A ketogenic diet has been used to reduce seizures in people with medication-resistant epilepsy since the 1920s, and new research has shown why it works.
The keto diet
A ketogenic, or “keto”, diet is very low in carbohydrates and high in fat, and includes moderate amounts of protein. Low amounts of carbohydrates encourage the body to derive energy from fatty acid oxidation in the mitochondria, leading to the synthesis of ketones. The ketones—β-hydroxybutyrate, acetoacetate, and acetone—enter the brain where they partly replace glucose as fuel.
Research from the University of Virginia School of Medicine recently identified that β-hydroxybutyrate interacts with a specific cellular receptor in the brain. The hydrocarboxylic acid receptor 2 (HCAR2) is a high-affinity receptor for niacin and β-hydroxybutyrate that mediates the secretion of adiponectin—a hormone that affects several metabolic processes—and decreases lipolysis.
“We discovered that HCAR2 helps β-hydroxybutyrate reduce seizures by regulating the activity and communication of brain cells,” said Dr. Jaideep Kapur, an epilepsy expert at the University of Virginia who led the research.
The team assessed the expression of HCAR2 in the mouse brain using RNA in situ hybridization assays and real-time quantitative PCR, finding that HCAR2 was localized to dentate granule cells in the hippocampus, which are associated with seizure activity. It was also found in microglia, the brain’s immune cells.
The researchers then performed whole-cell current clamp analysis to record synaptic current, comparing wild-type mice to a HCAR2 knockout mouse model.
In wild-type mice, β-hydroxybutyrate reduced neuronal excitability, reduced the firing frequency of dentate granule cells and suppressed excitatory synaptic signaling. It also diminished the duration and severity of seizures. These effects weren’t seen in the HCAR2 knockout mice, indicating that HCAR2 is key for mediating the anti-seizure effects of the keto diet.
Mimicking the effects of the keto diet
While the keto diet has its benefits for those with medication-resistant epilepsy, the highly restrictive eating can be hard to maintain and the high fat content can cause undesirable side effects, including gastrointestinal discomfort and micronutrient imbalances.
Through understanding that the keto diet prevents seizures through β-hydroxybutyrate–HCAR2 signaling that mediates the activity of neurons, the researchers have opened an avenue for drug discovery that could allow patients to reap the benefits of the keto diet without restrictive eating.
“This discovery helps find drugs that have the beneficial effects of the keto diet. Niacin, an FDA-approved lipid-lowering drug, also works on HCAR2,” explained Kapur.
The team’s initial work in mice indicated that niacin can reduce seizures through its action on HCAR2, but it also has multiple HCAR2-independent activities in the body. Further research is needed to confirm whether it also reduces seizures in humans without side effects.
Potential benefits for other neurological conditions
Other brain disorders that are characterized by neuronal hyperactivity, like Alzheimer’s disease, autism, and schizophrenia, may also benefit from the neuroprotective effects of the keto diet.
“These studies would allow us to come up with novel therapies for drug-resistant epilepsy and potentially other disorders such as multiple sclerosis and Alzheimer’s disease,” said Kapur.
Reference: Naderi S, Williamson J, Sun H, et al. Hydroxycarboxylic acid receptor 2 mediates β-hydroxybutyrate’s antiseizure effect in mice. Ann Neurol. 2025. doi: 10.1002/ana.78098
This article is a rework of a press release issued by the University of Virginia School of Medicine. Material has been edited for length and content.