Although the high-fat, calorie-restricted ketogenic diet (KD) has long been used to prevent childhood epileptic seizures that are unresponsive to drugs, physicians have not really understood exactly why the diet works.
New studies by a research team at Emory University School of Medicine show that the diet alters genes involved in energy metabolism in the brain, which in turn helps stabilize the function of neurons exposed to the challenges of epileptic seizures. This knowledge could help scientists identify specific molecular or genetic targets and lead to more effective drug treatments for epilepsy and brain damage.
The research will be presented at the annual meeting of the Society for Neuroscience in Washington, D.C. by Kristopher Bough, PhD, a postdoctoral student in the laboratory of Emory pharmacology professor Raymond Dingledine, PhD.
"These findings support our hypothesis that a dietary regimen can dramatically affect the expression of genes and the function of neurons within the brain, which enhances the ability of these neurons to withstand the metabolic challenges of epileptic seizures," Dr. Dingledine said.
The ketogenic diet causes molecules called ketone bodies to be produced as fat is broken down. Scientists have understood that these molecules somehow cause a change in metabolism leading to a potent anticonvulsant effect. According to some animal studies they also may limit the progression of epilepsy.
The Emory research team studied the link between diet and epileptic seizures on the behavioral, cellular and genetic level. They found, as had others, that in rats fed the KD the resistance to seizures develops slowly, over one to two weeks, in contrast to rats treated with conventional anticonvulsant drugs. On the cellular level, they found that the anticonvulsant effect of the ketogenic diet did not correlate with a rise in plasma ketone levels or with a decrease in plasma glucose. Because longer treatment with the KD was necessary to increase the resistance to seizures, they concluded that changes in gene expression might hold the key to the diet's anticonvulsant effects.
To identify which genes might be involved, the researchers used microarray "gene chips" to examine changes in gene expression for more than 7,000 rat genes simultaneously. They focused on the hippocampus, a region of the brain known to play an important role in many kinds of epilepsies. More than 500 of the genes they examined were correlated with treatment with the KD. The most striking finding was the coordinated up-regulation of genes involved in energy metabolism.