Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter

Spinal cord injury involves a component of glutamate-mediated white matter damage, but the cellular targets, receptors, and ions involved are poorly understood. Mechanisms of excitotoxicity were examined in an in vitro model of isolated spinal dorsal columns. Compound action potentials (CAPs) were irreversibly reduced to 43% of control after 3 hr of 1 mM glutamate exposure at 37 degrees C. AMPA (100 mu M) and kainate (500 mu M) had similar effects. Antagonists (1 mM kynurenic acid, 10 mu M NBQX, 30 mu M GYKI52466) were each equally protective against a glutamate challenge, improving mean CAP amplitude to similar to 80% versus similar to 40% without antagonist. Joro spider toxin (0.75 mu M), a selective blocker of Ca2+-permeable AMPA receptors, was also protective to a similar degree. Ca2+-free perfusate virtually abolished glutamate-induced injury (similar to 90% vs similar to 40%). MK-801 (10 mu M) had no effect. Glutamate caused damage (assayed immunohistochemically by spectrin breakdown products) to astrocytes and oligodendrocytes consistent with the presence of GluR2/3 and GluR4 in these cells. Myelin was also damaged by glutamate likely mediated by GluR4 receptors detected in this region; however, axon cylinders were unaffected by glutamate, showing no increase in the level of spectrin breakdown. These data may guide the development of more effective treatment for acute spinal cord injury by addressing the additional excitotoxic component of spinal white matter damage.