NICOTINE BLOCKS TNF-ALPHA-MEDIATED NEUROPROTECTION TO NMDA BY AN ALPHA-BUNGAROTOXIN-SENSITIVE PATHWAY

Excitotoxic neuronal death mediated by N-methyl-D-aspartate (NMDA) glu tamate receptors can contribute to the extended brain damage that ofte n accompanies trauma or disease. Both the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and nicotine have been identified as possible neuroprotective agents to NMDA assault. We find that TNF-alp ha protection of a subpopulation of cultured cortical neurons to chron ic NMDA-mediated excitotoxic death requires both the activation of the p55/TNFRI, but not p75/TNFRII, and the release of endogenous TNF-alph a. Nicotine protection to NMDA was mediated through an alpha-bungaroto xin-sensitive receptor. When coapplied, neuroprotection to NMDA by eit her TNF-alpha or nicotine was abolished but could be recovered with al pha-bungarotoxin. These results suggest that the cytokine TNF-alpha an d alpha-bungarotoxin-sensitive nicotinic neurotransmitter receptors co nfer neuroprotection through potentially antagonistic pathways. (C) 19 98 John Wiley & Sons, Inc.