Interestingly, in transformed cells, inhibition of NF-κB or ROS abrogates TGF-β1 stimulation of cell functions (Tobar et al. 2010). Hence, the ROS–NF-κB–TGF-β1 signaling cascade is a possible mechanism by which alcohol induces the apoptotic process in neurons—a process that is modulated by microglia. Another mechanism might relate to the microglial ability to reduce production of BDNF and cyclic adenosine monophosphate (cAMP) in neurons following ethanol activation. Thus, hypothalamic neuronal cell cultures treated with ethanol-activated microglia-conditioned medium showed decreased levels of both of these compounds. Treatment with BDNF or dibutyryl cAMP decreased the changes in the levels of intracellular free radicals, ROS, nitrite, glutathione, and catalase as well as neuronal apoptotic cell death that otherwise occurred when these cultures were treated with ethanol-activated microglia-conditioned medium. These findings suggest that ethanol increases the production of certain microglia-derived factors, thereby reducing cellular levels of cAMP and BDNF and increasing cellular oxidative stress and apoptosis in neuronal cells (Boyadjieva and Sarkar 2013b). However, further studies are needed to fully elucidate the mechanism(s) by which ethanol-activated signaling induces neuronal death.
