For decades, neurologists have known that a high-fat, low-carbohydrate diet can reduce drug resistant epileptic seizures.
But so far, how the diet worked, and why, was a mystery.
Now, a new study has unraveled a link between a protein that can modify cellular metabolism in the brain and susceptibility of an epileptic seizure.
Epilepsy is a disorder which is characterized by seizures, unpredictable and abnormal bursts of electrical activity in the brain.
Some cases of epilepsy are resistant to the traditional drug treatments but can be improved by a "ketogenic" diet.
Ketogenic diet, which is very low in sugars and high in fat, forces neurons to switch from their customary fuel of glucose to a type of fat byproduct called a ketone body.
"The potent effect of increased ketone metabolism on human epilepsy points to a link between fuel utilization and neuronal excitability," said Nika N. Danial, from Dana-Farber Cancer Institute and Harvard Medical School.
"However, the molecular underpinnings of this link are not fully understood," she said.
To study as to how the altered metabolism might protect the brain from seizures, Danial, co-senior author Gary Yellen, and their
colleagues explored the role of a protein called BAD (BCL-2-associated Agonist of Cell Death), which modulates glucose metabolism in multiple types of cells.
This allowed examination of altered fuel metabolism without radical dietary manipulations, which can have complex and at times adverse systemic effects.
The researchers found that modifications to BAD that reduced glucose metabolism and increased ketone body metabolism in the brain were associated with a decrease in seizure susceptibility.
They went on to show that this decrease in seizure susceptibility was due to increased activity of an ion channel that dampens neuronal excitability.
Compiled together, the findings identify ‘BAD’ as a regulator of fuel metabolism in the brain and implicate this protein in the regulation of seizures.
"BAD''s capacity to modulate energy metabolism in the brain, independent of dietary manipulation, makes it an attractive candidate for metabolic control of seizures," said Yellen.
"Small molecules modeled after BAD variants may help uncover new therapeutic targets to treat epileptic disorders," he added.
This study has been published by Cell Press in the journal Neuron.