Alcohol blocks TNFalpha but not other cytokine-mediated neuroprotection to NMDA.
BACKGROUND
We have investigated the effects of ethanol/alcohol (ETOH) on the pro-inflammatory CNS cytokine network that mediates neuroprotection to an excitotoxic challenge with the glutamate receptor agonist N-methyl-D-aspartic acid (NMDA).


METHODS
Cultured murine cortical neurons were incubated with either TNFalpha, IL-1alpha, IL-1beta, or IL-6 in the presence or absence of 20 mM ETOH, maintained in an alcohol equilibrated humidified chamber, and the effects of these cytokines on neuronal survival after a chronic 20 hr exposure to NMDA was quantified.


RESULTS
Neuroprotection induced by TNFalpha, but not IL-1alpha, IL-1beta, or IL-6, was inhibited by a concentration of alcohol (20 mM) that alone did not neuroprotect. Alcohol also affected the paracrine/autocrine induction of cytokine transcripts in neuronal cell cultures, which included enhancing the ability of TNFalpha to stimulate IL-6 transcripts. This result supports distinct cytokine-modulated neuroprotective pathways of which only TNFalpha is sensitive to low alcohol concentrations. We have shown previously that nicotine, acting through an alpha-bungarotoxin sensitive receptor, is also neuroprotective, but it too specifically abolishes TNFalpha-mediated neuroprotection. However, alcohol did not affect nicotine-induced neuroprotection.


CONCLUSIONS
We suggest that the effects of low concentrations of alcohol on neuronal cytokine networks proceed through antagonism of neuroprotective pathway(s) unique to TNFalpha.
Gahring
L C
LC
Salt Lake City Veterans Administration Medical Center, Department of Medicine, University of Utah School of Medicine, 84112-5330, USA. lorise.gahring@hci.utah.edu
Carlson
N G
NG
Wieggel
W A
WA
Howard
J
J
Rogers
S W
SW
D000818:Animals; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
D002492:Central Nervous System Depressants; D000431:Ethanol; D018690:Excitatory Amino Acid Agonists; D007375:Interleukin-1; D015850:Interleukin-6; D016202:N-Methylaspartate; D009538:Nicotine; D018722:Nicotinic Agonists; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors