Abstracts

Rationale: Despite substantial effort to develop improved therapies for epilepsy, a large fraction of patients still suffers from poorly controlled seizures, neuropsychiatric comorbidities, and drug side effects. A more complete understanding of the metabolic alterations found in the epileptic brain would likely lead to the development of improved diagnostic and therapeutic strategies. Previous studies have employed metabolomic techniques to investigate epilepsy-related changes in a variety of rodent animal models, as well as in humans. Although results have been mixed, some patterns of metabolic dysfunction have been tentatively identified. Prominent among these are changes in levels of glutathione, a critical cellular safeguard against oxidative stress. Further, alterations have been reported in amino acid metabolism including the glutamate, aspartate, glutamine pathway as well as that for glycine, serine, and threonine. The paucity of studies examining epilepsy-related changes in human brain tissue led us to compare metabolites in cortical tissue resected from epilepsy patients with that from patients without epilepsy.

Methods: Epilepsy neocortical tissue samples were obtained following brain surgery for therapy-resistant temporal lobe epilepsy (n=7) at the Hospital of the University of Pennsylvania. The control group (n=8) included both biopsy tissue and tissue obtained at necropsy from patients without a history of epilepsy. Metabolite concentrations were measured in the Metabolomic Core at the Children’s Hospital of Philadelphia by liquid chromatography coupled with mass spectrometry (LC-MS) using validated protocols. Unpaired two-tailed Student t-tests were used to determine p-values.

Results: Upon comparing cortical tissue resected from patients with or without epilepsy, no difference in reduced glutathione (GSH) levels was found. However, there were higher levels of the oxidated, disulfide form (GSSG) in the samples from epilepsy patients (p< 0.05), indicating a higher level of oxidative stress. The examination of glutamate pathway components revealed significantly elevated levels of glutamine (p< 0.05), but no significant differences in glutamate, GABA, asparagine, alanine, or N-acetyl-L-aspartate. No significant differences were found between groups in levels of serine, threonine, or glycine.