The metabolic basis of postictal hypoxia

Villa, Bianca Rebecca

The metabolic basis of postictal hypoxia

dc.contributor.advisor	Teskey Gordon Campbell
dc.contributor.author	Villa, Bianca Rebecca
dc.contributor.committeemember	Kurrasch Deborah Marie
dc.contributor.committeemember	Shutt Timothy
dc.contributor.committeemember	LeVan Pierre
dc.contributor.committeemember	Sullivan Patrick
dc.date	2023-06
dc.date.accessioned	2023-04-27T14:47:22Z
dc.date.available	2023-04-27T14:47:22Z
dc.date.issued	2023-04-21
dc.description.abstract	For 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.
dc.identifier.citation	Villa, B. R. (2023). The metabolic basis of postictal hypoxia (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	http://hdl.handle.net/1880/116114
dc.identifier.uri	https://dx.doi.org/10.11575/PRISM/dspace/40959
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University 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.
dc.subject	Epilepsy
dc.subject	Mitochondria
dc.subject.classification	Neuroscience
dc.title	The metabolic basis of postictal hypoxia
dc.type	doctoral thesis
thesis.degree.discipline	Medicine – Neuroscience
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.