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dc.contributor.advisorPatel, Manisha
dc.contributor.authorMcElroy, Pallavi Bhuyan
dc.contributor.committeememberJu, Cynthia
dc.contributor.committeememberRoss, David
dc.contributor.committeememberDay, Brian J.
dc.contributor.committeememberChu, Hong Wei
dc.date.accessioned2016-06-20T14:27:35Z
dc.date.available2017-06-16T08:20:26Z
dc.date.submitted2016
dc.descriptionIncludes bibliographical references.
dc.descriptionSpring
dc.description.abstractNeuroinflammation is an extremely deleterious event considered to be a cause and consequence of prolonged seizures. The exact mechanisms contributing to hyperexcitability-induced neuroinflammation are not very well-defined. Understanding these mechanisms can lead to novel anti-epileptogenic therapies. Oxidative stress and consequent redox alterations are also thought to contribute to epileptogenesis. The purpose of this dissertation project was to investigate whether and how the glutathione (GSH) redox status and reactive oxygen species (ROS) contribute to neuroinflammation in cellular and animal models of neuronal hyperexcitability. First, a potent small-molecule thiol compound was discovered that elevates intracellular GSH by a novel mechanism i.e., post-translational activation of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH biosynthesis. The increase in GSH attenuated lipopolysaccharide (LPS)-induced neuroinflammation by inhibiting mitogen activated protein kinase (MAPK) activation and also attenuated paraquat-induced neuronal damage. Second, inducing epileptiform activity with a K+-channel blocker in primary mixed cerebrocortical cultures resulted in concomitant increases in ROS and pro-inflammatory cytokine release. The GSH redox status was also found to be impaired in this model. Furthermore, elevating intracellular GSH with the GCL-activating compound reversed GSH depletion and decreased cytokine release. Finally, the role of seizure-induced ROS in controlling neuroinflammation was determined in the pilocarpine model of temporal lobe epilepsy (TLE). Pharmacological scavenging of ROS with a catalytic antioxidant attenuated seizure-induced oxidative stress, pro-inflammatory cytokine production and microglial activation through a redox-sensitive signaling pathway. Additionally, seizure activity arising from increased steady-state ROS levels in mice lacking a key antioxidant enzyme resulted in increased pro-inflammatory cytokine production. Collectively, this comprehensive study suggests oxidative stress as a crucial mechanism underlying inflammatory cytokine production in models of hyperexcitability. These data also highlight the importance of targeting ROS levels and GSH redox status to attenuate deleterious inflammatory processes and thereby delay/prevent epileptogenesis.
dc.identifierMcElroy_ucdenveramc_1639D_10312.pdf
dc.identifier.urihttp://hdl.handle.net/10968/1594
dc.languageEnglish
dc.publisherUniversity of Colorado Anschutz Medical Campus. Strauss Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 06/16/2017
dc.subject.meshOxidative Stress
dc.subject.meshSeizures
dc.subject.meshEpilepsy, Temporal Lobe
dc.titleTargeting oxidative stress to attenuate seizure-induced neuroinflammation in temporal lobe epilepsy
dc.typeText
dcterms.embargo.expires2017-06-16
thesis.degree.disciplineToxicology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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