Chunk #26 — Mechanisms of Neurodegeneration Related to Alcohol’s Effects on Neuroimmune Signaling in the Brain — Role of Hyperexcitability and Excitotoxicty
Another mechanism contributing to alcoholic neurodegeneration and associated with HMGB1–TLR4 signaling is the excessive stimulation of receptors that results in neuron damage and cell death (i.e., excitotoxicity). Chronic ethanol treatment of neurons leads to increased sensitivity to excitotoxicity (Chandler et al. 1994). This effect primarily involves the neuro-transmitter glutamate and its receptors. However, the relationship between ethanol and glutamate receptors is complex. Thus, although ethanol enhances overall glutamate excitotoxicity, in neuronal primary cultures it blocks excitotoxicity associated with a specific type of glutamate receptor (i.e., the NMDA receptor). This is consistent with many studies finding that ethanol inhibits NMDA receptors (Chandler et al. 1998). Yet at the same time, HMGB1–TLR4 signaling (Balosso et al. 2014) and IL-1β receptor signaling (Viviani et al. 2003)—both of which, as described above, are induced by chronic ethanol—increase NMDA receptor-mediated calcium flux, neuronal excitability, and excitotoxicity through activation of kinase signaling cascades, including activation of Src kinase and tyrosine-kinase (see figure 5). Furthermore, Suvarna and colleagues (2005) found that ethanol increases NMDA excitability in the hippocampus through kinase activation that alters receptor trafficking, leading to increased numbers of NMDA receptors containing the NR2B subunit at the synapse.
