Converging mechanisms in ethanol neurotoxicity

Abstract

Alcohol use disorder is a condition in which the individual keeps drinking alcohol despite repeated attempts to stop or control such behavior, which in turn generates negative social, occupational, and health consequences. Animal models have been developed to reproduce the deleterious effects of excessive ethanol intake, including ethanol-induced conditioned inflammation. There are several mechanisms underlying ethanol-induced toxicity. The excitotoxicity and downstream effects resultant of an imbalance in excitatory/inhibitory currents and the products of ethanol metabolism, in conjunction with the oxidative microenvironment product of oxidative/nitrosative stress rank among the most accepted mechanisms contributing to ethanol-induced neuronal dysfunction. Yet the emergence of mitochondrial dysfunction that decreases ATP along with increases in intracellular Ca2+ concentrations, plus the disruption of the NADH/NAD+ ratio is also relevant. Ferrous Fe overload and the inflammatory damage due to excessive alcohol intake or withdrawal are also key players underlying ethanol-induced neurotoxicity. Furthermore, a relationship between neuroinflammation and oxidative stress is recognized as a result of dopamine metabolism, inadequate functionality of the cystine-glutamate antiporter, mitochondrial dysfunction, and peripheral inflammation, that altogether lead to cell death. On this basis, a few therapeutic approaches have been approved to treat alcohol use disorder, albeit many others are still under scrutiny. The knowledge of the cellular and molecular mechanisms underlying alcohol use disorder is needed to provide new insights that fuel the development of new pharmacologically-relevant treatments.