Study uncovers alcohol's damaging effects on brain cells through oxidative stress

By Dr. Sanchari Sinha Dutta, Ph.D.May 9 2024Reviewed by Benedette Cuffari, M.Sc.

A recent study published in the journal Antioxidants reports that alcohol exposure can lead to the accumulation of oxidatively damaged proteins in neuronal cells.

Study: Alcohol Triggers the Accumulation of Oxidatively Damaged Proteins in Neuronal Cells and Tissues. Image Credit: Nitr / Shutterstock.com

The neurotoxicity of alcohol

Ethyl alcohol or ethanol is the most widely consumed psychoactive substance. Although low levels of alcohol consumption have been associated with specific health-protective effects, such as a reduced risk of diabetes mellitus, ischemic heart disease, and dementia, excessive consumption of this substance can lead to serious health complications.

In 2016, the estimated global mortality due to harmful alcohol use exceeded three million individuals. Considering disability-adjusted life years, alcohol use has been associated with over 5% of the global burden of disease. Previous epidemiological studies have identified an association between alcohol consumption and over 200 somatic diseases.

Previous studies investigating the effects of alcohol on the nervous system have reported an association between the excessive consumption of alcohol and an increased risk of dementia and cognitive decline. These phenotypes have been attributed to the atrophy of both white and gray matter in the brain, brain damage, and neuronal loss detected in the brains of alcoholics. The greatest adverse effects associated with heavy drinking have been observed among adolescents and older adults.

Study design

In the current study, scientists investigate the toxic effects of alcohol on both undifferentiated and differentiated human neuroblastoma cells, the most widely used cellular model to study neurodegenerative diseases. To this end, neuroblastoma cells were exposed to 0-200 millimolar (mM) ethanol for up to 24 hours.  

Alcohol-induced neurotoxicity was measured through a wide range of assays, including cell viability quantification, mitochondrial morphology and functionality assessments, production of reactive oxygen species (ROS), and cellular accumulation of oxidatively damaged proteins. Post-mortem brain tissues obtained from alcohol-addicted individuals were also analyzed to determine the reproducibility of any in vitro observations in humans.

Important observations

Alcohol exposure was found to reduce the metabolic activity and viability of both undifferentiated and differentiated cells in a dose- and exposure-duration-dependent manner. A significant reduction in cell viability was observed after six hours of exposure to alcohol concentrations of 20 mM or more.    

The reduction in cell viability was more pronounced in undifferentiated cells as compared to differentiated cells. At the lowest tested ethanol concentration of 10 mM, alcohol exposure led to a 6-11% induction in metabolic activity in differentiated cells and 1-10% induction in undifferentiated cells.

The microscopic observations indicated that alcohol exposure is associated with a significant reduction in neurite projections.

Effects of alcohol exposure on mitochondria

Transmission electron microscopy (TEM) analysis revealed significant alterations in mitochondrial morphology in alcohol-exposed cells. A substantial reduction in adenosine triphosphate (ATP) levels was also observed in both differentiated and undifferentiated neuroblastoma cells.

An induction in ROS production was observed following alcohol exposure, which peaked after three and six hours of exposure. ROS production was significantly higher in differentiated cells as compared to undifferentiated cells.

Accumulation of oxidatively damaged proteins

Total protein carbonyl content was assessed as a measure of oxidatively damaged proteins. To this end, alcohol exposure significantly increased the accumulation of oxidatively damaged proteins in both differentiated and undifferentiated cells after 12 or 24 hours of exposure. However, this accumulation was significantly higher in differentiated cells after 12 hours of exposure to 50 mM ethanol.  

The profile of damaged proteins observed in this study was similar to that observed in brain tissues of alcoholic individuals.

Study significance

Alcohol exposure significantly reduces viability and induces oxidative stress in both differentiated and undifferentiated neuronal cells in a dose- and exposure duration-dependent manner. Despite being more resistant to alcohol-induced cytotoxicity, differentiated neuronal cells exhibit higher susceptibility to alcohol-induced oxidative protein damage than undifferentiated cells. Moreover, the characteristics of oxidatively damaged proteins observed in the study resemble those found in adult post-mortem brain tissues.

Overall, the study findings suggest that cell differentiation may promote resistance to alcohol-induced death but cause these cells to become more susceptible to accumulating oxidatively damaged proteins.    

The cognitive decline that is frequently observed in heavy alcohol drinkers could be attributed to increased neuronal cell death and reduced functionality of surviving cells due to oxidative stress. Thus, therapeutic interventions targeting oxidative stress through the induction of cellular antioxidant capacity might have some protective effects against alcohol-induced neurotoxicity.