Why high-fat, low-carb diets help some epileptics

March 19, 2015 § Leave a comment

A series of pie charts depicting the calorific contributions from carbohydrate, protein and fat in four diets: the typical American diet; the Atkins diet during the induction phase; the classic ketogenic diet in a 4:1 ratio of fat to combined protein and carbohydrate (by weight); and the MCT oil ketogenic diet. Image from http://commons.wikimedia.org/wiki/File:Ketogenic_diets_pie_MCT.svg

A series of pie charts depicting the calorific contributions from carbohydrate, protein and fat in four diets: the typical American diet; the Atkins diet during the induction phase; the classic ketogenic diet in a 4:1 ratio of fat to combined protein and carbohydrate (by weight); and the MCT oil ketogenic diet. Image from http://commons.wikimedia.org/wiki/File:Ketogenic_diets_pie_MCT.svg

Antiepileptic drugs don’t work for one-third of patients. Instead, those patients usually eat ketogenic diets, high in fat and low in carbohydrates, which somehow stops seizures. In a paper just out in Science, researchers report how ketogenic diets work at the molecular level and say they designed a new drug that mimics the molecular effects of ketogenic diets.

“Current antiepileptic drugs are designed to target molecules that regulate electrical currents in neurons,” says Tsuyoshi Inoue at Okayama University in Japan, who led the work.  He adds that they “focused on antiepileptic actions of ketogenic diets” so they could find other ways to target epilepsy, particularly through metabolism.

Ketogenic diets force the body to rely on ketone bodies instead of glucose as an energy source. Inoue and colleagues explored what happens in single neurons in mouse brain slices when their energy source is switched from glucose to ketone bodies.

“We found that a metabolic pathway, known as astrocyte-neuron lactate shuttle, regulates electrical activities in neurons,” says Inoue.

An enzyme in the pathway is lactate dehydrogenase. When the energy source went from glucose to ketone bodies, the investigators realized that the switch in energy source inhibited the pathway via lactate dehydrogenase and caused the neurons to become hyperpolarized.

When the investigators inhibited lactate dehydrogenase in a mouse model of epilepsy, the animals suffered fewer seizures.

Next, the investigators used an enzymatic assay to see which existing antiepileptic drugs act on lactate dehydrogenase. They found a drug called stiripentol, used to treat a form of epilepsy called Dravet syndrome, inhibits lactate dehydrogenase. The investigators modified the drug’s chemical structure and found an analog that better suppresses seizures than the original.

Inoue says that inhibitors of lactate dehydrogenase can be “a new group of antiepileptic drugs to mimic ketogenic diets.”

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