Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy in which injury leads to epilepsy development by a process known as epileptogenesis. Metabolism and cellular bioenergetics are gaining increasing recognition in TLE. Two key metabolic processes, glycolysis and mitochondrial bioenergetics, have been implicated in the control of seizures and epileptogenesis. These processes may affect changes in mitochondrial respiration, morphology and overall function. It is hypothesized that changes in mitochondrial respiration are key contributors of mitochondrial dysfunction during epileptogenesis. The hypothesis predicts that increased glycolytic flux drives mitochondrial ROS production during epileptogenesis. The goal of this proposal is to determine the role of mitochondrial bioenergetics and its relationship with glycolysis in kainate-induced epileptogenesis. Therefore, the proposal will test whether glycolysis and mitochondrial respiration are altered in all phases of epilepsy devolopment (acute, latent, chronic). This will be achieved by measuring glycolysis and mitochondrial respiration rates in hippocampal synaptosomes isolated from epileptic and rats treated with the chemoconvulsant kainic acid. Different cell types and areas of the hippocampus will be used to further isolate where deficits are occurring. After characterization of these parameters, glycolytic inhibitors and catalytic antioxidant treatments will be used to attempt to attenuate mitochondrial deficits. Reactive oxygen species production, hippocampal cell death, and mitochondrial respiration will be assayed after treatments to determine if glycolysis or oxidative stress is mediating mitochondrial dysfunction seen in epilepsy. Understanding how mitochondrial dysfunction occurs during epileptogenesis, specifically through ROS production, could lead to new metabolic approaches to the treatment of TLE.
In this study we propose to study metabolic changes that occur in all phases of epilepsy development. Previous research in the field has focused on treating or alleviating seizures as opposed to epilepsy development. Therefore, understanding when and how mitochondrial deficits occur could lead to new therapies in preventing epilepsy development after injury.
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