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dc.contributor.authorOllen-Bittle, Nikita
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date.accessioned2019-06-25T15:17:49Z
dc.date.available2019-06-25T15:17:49Z
dc.identifier.urihttp://hdl.handle.net/1974/26325
dc.description.abstractIschemic stroke is one of the most prevalent, devastating and therapeutically challenging medical conditions. Following brain ischemia, failure of the Na+/K+ ATPase is linked with a massive cationic influx through an unidentified channel that drives spreading depolarization (SD). With focal stroke, SD can devastate neurons in the ischemic core as well as recur and expand the affected area for hours and even days after the initial incident. Despite the critical role of SD in ischemic brain pathophysiology, the link between Na+/K+ ATPase failure and the opening of the channel that drives SD onset is unclear. This study proposes that an SD activator (SDa) is released by metabolically stressed gray matter and drives SD genesis. We hypothesize that an unidentified SDa can be identified, is likely not glutamate and may originate from microglia. The role of glutamate in inducing SD was evaluated to determine if glutamate could be the SDa. Oxygen glucose deprivation (OGD)-induced SD in live brain slices was shown to persist treatment with glutamate receptor antagonists kynurenate and MK-801, although a delay in SD onset was observed. Glutamate application to live brain slices also showed that it did not initiate SD, but in some slices, glutamate promoted a slower localized signal spread surrounding the weight securing the slice. Microglia were also investigated as a source of the SDa; however, blockade of the channel KCa3.1 with TRAM-34, as well as blockade of M1 microglial activation with minocycline did not significantly affect SD initiation. Finally, high pressure liquid chromatography (HPLC) was utilized to characterize superfusate from brain slices that had undergone SD, while matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) was used to analyze SD-related compounds in fresh frozen brain slices. Size exclusion HPLC identified a ~2 kDa peak that was associated with SD and may contain an SDa. MALDI-IMS analysis of brain slices exposed to OGD revealed three compounds (m/z 593, m/z 610 and m/z 620) that are associated with SD genesis and propagation. Further characterization may yield a novel therapeutic target to mitigate neural damage during acute brain ischemia.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectspreading depolarizationen_US
dc.subjectstrokeen_US
dc.titleInvestigating the Initiation of Spreading Depolarizationsen_US
dc.typethesisen
dc.description.degreeMaster of Scienceen_US
dc.contributor.supervisorAndrew, R. David
dc.contributor.departmentNeuroscience Studiesen_US
dc.embargo.termsOne year restriction - protecting rights to commercial publicationen_US
dc.embargo.liftdate2024-06-24T15:52:04Z


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