Study Implicates Enzyme in Certain Epileptic Seizures

A low level of an enzyme found in persons with temporal lobe epilepsy (TLE) may provide important clues to the cause of the condition, which affects 40 percent of the 2.5 million Americans with epilepsy, a Yale study has

found. TLE is one of the most common forms of epilepsy and is drug resistant in nearly half of all cases. Some patients are helped when an area of the brain believed to be the site where the seizures originate is surgically removed.

Tore Eid, M.D., associate research scientist in the laboratory of Nihal de Lanerolle at Yale School of Medicine, and lead author of the study in the January issue of Lancet, found that patients with TLE are deficient in the enzyme glutamine synthetase. The enzyme, found in a cell type in the brain known as an astrocyte, transforms the neurotransmitter glutamate into the non-toxic chemical glutamine. The enzyme is important because it helps remove glutamate in the brain. Glutamate can be very toxic in high concentrations. The enzyme was reduced by 40 percent in people with TLE.

“We don’t know why glutamine synthetase is decreased in TLE, but this is something we are exploring in our laboratory right now,” Eid said. “We also want to see if we can stop the seizures and reduce the brain damage in TLE by boosting the activity of glutamine synthetase. If this turns out to be the case, then it is possible that glutamine synthetase could be a new target for drug therapy against this important and devastating disorder.”

The investigators arrived at their finding by looking at brain sections removed from patients with TLE.

The study builds on an investigation 11 years ago by Matthew During, M.D., and Dennis Spencer, M.D., acting interim dean of the medical school and former chair of neurosurgery. The earlier work shows that patients with TLE have very high concentrations of glutamate in the brain. Excess levels of glutamate in the brain can cause seizures, brain damage, and even death, yet it is also necessary in small amounts for normal functioning of the brain.

Co-authors include Spencer, de Lanerolle, Jung Kim, M.D., all of Yale, Marion Thomas, Elise Runden-Pran, Niels-Christian Danbolt, M.D., and Ole Ottersen, M.D., all of the University of Oslo, and James Lai and Gauri Malthankar of Idaho State University.

Citation: Lancet, vol. 363: pp 28-37 (January, 2004)

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