Teskey Gordon CampbellVilla, Bianca Rebecca2023-04-272023-04-272023-04-21Villa, B. R. (2023). The metabolic basis of postictal hypoxia (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.http://hdl.handle.net/1880/116114For many people with epilepsy the pathological sequelae associated with seizures dramatically reduce their quality of life. Over 80% of people who have seizures also have a variety of sensory, cognitive, and motor deficits following the electrographic seizure that can last minutes to days and there are currently no interventions. Despite their clinical relevance, how postictal symptoms occur is largely unknown. Growing evidence indicates that acute hypoxic attacks following seizures underlying several postictal manifestations. Oxygen consumption takes place mainly in the mitochondria and seizures have long been known to induce altered metabolic function. In this study, I examined mitochondria function as a central player in the postictal hypoxia (PIH) phenomenon and a rational target for intervention. I provided evidence that hippocampal mitochondria dysfunctions occur during PIH. Mitochondrial-based excessive oxygen conversion into reactive oxygen species (ROS) was identified to mediate, in part, this pathological event. Chronic treatment with the mitochondrial uncoupler 2,4 dinitrophenol (DNP) ameliorated PIH. DNP reduced mitochondria-associated ROS production and the associated oxidative damage. I also described the protective effects of mild uncoupling on postictal cognitive deficits. Finally, I provided further evidence for the causative link between PIH and epilepsy pathology. Blocking the hypoxia, but not the seizures, in fact, revealed that epilepsy-induced interictal behavioural comorbidities are dependent on postictal hypoxia. Collectively, our work has brought new insights to the mechanistic basis of the postictal and interictal state and helps lay a foundation for metabolism-based experimental therapeutics that are especially timely given that post-seizure hypoxia interventions are moving to clinical trials.enUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.EpilepsyMitochondriaNeurosciencedoctoral thesis