DESCRIPTION (provided by applicant): The long-term objective of this application is to understand the chemical mechanism of epilepsy, in order to: (a) discover novel therapeutic targets that prevent seizures more efficiently and with fewer side effects, and (b) establish predictive biomarkers of impending seizures several hours before they occur. This objective is in line with NINDS' program towards real cures of epilepsy, defined as "no seizures, no side effects". The aim here is to perform a comprehensive study of the chemical profile (metabolome) of spontaneous seizures in a laboratory model of mesial temporal lobe epilepsy, which is one of the most common forms of drug-resistant epilepsies. The central hypothesis is that epileptic seizures have unique chemical signatures which include pre-seizure changes in naturally occurring chemicals and metabolic pathways in the brain. It is postulated that these changes can be exploited as novel therapeutic targets for and predictive biomarkers of epileptic seizures. To accomplish the objective of this application, the brain and blood chemistry in a laboratory model of mesial temporal lobe epilepsy will be sampled by in vivo microdialysis and capillary blood collections for several days, until epileptic seizures have been captured. The comprehensive chemical composition of the samples will be determined by several mass spectrometry (metabolomics) approaches. The chemical profile will be correlated with electrophysiological data, especially the occurrence of seizures, using continuous, video-intracranial electroencephalogram (EEG) recordings. Preliminary studies have shown that this approach can detect and quantify hourly changes in more than 1,000 different small molecule (<1,000 Da) chemicals over a period of several days. The same studies have indicated that specific chemicals change in concentration several hours before the occurrence of a seizure.

Many patients with epilepsy suffer from unpredictable attacks of spontaneous seizures that cannot be treated with current antiepileptic drugs. The expected outcomes of the work proposed here are to identify early and reliable biomarkers of impending seizures and to better understand the chemical mechanism of seizure generation in epilepsy. These results, which are expected to dramatically improve the treatment of seizures, are likely to have a major and paradigm-changing positive impact on the serious public health problem of drug- resistant epilepsy.