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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Stewart, Randall R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Pharmacy
United States
Zip Code
Heischmann, Svenja; Gano, Lindsey B; Quinn, Kevin et al. (2018) Regulation of kynurenine metabolism by a ketogenic diet. J Lipid Res 59:958-966
Gano, Lindsey B; Liang, Li-Ping; Ryan, Kristen et al. (2018) Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy. Free Radic Biol Med 123:116-124
Pauletti, Alberto; Terrone, Gaetano; Shekh-Ahmad, Tawfeeq et al. (2017) Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain 140:1885-1899
Patel, Dipan C; Wallis, Glenna; Dahle, E Jill et al. (2017) Hippocampal TNF? Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy. eNeuro 4:
McElroy, Pallavi B; Liang, Li-Ping; Day, Brian J et al. (2017) Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation. Exp Neurol 298:13-22
Pearson-Smith, Jennifer N; Liang, Li-Ping; Rowley, Shane D et al. (2017) Oxidative Stress Contributes to Status Epilepticus Associated Mortality. Neurochem Res 42:2024-2032
Pearson, Jennifer N; Warren, Eric; Liang, Li-Ping et al. (2017) Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis. Neurobiol Dis 98:88-99
Pearson-Smith, Jennifer N; Patel, Manisha (2017) Metabolic Dysfunction and Oxidative Stress in Epilepsy. Int J Mol Sci 18:
McElroy, Pallavi B; Sri Hari, Ashwini; Day, Brian J et al. (2017) Post-translational Activation of Glutamate Cysteine Ligase with Dimercaprol: A NOVEL MECHANISM OF INHIBITING NEUROINFLAMMATION IN VITRO. J Biol Chem 292:5532-5545
Grone, Brian P; Marchese, Maria; Hamling, Kyla R et al. (2016) Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish. PLoS One 11:e0151148

Showing the most recent 10 out of 53 publications