Our findings point to a novel pathway of neurodegeneration associated with alcohol abuse stemming from alcohol-induced oxidative stress. We found that both alcohol-metabolizing enzymes (ADH and CYP2E1) are active in human neurons. While ADH is modestly expressed, EtOH exposure significantly up-regulates the CYP2E1 activity and protein content in primary human neuronal cultures. The present study demonstrates that EtOH metabolism by these enzymes up-regulates the production of ROS and NO via the induction of NOX/XOX and iNOS activities by Ach. Induction of NOX/XOX and iNOS activities and protein expression by Ach is modulated through a transcriptional regulation resulting in enhanced formation of ROS, NO, and ONOO- in the CNS. The sensitive methods detecting ROS and NO allow dissection of mechanisms of alcohol-induced oxidative damage and neurodegeneration. The biological source of oxidants and their role as signaling molecules are extensively described in recent reviews [41,44]. We propose that chronic oxidative stress conditions initiate oxidative neuronal injury leading to neurodegeneration as illustrated in Fig. 8.
