Temporal lobe epilepsy (TLE) is a prevalent, often drug-resistant form of epilepsy usually preceded by injury which progressively leads to the development of recurrent unprovoked seizures by a process known as epileptogenesis. The role of mitochondria in TLE is recently emerging;however whether and how mitochondrial functions contribute to TLE remains unknown. It is hypothesized that mitochondrial oxidative stress plays a key role in epileptogenesis. We seek to determine whether and how mitochondrial reactive oxygen species (ROS) contribute to epileptogenesis. Preliminary data suggests that mitochondrial oxidative stress occurs to varying extent throughout epileptogenesis in two chemoconvulsant models of epilepsy. Using a diversity of approaches including state-of-the-art mitochondrial redox techniques, mass spectrometry and continuous video-EEG monitoring in two chemoconvulsant animal models, the following specific aims will be examined.
Specific Aim 1 will determine the occurrence of mitochondrial oxidative stress during epileptogenesis and establish a cause-effect relationship between oxidative stress and epilepsy development.
Specific Aim 2 will determine how mitochondrial ROS contributes to epileptogenesis. Specifically the role of posttranslational oxidative modification of complex I and mitochondrial DNA damage and repair will be examined.
Specific Aim 3 will determine if pharmacological inhibition of mitochondrial oxidative stress can prevent epileptogenesis. These studies will establish a potential role of mitochondrial oxidative stress in epileptogenesis and suggest novel therapeutic approaches for modifying the progression of TLE.
Temporal lobe epilepsy (TLE) is a prevalent form of acquired epilepsy often resistant to drugs and progressive in nature. Metabolic changes including mitochondrial dysfunction occur in TLE but how they contribute to its progression remains unknown. The goal of this project is to determine if a key function of mitochondria (reactive oxygen species) contributes to the development of epilepsy in animal models of TLE. Furthermore, the project will test the efficacy of drugs that are known to prevent mitochondrial dysfunction in TLE animal models.
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