Tumor necrosis factor-α 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 secondary 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 show that TNFalpha can potentiate the effects of glutamatergic afferent input to produce hyperactivation of brain-stem sensory neurons. Therefore, we hypothesized that TNFalpha might act cooperatively with glutamate to affect cell death in the spinal cord as well. Nanoinjections of either TNFalpha (60 pg) or kainate (KA; 32 ng) alone into the thoracic gray resulted in almost no tissue damage or cell death 90 min after injection. However, the combination of TNFalpha plus KA at these same doses produced a large area of tissue necrosis and neuronal cell death, an effect which was blocked by the AMPA receptor antagonist CNQX (17 ng). These results suggest that secondary injury may involve potentiation of AMPA receptor-mediated excitatory cell death by TNFalpha. (C) 2001 Academic Press.