Fasting has been believed since ancient times to curb seizures in epilepsy, and small patient studies in the early 1900s have revived the idea. But the reasons have remained mysterious. New research from Boston Children’s helps explain how fasting affects the brain at the molecular level. The findings could lead the way to new approaches that would avoid the need for fasting or even the ketogenic diet, which mimics some of the effects of fasting and is now sometimes used to treat epilepsy.
“This study is the first step in understanding how dietary therapies for epilepsy work,” says first author Christopher J. Yuskaitis, MD, PhD, a neurologist with the Epilepsy Center and Epilepsy Genetics Program at Boston Children’s Hospital. “The mechanisms have until now been completely unknown.”
Connecting the dots between diet and seizures
The researchers already knew that a cellular pathway known as the mTOR pathway is involved in many neurological disorders. In a previous study, they had shown that over-activation of this pathway in neurons increases susceptibility to seizures. Studies by others had shown that fasting inhibits mTOR activity, though these studies didn’t look at the brain.
This study is the first step in understanding how dietary therapies for epilepsy work. The mechanisms until now have been completely unknown.”
Finally, Yuskaitis and colleagues knew that a protein called DEPDC5 acts as a brake on the mTOR pathway. Intriguingly, mutations in the DEPDC5 gene have recently been linked to epilepsy, including focal epilepsy, infantile spasms, and sudden unexplained death in children.
“When we used an animal model that knocks out DEPDC5 specifically in the brain, we found that we could reduce seizures by using an mTOR inhibitor,” says Yuskaitis. “That gave us the idea to explore the connection between DEPDC5, mTOR, and fasting.”
Amino acid sensing
In the new study, the researchers showed that when seizure-prone mice fasted for 24 hours, mTOR signaling in their brains was reduced. In additional studies of rat neurons, they found that the lack of three amino acids (leucine, arginine, and glutamine) during fasting accounted for most of fasting’s effects on mTOR signaling.
Finally, the team showed that the presence of these amino acids is sensed by the DEPDC5 protein. When they used genetic techniques to eliminate DEPDC5 in the brain, mTOR activity was not reduced and fasting no longer protected the mice against seizures.
“Amino acid sensing seems to be critical for the beneficial effects of fasting on seizures,” says Yuskaitis. “This suggests that patients with DEPDC5 mutations can’t sense the loss of amino acids and may not benefit from dietary manipulation. But patients who don’t have DEPDC5 mutations may benefit from a targeted dietary strategy.”
Possible strategies, he suggests, include diets with lower levels of the three amino acids, or medications or supplements that block absorption of those amino acids.
Next step: Ketogenic diet
This study is only a first step. Yuskaitis and his colleagues now want to try diets in animal models that eliminate specific amino acids and observe the effects on seizures. They also want to explore how the ketogenic diet helps curb seizures. No one currently knows why this low-carbohydrate, high-fat diet works.
“We’re hoping this will help us uncover additional dietary-based therapies other than the ketogenic diet, which is sometimes difficult to follow long-term due to side effects,” says Yuskaitis.
More generally, such work may also provide a new lens on neurologic disorders.
“Using these rare genetic disorders, we are starting to gain fundamental insights into the role of nutrients in brain function,” says senior investigator Mustafa Sahin, MD, PhD, managing director of the Rosamund Stone Zander Translational Neuroscience Center at Boston Children’s, who oversaw the study. “Findings from these rare disorders may open doors to better treatments of epilepsy in general.”
The findings were published August 30 in the journal Cell Reports.
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