New Study Uncovers Ketogenic Diet's Protection Mechanism Against Epilepsy Seizures - Video

Keto diet's seizure-stopping secret finally cracked-University of Virginia researchers pinpoint a key brain receptor that unlocks its power, paving way for pill-based benefits without ditching carbs.

Published in Annals of Neurology, a team led by epileptologist Jaideep Kapur, co-director of UVA's Brain Institute, unraveled how the high-fat, low-carb ketogenic (keto) diet tames epilepsy—a use dating back to the 1920s for drug-resistant cases. Keto shifts the body from carbs to fat-burning, producing ketones like β-hydroxybutyrate (BHB) that fuel the brain. Beyond epilepsy, it shows promise against Alzheimer's, Parkinson's, and even autism by calming overexcitable neurons, but doctors needed the "how" to mimic it with easier treatments.

Researchers tested BHB's effects in lab mice prone to seizures, mapping its action via the hydroxycarboxylic acid receptor 2 (HCAR2) in the hippocampus—seizure hotspot. They found HCAR2 dense on excitatory neurons (seizure triggers) and microglia (brain's immune guards). Using genetic knockouts, electrophysiology, and imaging, they showed BHB binds HCAR2 to dial down neuron hyperactivity, curb glutamate release, and boost inhibition—slashing seizure severity without toxicity.

In knockout mice lacking HCAR2, BHB lost its anti-seizure punch, confirming the receptor's starring role. HCAR2 also tempered microglia overdrive, hinting at inflammation control relevant to neurodegeneration. Early tests flagged niacin (vitamin B3, an FDA-approved cholesterol drug) as a HCAR2 activator mimicking keto effects in mice, sidestepping diet side effects like gut woes or fat overload.

Kapur notes: "Many can't stomach keto's restrictions—this unlocks drugs delivering the same brain calm." Ongoing work probes HCAR2's microglia modulation for epilepsy, MS, and dementia therapies.

Backed by NIH grants, this breakthrough—free of conflicts—fuels UVA's Manning Biotechnology Institute push to fast-track brain cures. No more carb deprivation needed; targeted pills could soon protect brains universally.

REFERENCE: Naderi, S., et al. (2025). Hydroxycarboxylic Acid Receptor 2 Mediates β‐hydroxybutyrate’s Antiseizure Effect in Mice. Annals of Neurology. DOI: 10.1002/ana.78098. https://onlinelibrary.wiley.com/doi/10.1002/ana.78098