Tumor necrosis factor-alpha induces cFOS and strongly potentiates glutamate-mediated cell death in the rat spinal cord

Excitotoxic cell death due to glutamate release is important in the seconda ry injury following CNS trauma or ischemia. Proinflammatory cytokines also play a role. Both glutamate and tumor necrosis factor-alpha (TNFalpha) are released immediately after spinal cord injury. Neurophysiological studies s how that TNFalpha can potentiate the effects of glutamatergic afferent inpu t to produce hyperactivation of brain-stem sensory neurons. Therefore, we h ypothesized that TNFalpha might act cooperatively with glutamate to affect cell death in the spinal cord as well. Nanoinjections of either TNFalpha (6 0 pg) or kainate (KA; 32 ng) alone into the thoracic gray resulted in almos t no tissue damage or cell death 90 min after injection. However, the combi nation of TNFalpha plus KA at these same doses produced a large area of tis sue necrosis and neuronal cell death, an effect which was blocked by the AM PA receptor antagonist CNQX (17 ng). These results suggest that secondary i njury may involve potentiation of AMPA receptor-mediated excitatory cell de ath by TNFalpha. (C) 2001 Academic Press.