The role of the amino acid D-leucine has been a mystery. Now, recent studies in mice, led by Johns Hopkins researchers and published in Neurobiology of Disease, suggest that it could play a vital role in halting seizures, offering a novel signaling pathway that differs from any of those currently targeted by anti-seizure medications.

 

“Epilepsy treatments over the last 50 years have not improved much, so there’s an acute need for better therapeutic approaches, especially for the millions of people with drug-resistant epilepsy,” says Johns Hopkins pediatric neurologist Adam Hartman. “If confirmed in larger animals and humans, our results carry a real promise for those suffering from unremitting seizures.”

 

Hartman and his colleagues started out with the premise that certain amino acids may play a role in seizure prevention because they produce some of the same metabolic byproducts as high-fat ketogenic diets, an alternative therapy for patients whose seizures are not well-controlled on medication. A form of the diet was used as standard epilepsy treatment in the 1920s and 1930s during the pre-medication era but fell out of favor when the first epilepsy drugs emerged. An improved version of the diet, brought back into vogue by the late Johns Hopkins neurologist John Freeman and recently retired Johns Hopkins epileptologist Patti Vining, offered relief to countless children with drug-resistant seizures. However, the food regimen requires complex calculations, can be challenging to follow and doesn’t always provide complete seizure control.

 

In an initial set of experiments, researchers pretreated mice with the amino acid L-leucine and another one, called D-leucine, which has an identical structure to L-leucine except it is its biochemical mirror image. When researchers induced seizures with an electric shock, animals pretreated with either amino acid fared better, developing seizures at notably higher electric currents than mice that received placebo, a sign of greater seizure resistance.

 

To see whether D-leucine and L-leucine could also interrupt ongoing seizures, researchers induced seizures in a group of animals and, once convulsions began, they administered low and high doses of both amino acids. L-leucine failed to abort ongoing seizures, while D-leucine effectively interrupted convulsions. Strikingly, the researchers say, D-leucine terminated seizures even at low doses.

 

Next, researchers compared the ability of D-leucine to terminate prolonged, unrelenting seizures against the sedative diazepam, commonly used to stop such seizures in humans. Both treatments terminated seizures. In addition, mice treated with D-leucine resumed normal behavior faster and experienced none of the drowsiness and sluggishness observed in animals treated with the drug, also common side effects seen in human patients.

 

A final set of experiments showed that D-leucine interacted with none of the signaling pathways known to spark or avert seizures.

 

“Our results suggest that D-leucine affects neurons differently from other known therapies to control seizures,” says Hartman’s colleague J. Marie Hardwick, a microbiologist and immunologist at the Johns Hopkins Bloomberg School of Public Health. “This finding gives us hope of new approaches to epilepsy on the horizon.”

 

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