Alcohol use may increase the risk of epilepsy by activating an immune pathway linked to inflammation and oxidative stress, according to new research.
A study published in Genes & Diseases used an integrated multiomic approach to investigate the relationship between alcohol consumption and epilepsy risk.
Researchers from Lanzhou University, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Fudan University, Massachusetts General Hospital and Harvard Medical School, and The First Affiliated Hospital of Nanjing Medical University analysed population-level and genomic data alongside machine learning models.
The team used data from the Global Burden of Disease Study 2021, Mendelian randomisation and machine learning to explore whether alcohol use may contribute to epilepsy and to identify possible biological mechanisms.
The analysis found evidence supporting a causal relationship between alcohol consumption and increased epilepsy risk.
Researchers then investigated the molecular pathways that may explain the link.
Their findings identified neutrophil extracellular trap formation, known as NET formation, as a key biological process connecting alcohol exposure with epileptogenesis.
NETs are web-like structures released by neutrophils, a type of white blood cell, as part of the immune response.
While they can help fight infection, excessive NET activity has been linked to inflammation and tissue damage.
Using three machine learning methods, LASSO, random forest and SVM-RFE, the researchers identified two hub genes, MPO and ELANE, as key regulatory points in the pathway.
The findings suggest innate immune activation and neutrophil-driven responses may contribute to neuronal hyperexcitability, making seizures more likely.
Further pathway analysis highlighted inflammatory and immune-related processes associated with NET release, supporting the role of these structures in neurotoxicity and seizure susceptibility.
The researchers also tested their findings in mouse models.
They found that acute alcohol exposure significantly increased MPO protein expression in the hippocampus, a brain region involved in memory and seizure activity.
This increase was seen in normal mice and in mice with chronic or acute epilepsy models.
By contrast, ELANE expression remained unchanged.
Behavioural tests showed that acute alcohol exposure shortened seizure latency, meaning seizures occurred more quickly.
However, pretreatment with the MPO inhibitor 4-aminobenzoic acid hydrazide, known as 4-ABAH, significantly prolonged seizure latency.
The researchers said this suggests MPO activity may play an important role in alcohol-induced seizure susceptibility.
Inhibiting MPO appeared to reduce oxidative stress and limit NET-associated inflammatory damage, helping reduce neuronal excitability and seizure risk.
The findings suggest that targeting the NET pathway could represent a potential therapeutic strategy for alcohol-associated epilepsy.
The authors said the study shows how alcohol exposure may promote epilepsy risk through MPO-mediated NET formation, bringing together immune activation, oxidative stress and neuronal dysfunction.
They added that multiomic strategies could help uncover complex disease mechanisms and support the development of new approaches to prevent or reduce alcohol-associated epileptogenesis.