Nicotine blocks TNF-alpha-mediated neuroprotection to NMDA by an alpha-bungarotoxin-sensitive pathway.
Excitotoxic neuronal death mediated by N-methyl-D-aspartate (NMDA) glutamate receptors can contribute to the extended brain damage that often 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-alpha protection of a subpopulation of cultured cortical neurons to chronic NMDA-mediated excitotoxic death requires both the activation of the p55/TNFRI, but not p75/TNFRII, and the release of endogenous TNF-alpha. Nicotine protection to NMDA was mediated through an alpha-bungarotoxin-sensitive receptor. When coapplied, neuroprotection to NMDA by either TNF-alpha or nicotine was abolished but could be recovered with alpha-bungarotoxin. These results suggest that the cytokine TNF-alpha and alpha-bungarotoxin-sensitive nicotinic neurotransmitter receptors confer neuroprotection through potentially antagonistic pathways.
Carlson
N G
NG
Geriatric Research, Education and Clinical Center, Veterans Administration Medical Center, University of Utah School of Medicine, Salt Lake City 84112, USA.
Bacchi
A
A
Rogers
S W
SW
Gahring
L C
LC
D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D004338:Drug Combinations; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D051379:Mice / Q000196:embryology; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D002038:Bungarotoxins; D004338:Drug Combinations; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016202:N-Methylaspartate; D009538:Nicotine