Binge drinking stimulates neuroimmune-gene induction, which increases neurodegeneration through increased oxidative stress, particularly NADPH oxidase-induced oxidative stress. In addition, HMGB1–TLR4 and NF-κB signaling are increased, leading to enhanced expression of NF-κB target genes and, ultimately, to persistent and sensitized neuroimmune responses to ethanol and other agents that release HMGB1 or directly stimulate TLR receptors and/or NMDA receptors. Persistent neuroimmune-gene induction alters stress-coping mechanisms and the sympathetic nervous system, resulting in the HPA-mediated enhancement of peripheral cytokines, which further exacerbates the neuroimmune response. In addition to neuroimmune signaling, glutamate excitotoxicity also is linked to alcoholic neurodegeneration.
