Alcohol Blocks TNFα but Not Other Cytokine‐Mediated Neuroprotection to NMDA

Abstract

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). 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. 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. We suggest that the effects of low concentrations of alcohol on neuronal cytokine networks proceed through antagonism of neuroprotective pathway(s) unique to TNFalpha.