-amino-3-hydroxy-5-methy l-4-isoxazolepropionic acid (AMPA) and kainate classes. Because activa tion of AMPA and kainate receptors can be toxic to oligodendrocytes in vitro, I examined the nature of the damage caused by kainate, an agon ist of both receptor classes, applied directly onto the optic nerve. A cute infusion or chronic slow delivery of the agonist caused massive n erve damage that was more extensive in the latter. Interestingly, chro nic delivery also produced inflammation and demyelination in well circ umscribed areas of the nerve, together with other pathological feature s that closely resemble those observed in multiple sclerosis patients. Acute and chronic kainate lesions were both prevented by the non-N-me thyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-di one. However, GYKI53655, a specific AMPA receptor antagonist, did not significantly reduce the size of the lesion, suggesting that the kaina te toxicity was mainly mediated through activation of kainate-preferri ng glutamate receptors. These observations suggest that alterations in glutamate signaling may be detrimental to oligodendrocytes and may be involved in the pathogenesis of multiple sclerosis and other demyelin ating diseases.