A new study unravels a link between a protein that can modify cellular metabolism in the brain and seizure susceptibility. The research, published by Cell Press in the May 24th issue of the journal Neuron, may lead to the development of new treatments for epilepsy.
Epilepsy is a disorder characterized by seizures, unpredictable and abnormal bursts of electrical activity in the brain. Some cases of epilepsy are resistant to traditional drug treatments but can be improved by a "ketogenic" diet. This type of 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," explains senior study author, Dr. Nika N. Danial, from Dana-Farber Cancer Institute and Harvard Medical School. "However, the molecular underpinnings of this link are not fully understood."
To examine how altered metabolism might protect the brain from seizures, Dr. Danial, co-senior author Dr. 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 drastic dietary manipulations, which can have complex and at times adverse systemic effects. The researchers discovered 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 reduction in seizure susceptibility was due to increased activity of an ion channel that dampens neuronal excitability.
Taken 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," concludes Dr. Yellen. "Small molecules modeled after BAD variants may help uncover new therapeutic targets to treat epileptic disorders."
Giménez-Cassina et al.: "BAD-Dependent Regulation of Fuel Metabolism and KATP Channel Activity Confers Resistance to Epileptic Seizures."