Scientists Finally Crack the Century-Old Mystery of How the Ketogenic Diet Stops Seizures

For more than a century, doctors have known that a high-fat, low-carbohydrate diet can dramatically reduce seizures in patients with epilepsy-even when powerful medications fail. What they didn’t know was exactly how this worked. Now, researchers at the University of Virginia have finally uncovered the molecular mechanism behind this therapeutic mystery, a discovery that could eventually allow patients to gain the benefits of the notoriously restrictive ketogenic diet without having to follow it at all. The study, published in the Annals of Neurology , identifies a specific cellular receptor called hydroxycarboxylic acid receptor 2 (HCAR2) as the key player in translating the ketogenic diet’s effects into seizure protection. When the body breaks down fat for fuel-as it does on the keto diet-it produces molecules called ketone bodies. The most common of these, β-hydroxybutyrate, binds to HCAR2 receptors in the brain, calming overexcited neurons that would otherwise trigger seizures. “The body converts the keto diet to a ketone body called β-hydroxybutyrate. We discovered that HCAR2 helps β-hydroxybutyrate reduce seizures by regulating the activity and communication of brain cells,” said Jaideep Kapur, the study’s senior author and co-director of UVA’s Brain Institute. “Many individuals are unable to tolerate the keto diet due to high fat content and side effects. This discovery helps find drugs that have the beneficial effects of the keto diet.” A Therapeutic Tool From Ancient Times The connection between diet and seizure control has been recognized since antiquity. Fasting as a treatment for epilepsy appears in the Hippocratic collection from the fifth century BC, where a man suffering from convulsions was reportedly cured through complete abstinence from food and drink. Biblical accounts also reference fasting as a treatment for seizures. The modern medical application emerged in 1921, when Dr. Russel Wilder at the Mayo Clinic in Minnesota proposed that a specially designed diet might replicate the seizure-controlling benefits of fasting without requiring patients to starve themselves indefinitely. Wilder’s approach was elegantly simple: by dramatically restricting carbohydrates while increasing fat intake, the body would be forced to burn fat for fuel, producing ketone bodies in the blood-a state called ketosis. His initial trial on just three epilepsy patients marked the birth of the ketogenic diet as a medical treatment. The results were remarkable. Dr. Mynie Peterman, Wilder’s colleague at Mayo, refined the protocol and reported in 1925 that 95 percent of 37 young patients showed improved seizure control, with 60 percent becoming completely seizure-free. Through the 1920s and 1930s, the ketogenic diet gained widespread use, with more than 400 patients enrolled in studies by the end of that decade. Then came the pharmaceutical revolution. As new anticonvulsant drugs became available, the demanding dietary therapy fell out of favor. By the 1990s, only a handful of medical centers still offered it. The ketogenic diet had become a medical curiosity, remembered mainly as a historical footnote. The Persistence of Drug-Resistant Epilepsy The return to dietary therapy came from an unexpected place: the limits of modern pharmacology. Despite the development of more than...

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